See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/346718524

Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile and

Various Therapeutic Targets: A Review

Article  in  Current Organic Synthesis · December 2020

DOI: 10.2174/1570179417666201207215710

CITATIONS READS

6 1,182

6 authors, including:

Shaik Khasimbi Faraat Ali

Delhi Institute of Pharmaceutical Sciences and Research Indian Pharmacopoeia Commission Ministry of Health and Family Welfare Governm…
13 PUBLICATIONS   57 CITATIONS    43 PUBLICATIONS   93 CITATIONS   

SEE PROFILE SEE PROFILE

Anjali Sharma Garima Chauhan

Delhi Institute of Pharmaceutical Sciences and Research Delhi Institute of Pharmaceutical Sciences and Research
15 PUBLICATIONS   130 CITATIONS    11 PUBLICATIONS   25 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Formulation development and validation of some pharmaceutical drugs View project

All content following this page was uploaded by Faraat Ali on 02 February 2021.

The user has requested enhancement of the downloaded file.

 Send Orders for Reprints to reprints@benthamscience.net

Current Organic Synthesis, 2021, 18, 1-24 1

REVIEW ARTICLE

Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile and

Various Therapeutic Targets: A Review

Shaik Khasimbi1, Faraat Ali2, Kiran Manda3, Anjali Sharma1, Garima Chauhan1 and Sharad Wakode1,*

1
Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), DPSRU, Sector-3,
Pushp Vihar, New Delhi, India-110074; 2Laboratory Services, Botswana Medicines Regulatory Authority, Gaborone, Botswa-
na;3Department of Pharmaceutical Chemistry, Andhra University South Campus, Andhra University, Visakhapatnam, Andhra Pra-
desh, 530003

ARTICLE HISTORY
Received: October 01, 2020
Revised: October 15, 2020
Accepted: October 16, 2020
DOI:
10.2174/1570179417666201207215710
Abstract: Background: This review elaborates the updated synthetic and pharmacological approaches of a
known group of dihydropyrimidinones/thiones from the multi-component reaction like Biginelli reaction, which
was named Pietro Biginelli in 1891. This review consists of the reaction of an aromatic aldehyde, urea and ethyl
acetoacetate leading to dihydropyrimidinone/thione. Currently, the scientific movement to develop economically
viable green methods using compounds that are reusable, non-volatile, easily obtained, etc.
Objective: This review covers the recent synthesis and pharmacological advancement of dihydropyrimidi-
nones/thiones moiety, along with covering the structure-activity relationship of the most potent compounds,
which may prove to become better, more efficacious and safer agents. Thus, this review may help the researchers
in drug designing and development of new Dihydropyrimidinones entities.
Conclusion: This review focuses on the wide application of dihydropyrimidinone/thione review reports the de-
sign, synthesis and pharmacological activities of nitrogen-sulphur containing dihydropyrimidinone moiety by us-
ing multi-component reaction. Dihydropyrimidinones (DHPM) pharmacophore is an important heterocyclic ring
in medicinal chemistry. It is derived from multi-component reactions, “Biginelli reaction” and plays a critical
role as anticancer, antioxidant, antimicrobial, anti-inflammatory, anti-HIV-1, antimalarial, anti-inflammatory, an-
tihypertensive and anti-tubercular agents. Exhaustive research has led to its vast biological profile, with a wide
range of therapeutic application.

Keywords: Dihydropyrimidinones, anti-microbial, anti-depressant, anti-cancer, antifungal, anthelmintic, anti-diabetic.

1. INTRODUCTION been reported with a broad spectrum of bioactivities including anti-

The Biginelli reaction has been gaining importance in organic
and pharmaceutical chemistry in the last few years [1]. 1893 was a
milestone year for the discovery of the heterocyclic derivatives of
the Biginelli adducts, which were named after the Italian chemist
Pietro Biginelli. He was the first to report acid-catalyzed, and its
cyclocondensation reaction in a simple one-pot process, which led
to the synthesis of Biginelli adducts [2-3]. The MCRs produce 3,4-
dihydropyrimidinones/thiones from carbonyl compounds like ke-
toester, aldehyde and urea or thiourea (Fig. 1) [4]. It is a conven-
tional linear-type synthesis, which involves three or more compo-
nents producing a new product by the single step reaction [5]. The
reaction mechanism for the formation of dihydropyrimidine skele-
ton is depicted in Fig. (2). The fisrt step in this mechanism is be-
lieved to be the condensation between the aldehyde and urea, with
some similarities to the Mannich condensation. The iminium inter-
mediate generated acts as an electrophilic for the nucleophilic addi-
tion of the ketoester enol, and ketone carbonyl of the resulting ad-
duct undergoes condensation with the urea NH2 to give the cyclised
product. Dihydropyrimidines (DHPMs) have molecular diversity in
organic and medicinal chemistry with a wide variety of biological
and pharmacological applications [6-7]. DHPMs derivatives have
*Address correspondence to this author at the Department of Pharmaceutical Chemis-
try, Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), DPSRU,
Sector-3, Pushp Vihar, New Delhi, India-110074; E-mail: sharadwakode@gmail.com
bacterial [9], anti-HIV [10], analgesic [11], antiarrhythmic [12],
anti-inflammatory [12], anticancer[13], antihypertensive [14], anti-
convulsant [15], antidiabetic [16], antitubercular [17], inhibition of
DNA and RNA synthesis [18], locking adenosine receptors [19],
and inhibition of Eg5 Myosin Kinase enzyme, respectively [20].
Some of the dihydropyrimidine scaffold containing drugs available
in the market such as methylthiouracil, 5-fluorouracil, emivirine,
aminophylline, idoxuridine and list of patent etc. has been described
in Fig. (5) and Table. 1, respectively.
Fig. (1). Synthesis of Dihydropyrimidinone/thion. (A higher resolu-
tion/colour version of this figure is available in the electronic copy of the
article).
The dihydropyrimidinone (DHPM) or pyrimidinone is well
known and has widely recognized bioactive application in the area
of drug discovery that stimulated the invention of a range of syn-
thetic methods and chemical transformation/reactions[6-42]. It con-
sists of five major basic nucleic acids, most important molecules
such as a cytosine which is found in RNA and DNA, Uracil in
RNA, and thymine in DNA molecules. Their involvement as RNA,

1570-1794/21 $65.00+.00 © 2021 Bentham Science Publishers

2 Current Organic Synthesis, 2021, Vol. 18, No. 0 Khasimbi et al.

Fig. (2). Reaction Mechanism for dihydropyrimidinone/thione synthesis.

Fig. (3). Structures of dihydropyrimidinones moiety present in DNA, RNA.

Fig. (4). Drugs in therapy with dihydropyrimidinone scaffold.

Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile Current Organic Synthesis, 2021, Vol. 18, No. 0 3

Table 1. List of Patent approved DHPM derivatives.

Sl. No Patent Number Patent date Inventors Description

Marco Busch, Jan Dittgen

Jens Frackenpohl, Isolde Hauser-Hahn, Ines Heinemann,
AU2011298423B2 [40] 2015-11-05 Martin Jeffrey Hills, Thomas Muller, Christopher Hugh 1,3-Diazines;Hydrogenated 1,3-diazines
Rosinger, Monika H. Schmitt, Pascal Von Koskull-Doring,
Lothar Willms, Hans-Joachim Zeiss
1,3-diazine or hydrogenated 1,3-diazine rings not
condensed with other rings having two double bonds
Essa H. Hu, Daniel R. Sidler, Ulf H. Dolling, Michael A.
WO1997021687A1[41] 1997-06-19 between ring members or between ring members and
Patane.
non-ring members with hetero atoms directly attached
to ring carbon atoms
David Banner, Hans Hilpert, Roland Humm, Harald Mauser,
EP2427437A1[42] 2014-03-07 Alexander V. Mayweg, Fabienne Ricklin, Mark Rogers- Dihydropyrimidinones for use as bace2 inhibitors
Evans
2-aryl-5,6-dihydro pyrimidinones and herbicidal use
US5629264A [43] 1997-05-13 Colin M. Tice, Lois M. BrymanRenee C. Roemmele
thereof.
Essa Hsinyi Hu, Daniel R. Sidler, Ulf H. Dolling, Michael A.
US5786472A [44] 1998-07-28 Process for making dihydropyrimidinones
Patane.
Nussbaum Franz Von, Dagmar Karthaus, Sonja Anlauf,
4-(4-cyano-2-thioaryl) dihydropyrimidinones and use
SG186679A1 [45] 2013-01-30 Martina Delbeck, Volkhart Min-Jian Li, Daniel Meibom,
thereof
Klemens Lustig, Jens Schamberger.
Gnamm Christian, Hoesch Holger, Peters Stefan, Oost substituted bicyclic dihydropyrimidinones, pharma-
BR112015017929A8 [46] 2019-11-05
Thorsten, Jörg Ries Uwe ceutical composition comprising them and use.
Nussbaum Franz Von,, Dagmar Karthaus, Sonja, Anlauf,
Martina Delbeck, Volkhart Min-Jian Li, Daniel Meibom, Sulfonic amide and sulfoximine-substituted diaryl-
HK1171451A1 [47] 2015-10-30
Klemens Lustig, dihydropyrimidinones and usage thereof
Dirk Schneider.
Use of compositions obtained by calcining particular
AU2014220639A1 [48] 2015-08-13 Vincent Escande, Claude Grison metal-accumulating plants for implementing catalyti-
cal reactions
Saturated ring fused dihydropyrimidone or dihy-
TW202000652A [49] 2020-01-01 ----
drotrione compound and its medical use
CN110201714A [50] 2019-09-06 Liwan Zhang Dihydropyrimidinones synthetic method and catalyst
Heike Gielen-Haertwig, Barbara Albrecht, Jörg Keldenich,
1,4-diaryl-dihydropyrimidin-2-ones and their use as
EP1723121B1 [51] 2012-07-25 Volkhart Li, Josef Pernerstorfer, Karl-Heinz Schlemmer,
human neutrophil elastase inhibitors
Leila Telan
2-(Pyrimidin-5-yl)-thiopyrimidine derivatives as
Gabriela Chiosis, Tony Taldone, Anna Rodina, Pallav Patel,
EP2467142B1 [52] 2016-09-21 Hsp70 and Hsc70 modulators for the treatment of
Yanlong Kang
proliferative disorders
Scott E. Schaus, Lauren Brown, John Connor, Ken William
US9567331B2 [53] 2017-02-14 Pyridopyrimidinone inhibitors of viruses
Dower
2018-10-30
US10047071B1 [54] Mashooq Ahmad Bhat, Mohamed A. Al-Omar Dihydropyrimidinone derivatives

Methods for heat shock protein dependent cancer

US8754094B2 [55] 2011-06-30 Olcay Batuman, Jeffrey L. Brodsky
treatment
Mark Joseph Tebbe, Holly Victoria Atton, Craig Avery,
Steven Mark Bromidge, Mark Kerry, Adrian Kotei Kotey,
Heteroaryl derivatives as sepiapterin reductase
EP3356345A1 [56] 2018-08-08 Nathaniel J. Monck, Mirco Meniconi, Mark Peter Ridgill,
inhibitors
Heather Tye, Eddine Saiah, Kai Peter Johnsson, Katarzyna
Irena Gorska, Hairuo Peng, John Michael Mccall.
Substituted pyrimidinone and pyridone compounds
US6096753A [57] 2006-11-07 Ulrike D. Spohr, Michael J. Malone, Nathan B. Mantlo
and methods of use
Heike Gielen-Haertwig, Volkhart Min-Jian Li, Ulrich
Pyrimidinone derivatives as therapeutic agents
Rosentreter, Karl-Heinz Schlemmer, Swen Allerheiligen,
ES2414865T3 [58] 2013-07-23 against acute and chronic, ischemic and remodeling
Leila Telan, Lars Bärfacker, Jörg Keldenich , Mary F.
inflammatory processes
Fitzgerald, Kevin Nash, Barbara Albrecht, Dirk Meurer
dihydropyrimidinone-derived selenoesters, process
Luiz Braga Antonio, Augusto Rocha Barbosa Flavio,
for obtaining dihydropyrimidinone-derived selenoes-
Rafique Khan Jamal, Faria Santos Canto Rômulo, Saba
BR102017007303A2 [59] 2018-10-30 ters and their application as antioxidants and acetyl-
Sumbal,
cholinesterase inhibitors in the treatment of alzhei-
Do Nascimento Vanessa
mer's disease.
4 Current Organic Synthesis, 2021, Vol. 18, No. 0
Scheme 1.
Uracil, and DNA has become very important in the world of syn-
thetic organic chemistry (Fig. 3).
2. GENERAL METHODS OF SYNTHESIS OF DHPM
K. Tajbakhash [2005] et al. synthesized 3,4-dihydropyrimidin-
2(1H)-ones from aldehyde (1mmol), ethyl acetoacetate (1mmol), in
glacial acetic acid (2.5mmol) at 100°C for 4-5hrs by using natural
heulandites type zeolite (HTMA) as a catalyst for the one-pot con-
densation reaction for an appropriate duration of time, as indicated
by the thin-layer chromatography, resulting in obtaining high yields
under mild conditions [60-62] (Scheme-1).
K. Aswin [2014] et al. synthesized 3, 4-dihydopyrimidi-2(1H)-
ones and thiones from the mixture of aromatic aldehyde (5mmol),
ethyl acetoacetate (0.58g, 5mmol) and urea (0.45g,7.5mmol) or
thiourea (0.45g,7.5mmol) by using DBSA (5% mol) as a catalyst
under solvent free conditions at 60°C, and introduced at the center
of the cavity of a microwave oven. The reaction has been monitored
by the thin-layer chromatography. All products obtained a good
yield by the simple, efficient procedure, and their structures were
identified by the 1H NMR, FT-IR, and MS-spectroscopic data [63]
(Scheme-2).
Scheme 2.
H. A. Stefani [2007] et al. synthesized 3,4-dihydropyrimidin-
2(1H)-ones from aromatic aldehyde (1.36g, 10mmol), methyl
acetoacetate (1.30g, 10mmol) and urea (0.6g,10mmol) by using 1ml
pineapple juice as a catalyst under microwave irradiation under
solvent free conditions at room temperature, with monitoring by
TLC. This reaction utilized solvent-free condition and was synthe-
sized to get a good yield that is easily isolable [64] (Scheme-3).
Scheme 3.
S. Patil [2011] et al. synthesized 3,4-dihydropyrimidin-2(1H)-
ones from aromatic aldehyde (1.06g, 7.5mmol), methyl acetoacetate
(1.15g, 8mmol) and urea (1.6g, 9.5mmol) by using 1.5ml pineapple
juice as a catalyst under microwave irradiation. This reaction was
solvent-free with a totally non-polluting substance and several ad-
vantages, such as a shorter reaction time, simple workup, mild reac-
tion conditions, and a reduced environmental impact [65] (Scheme-
4).
Khasimbi et al.
Scheme 4.
M. C. R. Moosavifar [2012] et al. synthesized 3,4-
dihydropyrimidin-2(1H)-ones from heteropoly acid supported on
Y-zeolite as a catalyst for the mixture of ethyl acetoacetate
(1mmol), aldehyde (1mmol) and urea (1.5mmol), along with the
acetonitrile (10 ml) solvent. In this method, no appreciable progress
was observed due to large sized compounds for the super-cage di-
mension of Y zeolite. This method was recovered and reused sever-
al times without an efficient loss of catalytic activity [66] (Scheme-
5).
Scheme 5.
D. L. Silva [2011] et al. synthesized 3,4-dihydropyrimidin-
2(1H)-ones/thiones from a mixture of aldehyde (1.25g, 5mmol)
ethylacetoacetate (1.30g, 1mmol) and urea (0.89g, 0.66mmol) or
thiourea (0.9g, 0.96mmol)in ethanol by using p-sulfonic acid ca-
lixarenes as an efficient and reusable organocatalyst at 8hrs. The p-
sulfonic acid has been lately incorporated with magnificent and
recyclable organo catalysts for the synthesis of organic compounds,
solvent free conditions, non-toxicity, good-to-excellent yields for
the pharmaceutically significant structures and especially the ease
of catalyst for the recovery to make the procedure valuable and
environmentally benign [67] (Scheme 6).
Scheme 6.
S. Chitra [2012] et al. synthesized 3,4-dihydropyrimidin-2(1H)-
ones and thiones from the mixture of acetyl acetone (10mmol),
thiourea (15mmol), aldehyde (10mmol) in the presence of CaF2
(1mmol, 10 mol%)and EtOH(20ml) at 40°C. The reaction was
compared with the classical Biginelli reaction conditions. This new
method has the advantage of excellent yields and shorter reaction
times. Moreover, the catalyst can be reused without any reduction
in efficiency [68] (Scheme 7).
N. S. Ghotkar [2015] et al. synthesized 3,4-dihydropyrimidin-
29(1H)-ones from the mixture of aldehyde (0.2mmol), -Ketoester
(0.25mmol) and urea (0.5g, 0.15mmol) by using layered double
hydroxide [LDH] (0.5g) as eco-friendly catalyst at 4hrs.The catalyst
Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile Current Organic Synthesis, 2021, Vol. 18, No. 0 5

has proven to be highly region specific, and a chemo selective ac- (acetonitrile or water), containing a catalyst by producing them
tivity, with no toxicity. It is also cheap, eco-friendly and an easily without any loss of activity [73] (Scheme-12).
synthesized catalyst, with mild conditions, easy isolation of the
product and higher yields [69] (Scheme-8).

Scheme 11.
Scheme 7.

Scheme 8.
S. L. Jain [2007] et al. synthesized 3,4-dihydropyrimidin-
2(1H)-ones from benzaldehyde (5mmol), urea (5mmol) and
ethylacetoacetate (5mmol) in dry acetonitrile by using Metal-
lophthalocyanines (5 mol%) as a catalyst. This method is solvent-
free and a catalyst under mild and neutral reaction conditions [70]
(Scheme-9).
Scheme 12.
A. Khosropour [2005] et al. synthesized steroidal derivatives
from the aldehyde (1mmol), urea (1.5mmol) and active hydrogen
atom compounds by using TMSCI (0.5mmol), DMF (1mmol) and
MeCN (1.5mmol) at 90°C in 12hrs. The reaction was monitored by
a thin-layer chromatography [74] (Scheme-13).

Scheme 13.

Scheme 9. H. Zhou [2006] et al. synthesized pentacyclic-DHPMs deriva-

C. Raju [2012] et al. synthesized 3,4-dihydropyrimidin-2(1H)-
ones and thiones from the mixture of aldehyde, beta-Ketoester and
urea/thiourea reaction carried by pyridinium trifluoroacetate as a
catalyst. This method mainly reduced with utility of microwave
synthesizer, and also further evaluated for anticancer and antioxi-
dant activity for drug processing discovery. In general, the reaction
time for the synthesis has been reduced along with the utility of
microwave assisted synthesis. The evaluation of anticancer and anti-
oxidant activity of the synthesized novel tetrazolopyrimidines will
be of future interest [71] (Scheme-10).
tives from cyclopentanone (20mmol), aldehyde (1, 1.00g,
8.18mmol) and urea 1.47, 10.63mmol) /thiourea (1.50g, 9.5mmol)
in activated hydrogen atom by using Vitamin-B1 1.18ml,
13.29mmol, 80%) and EtOH (45ml) where the added mixture was
heated to reflux for 30min. Under this condition, the novel DHPM
received a highest yield up to 95%. This method has been more
advantageous for short reaction times and excellent yields [75]
(Scheme-14).

Scheme 14.

Peter Wipf [1995] et al. synthesized 3,4-dihydropyrimidin-

2(1H)-ones from the aldehyde(1.25g, 5mmol), urea (1.30g, 1mmol)
and ethylacetoacetate (0.89g, 0.66mmol) by using THF (5mmol),
Scheme 10. BnBU(5.8mmol), DBU (1.5mmol) as a catalyst in one-pot cy-
clocondensation reaction. This reaction method was used for the
resin-linked GABA urea and provided purity and a high yield of
Gonzalez-Olvera [2016] et al. synthesized 1,2,3-triazole ring compounds with subsequently, a direct solution phase screening
contains DHPMs derivatives from the aldehyde-1,2,3-triazole, reaction [76] (Scheme-15).
ethylacetoacetate and urea with Ce(OTf)3 acting as a catalyst and
carrying out a one-pot condensation reaction. The reaction that
carried out the corrosion inhibition of steel grade API5LX52 in 1M
hydrochloric acid in the synthesis of novel compounds was investi-
gated by using an electrochemical impedance spectroscopy tech-
nique. This measurement revealed that heterocycles inhibit acidic
corrosion of steel [72] (Scheme-11).
H. R. Kalita [2007] et al. synthesized 4-dihydropyrimidino-
2(1H)-ones from the mixture of aldehyde, ethylacetoacetate, and
urea in acetonitrile or water by using CuI as a catalyst at room tem-
perature. This reaction mixture was separated by the mother liquor Scheme-15.
6 Current Organic Synthesis, 2021, Vol. 18, No. 0 Khasimbi et al.

I. Cepanec [2005] et al. synthesized 3,4-dihydropyrimidin-

2(1H)-ones from the aldehyde (1,1.06g, 0.01mmol),urea (0.72g,
0.012mmol, 1.2equiv) and ethylacetoacetate (2, 1.22g, 0.0105mol,
1.05equiv) in the presence of FeCl3 (0.2g, 2mmol), tetraethyl ortho-
silicate (2.2ml, 2.08g, 0.01mmol, 1equiv) as a catalyst. This method
was used for the improved reaction condition to allow for the prepa-
ration of compounds, for purity and a high yield under mild reac- Scheme 19.
tion condition [77] (Scheme-16).
H. Hazarkhani [2004] et al. synthesized DHPMs analogous
from the ethylacetoacetate (1.30g, 10mmol), 4-tolyaldehyde (1.2g,
10mmol) and urea (0.84g, 14mmol) by using N-Bromosuccinimide
(NBS) (0.36g, 2mmol) in 95% EtOHwas heated under reflux for
10hrs. The reaction was monitored by the TLC plates. The reaction
mixture was solidified washed with water and recrystallized from
95% EtOH in order to get 2.5g (90%). This reaction NBS has been
Scheme 16
used for a mild and neutral catalyst, efficient for the preparation of
novel compounds for a high yield [81] (Scheme-20).
J. P. Wan [2011] et al. synthesized 3,4-dihydropyrimidin-
2(1H)-one from aromatic aldehyde (1mmol), enaminone (1mmol),
aromatic amine (1.2mmol)and thiourea (1.2mmol) in the presence
of TMSCI/CAN (10%mmol) at room temperature. This reaction
method showed simple procedure, involving a short time and sol-
vent-free condition [78] (Scheme-17).

Scheme 20.

Scheme 17.
F. Shi [2006] et al. synthesized 3,4-dihydropyrimidin-2(1H)-
ones from the 1,2-diphenyl ethanone (7.60mmol), aldehyde
(1.60mmol) and urea (9.20mmol) in the presence of oxalic acid
(0.15mmol) as catalyst in a one-pot reaction. The reaction was
monitored using TLC plates, hexane and ethyl acetate (80:20) as a
solvent system. This method has also been more advantageous be-
cause of high yield, short time reaction, and a new series of poten-
tial biologically active compounds that are inhibiting towards the
Cdk4 [79] (Scheme-18).
N. Hamid [2007] et al. synthesized Pyrimido-2,4,7-trion deriva-
tives from the 6-amino-1,3-dimethyluracil (0.5mmol), benzalde-
hyde (1mmol), urea (1.5mmol)and acetic acid (0.5mmol) in Pyrex
test tube was irradiated for 5 min at atmosphere with a power of
900W. The reaction was monitored by TLC plates. The reaction
mixture was also solidified and washed with ice-cold water (15ml),
and recrystallized from EtOH/ H2O. The method has been advanta-
geous for high yields (90%-93%) with a simple procedure and short
reaction time (5min) [82] (Scheme-21).

Scheme 21.

T. Shujian [2007] et al. synthesized Pyrimido-2,4,7-trion deriv-

atives from 3-methylpyridine-2,6(1H,3H)-dione (1.5g, 1mmol),
Scheme 18. aromatic aldehyde (0.26g, 0.5mmol) and urea (1.2g, 2mmol) under
microwave-assisted reaction conditions. The reaction was moni-
tored by TLC plates. The reaction mixture was solidified, washed
L. Yadav [2007] et al. synthesized fused-DHPMs derivatives
with hot water (50ml) and recrystallized from EtOH to acquire the
from the cyclohexane-1,3-dione (1.30g, 1mmol), aldehyde (0.89g,
crystalline solid (75%) yield [83] (Scheme-22).
0.66mmol) and thiourea (0.9g, 0.96mmol) or urea (0.89g,
0.66mmol) in the presence of NH4VO3/MWI as a catalyst. The
reaction was monitored by TLC. The reaction mixture was solidi-
fied within 15-25min. The reaction mixture was washed with hot
water. The reaction was nanoclay-catalysed, and under solvent-free
microwave irradiation conditions in one-pot synthesis, in order to
Scheme 22.
get a high yield of diastereoselectivity, expedition, with thiosugar-
annulated in the multifunctionallized dihydropyrimidinone via in-
termolecular domino cyclocondensation of reaction with isolable A. Zonouzi [2013] et al. synthesized amino-5H-chromeno[2, 3-
intermediate [80] (Scheme-19). d]pyrimidine-2-yl-phenolic, water-promoted one-pot reaction is
better by simply using parallel procedures from the salicyladehyde,
Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile
2-iminocoumarin and secondary amines in the presence of LiClO4
(5mol %) in EtOH conditions, 15hrs. This reaction method has been
using fluorescence emission intensity (290nm) for the novel com-
pounds. The details of the reaction were interested in exchangeable
intermolecular H-bonding of the compounds as reported by the X-
ray analysis data [84] (Scheme-23).
Scheme 23.
S. V. Ryabukhin [2007] et al. synthesized by N1-alkyl, N1-aryl
and N1, N3-dialkyl-3,4-dihy dropyrimidin-2(1H)-ones from N-
substitutes urea (4.4-5.2mmol), aromatic aldehyde (4mmol) and
ethylacetoacetate (4;4ml) were placed in a 15ml ace pressure tube
and dissolved in TMSCl (24mmol)/DMF (10ml) at 1-3day reflux
condition The reaction was monitored by TLC plates (n-
hexane/EtOAc, 80:20). The white precipitate was filtered, and so-
lidified washed with i-PrOH. The product was purified by recrystal-
lization from an appropriate solvent. It was promoted in the water
scavenger method getting a high yield [85] (Scheme-24).
Scheme 24.
S. Toshiaki [2009] et al. synthesized 5-disubstituted pyrimidine
derivatives from the enamines (0.22g, 1mmol), triethyl orthofor-
mate(0.25g, 1mmol) and ammonium acetate (1.00g, 1.2mmol) in
the presence of ZnCl2 (1mmol) as a catalyst in this reaction. The
reaction was monitored by TLC plates (n-hexane/MeOH, 80:20).
The reaction was successfully carried out for the synthesis of mono-
and disubstituted compounds [86] (Scheme-25).
Scheme 25.
A. Davoodnia [2006] et al. synthesized pyrazolo [3,4-
d]pyrimidin-4-one derivatives from 5-amino-1-phenyl-3-
susbtituted-1H-pyrazole-4-carboxamide (0.002mol) and orthoesters
(0.003mol) was subjected to microwave irradiation at 700W for
6min. with silica gel under solvent-free conditions. The reaction
was monitored by TLC plates (CHCl3: MeOH, 80:20). The white
precipitate was filtered, and solidified washed with ethanol: ethyl
actetate and getting good yield [87] (Scheme-26).
Scheme 26.
Current Organic Synthesis, 2021, Vol. 18, No. 0 7
M. Z. Ghodsi [2013] et al. synthesized 1,3-disubstitute barbitu-
ric acid from the pyrano-pyrimidine dione (0.02g) ,4-nitroaldehyde
(0.362ml, 2.4ml) and diisocyanomethane (0.132g, 2mmol) in the
presence of SBA-Pr-SO3H (0.02g) was activated in vacuum at
100°C. The reaction was monitoring TLC. The reaction mixture
was heated for 15min in bath oil at 140°C. The white precipitate
was filtered, solidified and washed with hot water, getting a good
yield. This synthesis helps to avoid the atom economy and hazard-
ous chemicals. The pyrano [2,3-d] pyrimidine dione was reported
for the first time in urease inhibitory activity [88] (Scheme-27).
Scheme 27.
K. Aswin [2013] et al. synthesized 4,6-diphenyl-3,4-
dihydropyrimidin-2(1H)-thione from 1,3-diaryl-2-propen-1-one
(2mmol), thiourea (3mmol) in the presence of PPh3 (0.2mmol) at
65°C in ethanol. The reaction was monitoring TLC. The white pre-
cipitate was filtered, solidified washed with hot CH2Cl2 (20ml).
This catalyst help in recycling without a loss of activity, nontoxic
simple work-up, inexpensive materials, short time reactions and
getting high yield [89] (Scheme-28).
Scheme 28.
C. Wang [2017] et al. synthesized pyrazolo[3,4-d]pyrimidine
derivatives from 4-amino-6-chloropyrimidin-5-carbonitrile
(2mmol) and isopropyl-hydrazine hydrochloride (1.5mmol) under
cyclization using acid chloride (2ml). The synthesized series of
compounds were evaluated for the RET kinase inhibitors on
BaF3/CCDC6-RET cell assays [90] (Scheme-29).
Scheme 29.
Y. Y.Huang [2012] et al. synthesized pyrazolo [3,4-
d]pyrimidine derivatives from α-chloro-5-amnio pyrazole
(1.0equiv) in the presence of formamide (2.0ml) and added PBr3
(3.0equiv). The reaction mixture was heated at 80-90°C for 4hrs,
and the reaction was monitoring TLC. The solution was added with
saturated aq. NaHCO3 (15ml) and extracted with CH2Cl2 (15ml).
This reaction provided the desired product, 70-87% yield. A plausi-
ble mechanism helps the activation of α-chloroacetamide by using
Vilsmeier-Haack reagent for accounting the transformation [91]
(Scheme-30).
Scheme 30.
8 Current Organic Synthesis, 2021, Vol. 18, No. 0 Khasimbi et al.

A. R. Hajipour [2012] et al. synthesized DHPMs derivatives

from the aldehyde (1mmol, 0.14g), urea (2mmol, 1.0g) and cyclo-
pentanone (1mmol) in the presence of N-(4-sulfonic acid) butyltri-
methyl ammonium hydrogen sulphate (64% w/w, 1mmol) and then
HNO3 (0.5ml, 65%)was added and the mixture was ground with a
pestle at room temperature. The reaction was monitored by TLC
plates (n-hexane/EtOAc, 80:20). The white precipitate was filtered Scheme 33
off and the solvent was removed by evaporation. The residue was
dissolved in Ac2O (30ml) and washed with NaHCO3 (20ml) and
dried (MgSO4). The organic layer was collected, dried over NaSO4,
filtered and finally concentrated under reduced pressure, and then
obtained (1mmol, 0.18g, 100%). This method has seen a variety of
aromatic compounds with nitro substitution for the activation and
deactivation of aromatic rings [92] (Scheme-31).

Scheme 31.
Z. Y. Tian [2007] et al. synthesized 5-fluorouracil derivatives
from the 5-fluorouracil (7, 1.3g, 10mmol), formaldehyde (37 wt%,
aq., 1.2g, 15.5mmol) in water (10g) and urea acetonitrile (10mmol)
by using DMAP (N,N-dimethypyridin-4-amine) (80mg, 14mmol)
and DIC (22ml, 14mmol) added, and the mixture was stirred at
room temperature for 44-70hr. The reaction was monitoring TLC
plates. The white precipitate was filtered off and the solvent was
removed by evaporation. The residue in Ac2O (30ml) was washed
by diluted HCl (pH=3-4), aq. NaHCO3 (pH=7-8) and water. The
organic layer was collected, dried over NaSO4, filtered and finally
concentrated under reduced pressure. These compounds were bio-
logically evaluated against the antitumor activity against in vitro of
B16, CHO and K562 cells and in vivo of liver cancer. H22 activity
demonstrated that some of these compounds effectively inhibit the
growth of tumor cell [93] (Scheme-32).
J. Lu [2002] et al. synthesized 3,4-dihydrpyrimidin-2(1H)-one
from ethyl acetate (10mmol), urea (15mmol) and aldehyde
(10mmol) in the presence of FeCl3 or NiCl2 (2.5mmol) and conc.
HCl (12 drop) in EtOH (20ml) as a catalyst in the presence of con-
centrated HCl. This reaction was compared with classical Biginelli
reaction conditions with the advantage of excellent yield of (53-
97%) and short time reaction (4-5hrs) [94] (Scheme-33).
Sweet and Fissekis [1973] et al. synthesized dihydropyrimidin-
2(1H)-ones or thiones from aldehyde (0.61g, 5mmol), urea (0.38g,
5mmol, 1equiv) and ethylaceto actetate (0.65g,5mmol) in the presence
of [bmim][MeSO4](0.012g, 1mol%) as a organocatalyst in this reaction.
The reaction was monitored by TLC plates. The reaction mixture was
diluted and solidified with H2O (1ml) and EtOH (5ml). The solid was
washed with EtOAc (1.17g, 90% yield)[95] (Scheme-34).
Scheme 32
Scheme 34.
Atwal and O'Reilly [1987] et al. synthesized 3,4-
Dihydropyrimidin-2(1H)-one from 3-nitrobenzaldehyde (400mg,
2mmol), ethylacetoacetate (425g, 2.5mmol) and urea (500mg,
2mmol) in DMF (5ml), treated with NaHCO3 (622g, 7.4ml). This
reaction has been synthesized for the novel compounds with solvent
free conditions and high yield [96-97] [Scheme-35].
Scheme 35.
O.Kappe [1997] et al. synthesized 3,4-Dihydropyrimidin-
2(1H)-one from the enone (2.18g, 10mmol) and thiourea (0.76g,
10mmol) in MeOH (10ml) containing conc. HCl (1ml) was heated
at reflux for 3-5hr. This reaction is interception with the iminium
ion by the ethylacetoacetate to produce open-chain ureides for the
subsequent cyclization for the Biginelli dihydropyrimidines [98]
(Scheme-36).
L. Cepanec [2007] et al. synthesized 3,4-dihydropyrimidin-
2(1H)-one from ethylaceto acetate (1.44g, 0.01mol) in anhydrous
acetonitrile (8ml), urea (0.90g, 0.015mol, 1.5equiv) and antimony(
Ⅲ)chloride (0.23g, 10ml%, 0.46g, 20mol%; 0.68g, 30mol%; 2.28g,
100mol%) were added. This method was processed through 3-
ureido-crotonates to follow by the cyclisation of aromatic aldehyde
to synthesize DHPM [99] (Scheme-37).
J. H Schauble [2005] et al. synthesized 3,4-dihydropyrimidin-
2(1H)-ones from urea (2mmol), aldehyde (1.5mmol) and
ethylacetoacetate (1.58mmol) in the presence of RuCl3 (2.6g,
05mmol) as a catalyst in one-pot synthesis under free-solvent reac-
tion conditions. This method occurs via abstraction to give the
trans-diethers [100] (Scheme-38).
M. M. Heravi [2006] et al. synthesized 1H-pyrazolo [3,4-
d]pyrimidin-4(1H)-ones from alpha-ketoester (15 mmol), aromatic
aldehyde (10 mmol) and urea or thiourea (15 mmol)in acetic acid
(15ml) was treated with heteropoly H3PW12O14(2 mol%, 0.03g) and
preyssler type of H14[NaP5W30O110] (2.5mol%, 0.025g). The 12-
molybdoposphoric acid was refluxed with acetic acid catalyzed of
three-components condensation reaction with high yields [101]
(Scheme-39).
Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile
Scheme 36.
Scheme 37.
Scheme 38.
Scheme 39.
E. Abdel-latif [2016] et al. synthesized 4-oxo-1-tosyl-4,5-
dihydro-1H-pyrazolo[3,4-d] pyrimidine-3-carbonitrile from pyri-
dine (20ml), carbon disulfide(4mmol, 0.3ml) and urea (0.57g,
2mmol) in the presence of formic acid (2mmol, 0.025g) added drop
wise. The reaction was monitoring TLC plates. The reaction mix-
ture was cooled at room temperature, poured into ice water and
neutralized with HCl. The precipitated product was filtered off,
washed and recrystallized from EtOH-DMF mixture (1:1) t pro-
duced dark green colour crystals. The synthesized compounds were
evaluated for the cytotoxicity of anticancer activity against the hu-
man laryngeal epidermoid carcinoma cells (Hep2) for the highest
significant effect [102] (Scheme-40).
Scheme 40.
S. R. Ray [2011] et al. synthesized dihydropyrimidin-2(1H)-
ones or thiones from aldehyde (0.61g, 5mmol), urea (0.38g, 5mmol,
1equiv) and ethylaceto actetate (0.65g,5mmol) in the presence of
[bmim][MeSO4](0.012g, 1mol%) as a organocatalyst in this reac-
tion. This reaction was covered and reused with ionic liquid for five
consecutive times without a significant loss of catalyst efficiency
[103] (Scheme-41).
Current Organic Synthesis, 2021, Vol. 18, No. 0 9
Scheme 41.
3. PHARMACOLOGICAL ACTIVITIES OF BIGINELLI
PRODUCTS:
Various biologists depend on the synthesis of a novel series of
molecules having products with different scaffold mechanisms. The
novel molecules having various pharmacological and biological
activities were patented. Biginelli adduct of nifedipine is an aza
derivative [104]. Biginelli adduct synthesized from the aldehyde
urea/thiourea and activated methylene, leads to Dihydropyrimidin-
ones/thiones [DHPMs]. The DHPMs analogues are building blocks
that have molecular diversity. The synthesis of Biginelli adducts is
that the heterocyclic pyrimidine derivatives are most effective and
potent derivatives of various diseases in vitro/ in vivo conditions as
shown in Fig. (5). The synthesis of various series of DHPMs is
absolutely crucial, employing different reaction conditions by using
organic or inorganic catalysts under solvent-free conditions by one-
pot synthesis. The derived molecules’ having various significant
biological activities undergo clinical trials and facilitate the discov-
ery of new drugs. Computer-aided drug design (CADD), especially
the quantitative structure-activity relationship (3D-QSAR) method
as a prominent application of chemo metrics provides valuable
information for the design and synthesis of novel pharmacological
properties, which interacts with specific receptors. Two most suc-
cessful tools, comparative molecular field analysis (CoMFA), and
comparative molecular similarity indices analysis (CoMSIA), are
used widely. In addition to docking and molecular dynamics,
QSAR was carried out to analyze and understand silico studies, and
to search out possible binding modes of these new biological evalu-
ations.
Acetylcholinesterase enzyme (AChE) prevent the hydrolysis of
acetylcholine (ACh). They influence various disease conditions
inside a human body, such as bradycardia, hypotension, hyperten-
sion, bronchocostriction, GI tract hyper motility, and decreased
intraocular pressure [105]. In most drugs, the treatment may require
a titration or stepping up phase. This strategy is used to build a
10 Current Organic Synthesis, 2021, Vol. 18, No. 0
tolerance for adverse events or to reach a desired clinical effect
[106]. These drugs are potent and less toxic.
3.1. Inhibition of Acetylcholine Esterase
S. Arun Khamkaew [2013] et al. developed a new synthetic
method for the synthesis of DHPM derivatives. The synthesised
analogues (1) are identified to be highly active acetylcholinesterase
inhibitors used for Alzheimer’s disease. The concentration IC50
values of 1.34±0.031µM were more active towards standard drug
galanthamine (Fig. 6). Methoxy group in the aromatic ring of the
aldehyde precursor showed maximum inhibitory activity. The most
important step in the modification of drugs was the development of
new compounds in drug leading [107]. A. R. Flavio [2013] et al.
synthesized a novel series of dihydropyrimidinone derivatives.
Those analogues (2-5) and (6) in the presence of a methyl group in
place of the hydrogen in the N-1 of the heterocycle slightly reduced
the activity, and were observed to be the most effective acetylcho-
linesterase inhibitors by applying the Ellmann’s method. Compared
to galanthamine, the synthetic analogues exhibit antioxidant activity
and were evaluated by TBARS and iron chelation assays
(100µmol/L) in comparison with Butylated hydroxytoluene (BHT)
[108] (Fig. 6). R. F. S. Canto [2014] et al. developed and synthe-
sized, evaluated a series of dihydropyrimidinone analogues. The
synthesized analogues of seleno-DHPM, corresponding with differ-
ent 6-chloromethyl-DHPM-curcuminoids hybrids (7(a-g)) were
shown to be excellent acetylcholinesterase inhibitors in comparison
to the standard drug galanthamine (23.79 ± 0.14µg/L), and also
antioxidant activity in comparison to the standard drug EDTA (4.65
± 0.02µg/L) [109] (Fig. 6).
Fig. (5).Various pharmacological applications of 3, 4-Dihydropyrimidin-
2(1H)-(thio) ones.
3.2. MCH1-Receptor Antagonistic Activity
The melanin-concentrating hormone receptors, found in all
mammals [110], are involved in various functions like regulation of
appetite, stress, anxiety and depression [111]. This encoded protein
can inhibit cAMP and calcium flux, involved in the neuronal regu-
lation of food consumption. A novel series of dihydropyrimidinone
derivatives have been designed, synthesized and evaluated by J. M.
Goss [2008] et al. The enantioselective synthesis of DHPM deriva-
tives by using cinchona alkaloid-catalyzed Mannich reaction was
carried out of the compound containing N3 position of the DHPM
with 3-(4-phenylpiperidin-1-yl) propylamine as a side chain of the
compound exhibit Kd of 0.18nM with the specific binding of 98%
Khasimbi et al.
in COS-7 cells. This showed human MCH1-R(8) inhibiting the
melanin concentrating hormone receptor and was compared with
the enantioselective synthesis of SNAP-7941 [112] (Fig. 7). Y.
Jiang [2007] et al. synthesized, and designed new compounds
which are 2,2-diarylacetamide replacements of the MCH1 receptor
affinity of binding compounds are N-[5[1-{3[2,2,-bis-(4-fluoro-
phenyl)-acetylamino]-propyl}-pyrimidin-4-yl)-2,4-difluoro-henyl]-
isobutyamide(9) and N-[3[1-{3[(s ),2,-(4-fluoro-phenyl)-
propionylamino]-propyl}-pyrimidin-4-yl)-4-methylphenyl] isobu-
tyamide (10). These inhibit the MCH-1 receptor, with a minimum
effective dose of 0.3mg/kg in oral, in vivo condition on rat model,
which was compared with SNAP-7941 [113] (Fig. 7).
3.3. Inhibition of Hsp70 ATPase Activity
The Hsp70s is most important in cell protein folding. Protein is
vital for all living organisms and protects cells from stress [114]. It
participates in the disposal of damaged or defective protein. It
mainly interacts with CHIP (Carboxyl-terminus of Hsp70 interact-
ing Protein), an E3 ubiquity ligase, which allows undergoing ubiq-
uitination and proteolysis pathways [115]. A. N. Chaiang [2009] et
al. developed a novel series of dihydropyrimidinone derivatives.
All derived compounds contain esters of pyrimidine core mole-
cules, substituted at C-4, and alkylated at N1. Among the com-
pounds, (11), (12) and (13) are closely related structurally. They
contain benzyl ester pyrimidine core that is substituted in the posi-
tion of C-4 within arene moiety and an N-alkylated amide side
chain that is attached in a 3-5 carbon linker. Other compounds that
differ in their side chain lipophilicity, and in the Morpholine moiety
present on (14) and (15), which is absent in the (16). The most po-
tent compounds (11) and (12), have slightly different ester substitu-
tion on the pyrimidine core of the chain, as well as distinct noon
position of tetrasubstituted pyrrolo side chain. This position of
tetrasubstituted pyrrolo is potent because of modifications in their
ester. N1 liner length is present between the C-6 and C-4 aryl sub-
stitution (at phenyl and nitro), not showing less activity. Final com-
pounds (17) and (18) are derived structurally with a signature of the
pyrimidine heterocycles with minimal N1 side chain substitution
lacking amide function, Bn or H, butyl (18) and hexanoic acid. All
the compounds are more potent towards P. falciparum Hsp70 chap-
erones, and showed an adverse effect on parasite homeostasis in
human red blood cells. The compound is effective for the growth of
HepG2 and WI-38 cells. Compounds initially appeared to inhibit
[3H] hypoxanthine uptake by ˃50% at 5l M and displayed inhibi-
tion at 1lM. Compounds produced IC50 values from 30nm to 1.6mm
towards P. falciparum [116] (Fig. 8A). M. Christine [2008] et al.
also synthesized and evaluated DHPM derivatives. This derived
substituent attached to the pyrimidinone affects the biochemical and
anti-proliferative activity of the compounds. Some of the com-
pounds present p-tert-butlyphenyl group in either (19) and (20) that
are greatly enhanced, co-chaperone with stimulation of the Hsp70.
The p-nitrophenyl group present at both (21) and (22) has been less
effective. The substitution of the phenyl (22) or p-nitrophenyl
groups in DPHMs, among the strongest inhibiting of their breast
cancer cell proliferation. The addition of the aliphatic group present
at the cyclohexyl carboxaldehyde and cyclopropylcarboxaldehyde
(23) was important in the inhibition of breast cancer cell prolifera-
tion. The SAR was active towards the Hsp70 modulation, and re-
duced breast cancer cell proliferation. It undergoes hydrolysis of
Hsp70 ATPase, relatively stimulated by J-domain-containing pro-
teins on yeast. Based on this property, Compounds showing anti-
proliferation activity were evaluated 3.1 ± 0.4 to >50 µM [117]
(Fig. 8B).
3.4. Inhibition of Mitotic Kinesin Eg5 Activity
Kinesin is a motor type protein found in the eukaryotic cells. It
moves along with microtubule filaments, and is powered by the
hydrolysis of adenosine triphosphate (thus kinesin are ATPases)
Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile Current Organic Synthesis, 2021, Vol. 18, No. 0 11

Fig. (6). DHPMs based compounds are inhibition of acetylcholine esterase [106-109]. (A higher resolution/colour version of this figure is available in the elec-
tronic copy of the article).

Fig. (7). DHPMs based compounds as MCH1-Receptor antagonistic activity. [112-113]. (A higher resolution/colour version of this figure is available in the
electronic copy of the article).
12 Current Organic Synthesis, 2021, Vol. 18, No. 0 Khasimbi et al.

Fig. (8). A: DHPMs based compounds as inhibitors of Hsp70 ATPase activity [96]. (A higher resolution/colour version of this figure is available in
the electronic copy of the article).

Fig. (8). B: DHPMs based compounds as inhibitors of Hsp70 ATPase activity [117]. (A higher resolution/colour version of this figure is available in the elec-
tronic copy of the article).

[118]. It supports several cellular functions such as mitosis and
meiosis [119]. It was recently discovered in the yeast cells that
kinesin Cin8 (a member of the Kinesin-5 family) can move towards
the negative end as well or retrograde transport. This Cin8 can easi-
ly change direction on a microtubule and in turn lead to the plus end
movement of kinesin on a microtubule [120]. E. Klein et al. [2007]
synthesized and designed various series of monastrol derivatives.
The synthesized analogues were modified with the aromatic ring in
the C4, C6 or O3 position, and do not inhibit Eg5 basal ATPase ac-
tivity (24-26). The hydrolysis of ethyl ester present in (27) that has
condensation with different alcoholic and amines to yield (28, 29,
30 and 31), inhibits Eg5, a motor protein responsible for the for-
mation and maintenance of the bipolar spindle in mitotic cells. The-
se compounds with inhibited Eg5 activity were investigated by
using in vitro steady state ATPase assays, and cell-based assay.
These compounds were unable to inhibit Eg5 ATPase activity
Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile
Fig. (9A). DHPMs based compounds as Inhibitors of mitotic kinesin Eg5 Activity [121-122]. (A higher resolution/colour version of this figure is available in
the electronic copy of the article).
Fig. (9B). DHPMs based compounds as Inhibitors of mitotic kinesin Eg5 Activity [121-122]. (A higher resolution/colour version of this figure is available in
the electronic copy of the article).
in vitro and were proved to be potent Eg5 inhibitors in cell-based
assay [121] (Fig. 9A). D. S. Bose [2004] et al. synthesized 3,4-
dihydropyrimidin2-(1H)-ones.the synthesized analogues (33) was
showed mitotic kinesin Eg5 activity. The synthesized compound is
more potent than the monastrol [122] (Fig. 9B).
3.5. Inhibition of Hepatitis B Activity
Hepatitis B is a chronic liver infection mainly caused by the
Hepatitis B virus. Its symptoms include vomiting, yellowish skin,
tiredness, dark urine, abdominal pain and rapid onset of sickness,
finally causing death [123]. It primarily shows infection in the liver
by replicating in hepatocytes. A function receptor NTCP, closely
related to duck hepatitis B virus is called carboxypeptidase D [124].
The dihydropyrimidinone derivatives inhibit the growth or killing
Current Organic Synthesis, 2021, Vol. 18, No. 0 13
Hepatitis B virus, and are called anti-hepatitis drug. X. Zhao [2010]
et al. synthesised and developed 2,4-diary 4,6,7,8-
tetrahydroquinazolin-5(1H)-ones derivatives are inhibits the HBV
capsid assembly. The synthesized analogues are carboxyamidine
and were converted to the 2,4-diaryl-4,6,7,8-tetrahydroquinazolin-
5(1H)-one (33), (34), (35), (36), (37), and (38) as theypotentially
inhibit the HBV capsid assembly. The compounds are
(IC50=6.6mg/ml) and (IC50=11.2mg/ml).They show good inhibition
of HBV replication by comparing with Bay41-4109 [125] (Fig. 10).
3.5. Anti-Tuberculosis Activity
Tuberculosis mainly effects the lungs and is caused by Myco-
bacterium tuberculosis bacteria, The main symptoms are chronic
cough with blood-containing sputum, fever, night sweats and
14 Current Organic Synthesis, 2021, Vol. 18, No. 0 Khasimbi et al.

Fig. (10). DHPMs based compounds as Inhibitors of Hepatitis B Activity [125]. (A higher resolution/colour version of this figure is available in the electronic
copy of the article).

weight loss. It is not only caused by the M. tuberculosis, but also by 590), C. albicans (NCIM-C27) and Aspergillus flavus (NCIM-539)
M. bovis, M. africanum, M. canetti and M. microti [126]. Robert [129] (Fig. 11). A. R. Trivedi [2010] et al. synthesized with a range
Koch first identified and described the bacillus causing tuberculo- of electron withdrawing group and electron releasing group. 4-F, 4-
sis, M. tuberculosis. He received the Nobel Prize in physiology or Cl, 4-Br, 4-NO2, 4-CH3 were prepared according to the previously
medicine in 1905 for his recognition of the source of infection to be reported compounds, such as ethy4-[3-(4-fluorophenyl)-1-phenyl-
the infected milk of cattle by an application of the pasteurization 1H-pyrazol-4-yl]-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
process [127]. K. Singh [2011] et al. developed a novel series of carboxylate (52) and ethyl4-[3(4-nitrophenyl)-1-phenyl-1H-
3,4-dihydro pyrimidinones derivatives, which exbhit an anti-TB pyrazol-4-yl]-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
activity. The analogues MICs activity of the derived compounds are carboxylate (53), and were found to inhibit the M. tuberculosis, at a
presence of N-benzyl group at C-2 position (39) or better a 4- concentration of 6 mg/mL against the MTB, becoming more potent
hydroxyminoaniline substituted (41), which seems to big significant than the isoniazid [130] (Fig. 11).
antitubercular activity. The substation like ethyl ester, rather methyl
ester at C-5 position of the pyrimidine core (40, 45, 46 and 47) 3.6. Hyperglycaemia Activity
leads to improvement of the MIC values. The replacing of the 3-
Hyperglycaemia is defined as an increased glucose level in the
aminoaniline substituent in the (43) has only raised the MIC, with-
blood, the range being 11.2mmol/l (200mg/dl). If the range of glu-
out a significant effect on %age of inhibition. The replacing 6-
cose is 7mmol/l, this condition is called Diabetes. The affected
hydroxyphenylamino substitution from C-2 position of (44) with n-
hormones are the growth hormone, glucagon, cortisol, and cate-
butylamino substituent (42) has seen both increases in % inhibition
cholamine. Its main symptoms are ketoacidosis, kussmaut hyper-
of, as well as marginal decrease in MIC valuesthat inhibit the M.
ventilation, osmotic dieresis, increased thirst, glycosuria, nausea,
tuberculosis by using H37Rv strains, and a series of cell culture.
vomiting, and weight loss [131]. Increased proinflammatory cyto-
This was evaluated. These compounds produced not only anti-TB,
kines that interrupt carbohydrate metabolism, leading to excessive
but were also used for antiviral activity. The substituted compounds
glucose production, and reduced uptake in tissues may cause hy-
showed highest cytostatic activity (IC50: 13Mm) when used on
perglycaemia [132]. It is treated mainly by the direct administration
anti-tubercular disease [128] (Fig. 11). C. Sankar [2010] et al. syn-
of oral hypoglycaemic therapy and life style modification [133]. K.
thesized by 2Ar, 4c-diaryl-3-azabicyclo [3.3.1] 9-nonanone n-
L. Dhumaskar [2014] et al. developed a series of 3,4-
isonicotinoylhydrazones inhibits the M. tuberculosis compounds.
DHPM/thiones derivatives. The derived compounds, which consist
Some of the compounds contain (48), (49), (50) and (51) are strong
of a wide variety of aryl aldehydes, carry the electron withdrawing,
hydrogen-bonding atoms O, F, or Cl. Thus it seems that the for-
or electron donating groups’ presence at ortho, meta or para posi-
mation of hydrogen bond may play an important role in the desire
tion. In general, it was observed that aryl aldehydes have been an
action. These compounds are screened against M. tuberculosis
electron donating group that react slower when compared to the
H37Rv (ATTCC27294), and INH-TB by Luciferase phase assay
aryl aldehydes, which have been an electron withdrawing group.
method at the concentration levels of 1.00 and 2.00mg/ml reduction
The electron donating group reacts slower when compared to aryl
of percentage level 72-80%. These compounds are shown to exhibit
aldehydes, which is an electron withdrawing group. The analogues
antimicrobial activity against the bacterial strains such as a Staphy-
are (54) (55), and (56), and mainly inhibit the α-Amylase enzyme,
lococcus aureus (NCIM-2492), Bacillus subtilis (NCIM-2439),
which is involved in the carbohydrate metabolism that is generally
Escherichia coli (NCIM-2345), Klebsiella pneumoniae, and Pseu-
targeted to type-2 diabetes when compared with acarbose standard
domonas aeruginosa (NCIM-2035). They expressed a minimum
drug. The dependent on dose inhibition of α-amylase activity were
inhibitory concentration (mg/mL). These compounds were also
showed 97.2% at 300mg/ml [134] (Fig. 12). Z. Wang [2019] et al.
used for anti-fungal activity against the Candida albicans-6
further developed dihydropyrimidinone derivatives. The analogue
(NCIM-C27), C. albicans (NCIM-539), Aspergillus niger (ncim-
Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile Current Organic Synthesis, 2021, Vol. 18, No. 0 15

Fig. (11). DHPMs based compounds exhibit anti-tuberculosis activity [128-130]. (A higher resolution/colour version of this figure is available in the electronic
copy of the article).

Fig. (12). DHPMs based compounds exhibit hyperglycaemia activity [134-135]. (A higher resolution/colour version of this figure is available in the electronic
copy of the article).

(57) is mainly inhibiting the α-Glucosidase and α-amylase enzymes
by this two process in order to inhibit the glucose level in blood
[135] (Fig. 12).
3.8. Antibacterial Activity
Antimicrobial agents work by killing microorganism. Antibiot-
ics are antibacterial and antifungal. Agents that kill are microbicid-
al, while those that merely inhibit their growth are called biostatic.
Chemicals or medicines which prevent the growth or kill the mi-
croorganism are known as antimicrobial therapeutics [136]. On the
other hand, there has been increasing antimicrobial resistance of
bacteria, fungi, parasite and some viruses [137]. M. Ashok [2007]
et al. synthesized dihydropyrimidinone/thione derivatives. The
analogues (58), (59), (60), (61), (62) and (63) are more potentially
towards the antibacterial and antifungal activities. The concentra-
tion of compounds (2g) has shown excellent activity against the S.
aureus, P. aeruginosa, E. coli, K. pneumoniae, A. fumigatus, A.
flavus, C. albicans and P. marneffei [138] (Fig. 13). J. Lal [2012] et
al. developed a novel series of 3,4-DHPM derivatives (64(a-n)) that
are more potentially active against Staphylococcus aureus, Esche-
richia coli, Burkholderia pseudomallei, Salmonella typhi and Pseu-
domonas aeuriginosa, Aspergillus niger, A. flavus, Trichoderma
virid and Curvularia lunata,. In vitro minimum inhibitory concen-
tration was measured through the microdilution and food poisoning
method. In addition to the cytotoxicity of synthesized compounds,
they were evaluated against cancer lines such as a Hep-G2, HCT-
116, and QG-56. The zone of inhibition is at a concentration of (20,
40, 80 and 160 IM/ml) [139] (Fig. 13). P. Attri [2017] et al. synthe-
sized 3,4-dihydropyrimidinone derivatives. The analogues with
substitution of methyl, methoxy, nitro, hydroxyl of (65), (66),
(67),(68), (69) (70) (71), (72), and (73) are active against the anti-
bacterial activity by using methods like disk diffusion assay, and
determination of minimum inhibitory concentration (MIC).
16 Current Organic Synthesis, 2021, Vol. 18, No. 0
Fig. (13a). DHPM based compounds as antibacterial activity [138-140]. (A higher resolution/colour version of this figure is available in the electronic copy of
the article).
Compounds are active against E. coli, S. aureus, P. aeruginosa and
K. pneumonia and the minimum inhibitory concentration is 31.25-
62.50 ppm, which was evaluated by comparison with ampicillin.
These compounds are further used for their antioxidant property by
using DPPH assay with concentration ranges of 1.4-1.2 at 100 ppm
[140] (Fig. 13).
M. Brands [2003] et al. synthesized and carried out the pharma-
cological evaluation of dihydropyrimidinone derivatives from natu-
ral derivatives. Dipeptide antibiotic TAN-1057 was found to exhibit
potent antibacterial activity. Compounds (73), (74) and (75) are
evaluated on EC50 values for cytotoxicity levels by using macro-
phage cell lines (J774), with the inhibitory concentration ranges
between 02-2.0mg/kg active against the S. Aureus [141] (Fig. 13b).
A. M. Soliman [2014] et al. further developed pyrimidine, dihydro-
pyrimidinone and dihydroimdazole derivatives with excellent anti-
bacterial activity. The analogues (76), (77), (78), (79) and (80) are
active against the Gram-positive and Gram-negative bacteria,
namely Bacillus cereus, Bacillus subtilis, E. coli, Micrococcus lute-
us, S. aureus, P. aeruginosa and Micrococcus roseus by using the
diffusion method (cup and plate method) at 37±0.5°C at 24hrs [142]
(Fig. 13b). M. H. Bhuiyan [2011] et al. further developed the 3,4-
Khasimbi et al.
dihydropyrimidione derivatives, and are used to test antibacterial
activity. The analogues (81), (82), (83) (84), and (85) are more
active against the A. flavus, S. cerevisiae, Vibrio choloriae, Shigella
dysenteriae, Salmonella typhi and Candida albicans. The zone of
inhibition is measured in millimetres at 48hrs and (35±2)°C, and
was compared with ampicillin and nystatin [143] (Fig. 13b). R. H.
Tale [2011] et al. developed a series of 3,4-dihydropyrimidin-
2(1H)-ones. The compounds (86), (87), (88), (89), (90), (91), (92)
and (93) are excellent in exhibiting antibacterial activity against the
pathogenic bacteria, and fungi measured at MIC 10-30lg/mL also
produce anti inflammatory activity (68-62% TNF-a and 92-86% IL-
6 at MIC of 10IM) [144] (Fig. 13c).
3.9. Anti-cancer Activity
Cancer is the abnormal cell growth, spreading to the body parts.
It main symptoms are a lump, abnormal bleeding, prolonged cough,
unexplained weight loss and change in bowel movements causing
Helicobacter pylori, hepatitis B, hepatitis C, human papillomavirus
infection, Epstein-Barr virus and human immunodeficiency virus
(HIV). Some factors affecting changes in the genetic cells can be
caused by consuming tobacco, obesity, poor diet, excessive
Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile Current Organic Synthesis, 2021, Vol. 18, No. 0 17

Fig. (13b). DHPMs based compounds exhibit antibacterial activity [141-143]. (A higher resolution/colour version of this figure is available in the electronic
copy of the article).

Fig. (13c). DHPMs based compounds exhibit antibacterial activity [144]. (A higher resolution/colour version of this figure is available in the electronic copy of
the article).

drinking of alcohol, smoking, and lack of physical activity [145].
Mainly researchers focus on curing cancer by using angiogenesis
inhibitors like silver bullet [146]. Chemotherapy and therapeutic
combination are used to reduce cancer morbidity and mortality
[147]. A. S. Mostafa [2018] et al. synthesized 3,4-
dihydropyrimidnones derivatives, which showed anticancer activi-
ty. The analogues (95) with nitro group at the position C-5 are the
most active members among benzimidazole thioether series due to
high cytotoxic activity and another compound that contains dithio-
carbamate group (96). In vitro showed cytotoxicity and active hu-
18 Current Organic Synthesis, 2021, Vol. 18, No. 0
man cell lines against MRC-5(lungs), BJ (skin) and WPE1-NA22
(prostate), with the inhibitory concentration like (IC50 ¼ 44.16,
32.09, 32.04, 14.76Mm) NIC-H460, SK-MEL-5, and HL-60(TB)
cell lines and also active inhibition of VEGFR-2 and mTOR en-
zymes. The inhibitory concentration of IC50 values 1.20mM (com-
pound 95) and 1.97mM (compound 96) are with 75.99% and
68.52%, respectively. It was compared with sorafinib as standard
drug. The compounds are active against the mTOR with IC50 values
0.72mM (compound 95) and 0.64mM, with inhibition of 86.57%
and 94.88% when compared to the standard drug rapamycin [148]
(Fig. 14). U. Soumyanarayanan [2012] et al. developed novel
DHPM derivatives that were active against the proliferation of hu-
man hepatocellular carcinoma, and human epithelial carcinoma cell
lines by using an MTT assay. Compounds due to hydrogen bonding
interaction of water molecules along with the presence of oxygen
atom of morpholine in (97), (98), (99), (100), (101) and (102) are
active against the HepG2 and HeLa cell lines with IC50 of 124.46,
and 120.62µg/mL. SAR analysis and molecular modelling studies
of DHPM play a crucial role in the inhibition of Eg5 enzyme (mo-
tors slide microtubules during cell division), which showed anti-
cancer activity [149] (Fig. 14).
Fig. (14). DHPMs based compounds exhibit anti-cancer activity [148-149].
(A higher resolution/colour version of this figure is available in the elec-
tronic copy of the article).
3.10. Anti-malarial Activity
Malaria is an intermittent and remittent fever caused by the pro-
tozoan parasite, which enters into red blood cells and is transmitted
by female anopheles mosquito bite. The parasite passes through the
saliva tropical and subtropical regions. This is a mosquito-borne
infection disease. Some of the symptoms are yellow skin, seizures,
coma, headaches, vomiting, fever, tiredness and death. Parasites
such as P. falciparum, P. vivax, P. ovale and P. malariae are trav-
elled inside liver [150]. It was first discovered by Ronal Ross
(1905), who received the Nobel Prize for Physiology or Medicine
[151]. K. R. Rogerio [2018] et al. developed DHPM, active against
the P. falciparum and P. berghei parasite by using African green
monkey cells (BGM). Compounds (103), (104) and (105) are excel-
lent in antimalarial activity (IC50 of µM) (NCBI 2018), by using a
Khasimbi et al.
silico study with Protein kinase (PK3), and Glycogen synthase ki-
nase 3 (GSK-3 ) enzymes (Fig. 15). I. Radini, et al. [133] devel-
oped a novel series of DHPM derivatives that are in a different
position of aromatic ring group substituent nature (R1), showing
antiplasmodial activity. Both electron-donor and electron withdraw-
ing group at positions of 2, 3 and/ or leads to IC50 values have the
range from 1-10µM, with the expectation of compounds, which are
potentagainst P. falciparum. Compounds (106), (107), (108), (109),
(110), (111), (112) and (113) showed activity with (IC50vales of
1.91-2.21µg/mL), and was compared with antimalarial agent chlo-
roquine [152] (Fig. 15).
Fig. (15) DHPMs based compounds exhibit anti-malarial activity [152-153].
(A higher resolution/colour version of this figure is available in the elec-
tronic copy of the article).
3.11. Anti-convulsant Activity
Convulsions or epileptic seizures are produced due to the risk of
convulsions, and consequent excitotoxicity. Main neurotransmitters
are GABA or glycine receptors or ionotropic glutamate. It involves
nerve agents such as a sarin. The drugs which reduced convulsions
or epilepsy are called Convulsant [154]. R. W. Lewis [2010] et al.
synthesized 3,4-DHPM derivatives, which showed anticonvulsant
activity towards recombinant GABAA receptor subtype, containing
δ-subunit expressed in HEK293T cells. The synthesized analogues
(114), (115), and (116) are potentially active towards saturating
GABA concentration in HEK293T cells, demonstrating that these
molecules increased the efficacy of GABA on 2δ receptor with
expressed 100µM to x. oocytes and x. Laevis [155] (Fig. 16).
3.12. Anti-inflammatory Activity
Inflammation is the response to immune cells, blood vessels,
molecular mediators of body tissues to stimuli damaged cells, pro-
ducing pain, redness, and swelling, loss of function, fever, Osteoar-
Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile Current Organic Synthesis, 2021, Vol. 18, No. 0 19

thritis, atherosclerosis, and periodontal disease. The pains produced
by the COX1 & COX2 enzymes are due to increased prostaglandins
secretion, by creating inflammation. Drugs or chemicals that reduce
the inflammation, pain and swelling are called anti-inflammation
drugs, analgesics, and opioids (block the pain producing the signal-
ling on CNS to reduced the pain) [156]. A. Bhateware [2013] et al.
developed dihydropyrimidinone derivatives, which show potent
anti-inflammatory and anti-bacterial activity. The analogues (117),
(118), (119), (119), (120) and (121) are excellent in anti-
inflammation activity, anti-bacterial activity and antifungal activity.
Compounds are also XA active against the gram positive (+ve) and
gram negative (-ve) bacteria like S. aureus, B. subtilis, E. coli, and
P. aeruginosa and also against fungus like A. flavus, C. albicans
and A. niger (IC50 values of 20-40 mg/kg 0.3533±0.003 (40.42))
[157] (Fig. 17). S. N. Mokale [2010] et al. synthesized some novel
3-(4,6-disubstituted-2-thioxol1,2,3,4-tetrahydro pyrimidin-5-y) pro-
panoic acid dihydropyrimidinone derivatives, with potent anti-
inflammation activity. The analogues (122), (123), (124), (125) and
(126) were tested for anti- inflammation by using the rat paw edema
method (IC50 values of 20 mg/kg. Mean ± SEM n=6 (p<0.05)) when
compared with standard drug dicyclofenac [158] [Fig. 17]. S. Viveka
[2017] et al. developed a novel series of pyrazole integrated thia-
zolo[2,3-b]dihydropyrimidinone derivatives, which exbhit excellent
antiinflammatory activity and antibacterial activity. The synthesized
analogues (127), (128) and (129) were found to inhibit inflammation
towards the COX-2 isoenzyme (85.33%, 81.32% and 80.75%), and
was compared with indomethacin (p<0.05, p<0.01 & p<0.001), and
also found to be potent anti-bacterial agents against E. coli, S. aureus,
K. pneumoniae, P. aeruginosa, A. flavus and F. verticilliodes (MIC
3.12µg/mL, 6.25µg/mL & 25µg/mL)[159] (Fig. 17).
a pre-treated rat in-vivo condition at 96 hrs [162] (Fig. 19). M.
Mansouri [2012] et al. developed a series of 3,4-DHPM, which
exhibit the anti-oxidant activity. The analogues (134) and (135)
have more potential in showing anti-oxidant activity by using dif-
ferent methods like DPPH free radical scavenging, reducing power,
and hydrogen peroxide scavenging assay. Compounds have more
potent antioxidant activity (IC50 values of 0.6mg/ml) when com-
pared with Gallic acid in scavenging hydrogen peroxide [163] (Fig.
19). Vijay Kotra [2014] et al. synthesized a novel series of DHPM
with excellent antimicrobial, anti-inflammatory and anti-tumor
activities. Synthesized analogues (136), (137), (138), (139), (140),
(141), (142) and (143) were found to be active against the gram-
positive and gram-negative bacteria by using diffusion methods
(IC50 value of 30µg/ml), when compared with ciprofloxacin, and
showing antifungal activity against the A. niger and A. flavus (IC50
value of 50µg/ml) in comparison to standard drug flucozole. These
compounds also showed anti-oxidant activity by using the radical
scavenging method IC50 values of 100 mg/kg (71-75% & 76-79%).
They were also checked for the cytotoxic activity by using the
Brine Shrimp Lethality Test (BSLT) in comparison to the standard
podophyllotoxin [164] (Fig. 19).

Fig. (16). DHPMs based compounds exhibit anti- convulsant activity [155].
(A higher resolution/colour version of this figure is available in the elec-
tronic copy of the article).

3.13. Anti-hypertension activity

Hypertension is mainly an increase in blood pressure. Its major
risk factors are heart failure, chronic kidney disease, peripheral
vascular disease, stroke, and coronary artery heart disease. Decreas-
ing hypertension is mainly affected by different pathways, such as
calcium channel blockers, angiotensin converting enzyme inhibitors
and, angiotensin receptor blocker [160]. M. Hiren [2011] et al.
synthesized 3,4-dihydropyrimidinone derivatives, which are calci- Fig. (17). DHPMs based compounds exhibit anti-inflammatory activity
um channel blockers. The analogues (130) and (131) have two ni- [157-159]. (A higher resolution/colour version of this figure is available in
trogen atoms, which are bioisosteric with (CH) present in dihydro- the electronic copy of the article).
pyrimidinone. One methyl group (CH3) with bioisosteric and ke-
tone (C=O) standard showed inhibition of calcium channel at IC50
values of 20.00µg/mL (33.09%) with Log P=0.8-2.08, when com-
pared with standard drug nifedipine [161] (Fig. 18).

3.14. Miscellaneous
N. Priya [2011] et al. synthesized some novel series of DHPM
derivatives, which are effectively used to treat anti-hypertension.
The synthesized analogues (132-133) are active against the an-
tiplatelet activity by using Post Hoc test on rats. Compounds are Fig. (18). DHPMs based compounds exhibit anti-hypertension activity
producing 50% effective aggregation, induced by the ADP, colla- [161]. (A higher resolution/colour version of this figure is available in the
gen or thrombin (IC50 values of 52.0, 0.02mg/kg (133mmol/kg)) on electronic copy of the article).
20 Current Organic Synthesis, 2021, Vol. 18, No. 0 Khasimbi et al.

CADD = Computer-Aided Drug Design

CHIP = Carboxyl-Terminus of Hsp70 Interacting Protein
CoMFA = Comparative Molecular Field Analysis
CoMSIA = Comparative Molecular Similarity Indices Analysis
DBSA = Dodecylbenzenesulfonic acid
DHPMs = Dihydropyrimidin-Ones/Thiones
DMAP = N,N-Dimethypyridin-4-Amine
DMF = Dimethylforamide
DMF = DMA-Dimethylforamide-Dimethylacetal
GABA = Gamma-Aminobutyric Acid
GSK-3 = Glycogen Synthase Kinase 3
HCl = Hydrochloric Acid
HIV = Human Immunodeficiency Virus
HTMA = Heulandites Type Zeolite
LDH = Layered Double Hydroxide
MIC = Minimum Inhibitory Concentration
MTT = (3-(4,5-Dimethylthiazol-2-Yl)-5-(3-
Carboxymethoxyphenyl)-2-(4-Sulfopheyl)-2H-
Tetrazolium Bromide
NBS = N-Bromosuccinimide

Fig. (19). DHPMs based compounds exhibit miscellaneous activity [162- PK3 = Protein Kinase
164]. (A higher resolution/colour version of this figure is available in the QSAR = Quantitative Structure-Activity Relationship
electronic copy of the article). TBAF = Tetra Butylammoniumfluoride
TBARS = Thiobarbituric Acid Reactive Substances
CONCLUSION
TBTA = Tetrabutylammonium-Triphenyldifluorosilicate
DHPM/thiones have the most scaffold and displayed molecules
with formidable biological effects like antimicrobial, anti- TFA = Trifluoroacetic Acid
tubercular, antipsychotic, anticonvulsant, antidepressant, anti- TLC = Thin Layer Column Chromatography
inflammatory, anti-oxidant, antimalarial, antiarrhythmic, antifungal,
antifilarial, anti-HIV, calcium channel blockers, potassium channel TMSE = 2-(trimethylsilyl)ethyl)
blockers and anti-cancer drugs [6-42]. Various DHPM (synthesized
by using various catalysts such as Tetrabutylammonium-triphenyl CONSENT FOR PUBLICATION
difluorosilicate (TBTA), 2-(trimethylsilyl)ethyl (TMSE), tetrabu- Not applicable.
tylammoniumfluoride (TBAF) and trifluoroacetic acid(TFA)) are
used for the treatment of human polymaviruses on immune systems
that are suppressed in patients when comparison with cidofovir FUNDING
[166]. DHPMs offer new avenues to develop an efficient synthesis None.
using the dimethylforamide-dimethylacetal (DMF-DMA) by con-
ventional and microwave-irradiated techniques under free-solvent CONFLICT OF INTEREST
conditions [167]. In modern drug discovery, DHPMs scaffolds are
an important pharmacophore and researchers are keeping a keen The authors declare no conflict of interest, financial or other-
eye on the discovery of various DHPMs analogues for the synthesis wise.
of new and more potent drug discovery and development world-
wide [168-170]. This literature review clearly described the diversi- ACKNOWLEDGEMENTS
fied pharmacological activities with a high potency of flexible
Shaik Khasimbi acknowledges AICTE-National Doctrinal Fel-
DHPM/thiones analogues for various therapeutic targets in the field
lowship, New Delhi, India for granting Senior Research Fellowship.
of pharmaceutical chemistry. The potential abilities bring much
The author would like to thank the Delhi Institute of Pharmaceuti-
scope in developing novel and therapeutically active hybrids of
cal Science and Research, Delhi Pharmaceutical Science Research
DHPMs analogues for other therapeutic targets. Furthermore, inves-
University, New Delhi for providing the necessary facilities.
tigations on DHPMs moiety could help in some more interesting
results in biological activities of synthetic DHPMs derivatives,
motivating the researcher for improvement in the field of pharma- REFERENCES
ceutical chemistry. [1] Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Passerinii three-component
and Ugi four-component condensation are the most popular among other re-
action for their wide scope and synthetic utility. Chem. Eur. Jr., 2000, 6,
LIST OF ABBREVIATIONS 3321.
[2] Domling, A.; Ugi Angew, I. Passerinii three-component and Ugi four-
ADT = Adenosine Triphosphate component condensation are the most popular among many other reaction for
ATP = Adenosine Triphosphate their scope and synthetic utility. Chem. Int. Eur., 2000, 39, 3168.

BSLT = Brine Shrimp Lethality Test

Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile
[3] Biginelli, P. Synthesis of some hexahydroquinazolines using K3AIF6
(AI2O3/KF) as an efficient catalyst in some hexahydroquinazolinone deriva-
tives. Chim Ital., 1893, 23, 360-413.
[4] Biologically active dihydropyrimidone of the Biginelli type –a literature
survey. Eur. J. Med. Chem., 2000, 12, 1043-1046.
[5] Weber, L.; Illgen, K.; Almstetter, M. Discovery of new multi component
reaction with combinatorial methods. Synlett, 1999, 3, 366.
http://dx.doi.org/10.1055/s-1999-2612
[6] Kappe, C.O. 100 years of the Biginelli dihydropyrimidine synthesis. Tetra-
hedron, 1993, 49, 6937.
http://dx.doi.org/10.1016/S0040-4020(01)87971-0
[7] Kappe, C.O. Recent advances in the Biginelli dihydropyrimidine synthesis.
New tricks from an old dog. Acc. Chem. Res., 2000, 33(12), 879-888.
http://dx.doi.org/10.1021/ar000048h PMID: 11123887
[8] Kaur, R.; Chaudhary, S.; Kumar, K.; Gupta, M.K.; Rawal, R.K. Recent
synthetic and medicinal perspectives of dihydropyrimidinones: A review.
Eur. J. Med. Chem., 2017, 132, 108-134.
http://dx.doi.org/10.1016/j.ejmech.2017.03.025 PMID: 28342939
[9] N. Naidu, M. E. Sorenson, M.Patel, Y. Ueda, J. Banville, F. Beaulieu, S.
Bollini, H. Higley, Z. Lin, Synthesis and evaluation of C2-carbon-likned et-
erocyclic-5-hydroxy-6-oxo-dihydropyrimidine-4-carboxamides as HIV-1 in-
tegrase inhibitors. Bioorg. Med. Chem. Lett., 2015, 25, 717-720.
http://dx.doi.org/10.1016/j.bmcl.2014.11.060
[10] Said, S.A.; Amr, A.E-G.E.; Sabry, N.M.; Abdalla, M.M. Synthesized of
some heterocyclic system and their nucleoside of potent anti-inflammatory
activities. Eur. J. Med. Chem., 2009, 44, 4787-4792.
http://dx.doi.org/10.1016/j.ejmech.2009.07.013 PMID: 19682771
[11] Lauro, G. M, Strocchia, S. Terracciano, L. Bruno, K. Fischer, C. Pergola, O.
Werz, R. Riccio, G. Bifulco, Structural-based design of Microsomal prosta-
glandin E2synthase-1 (mPGES-1) inhibitors using a virtual fragment grow-
ing optimization scheme. Eur. J. Med. Chem., 2017, 80, 407-415.
http://dx.doi.org/10.1016/j.ejmech.2014.04.061 PMID: 24794772
[12] Dragovich, P.S.; Fauber, B.P.; Corson, L.B.; Ding, C.Z.; Eigenbrot, C.; Ge,
H.; Giannetti, A.M.; Hunsaker, T.; Labadie, S.; Liu, Y.; Malek, S.; Pan, B.;
Peterson, D.; Pitts, K.; Purkey, H.E.; Sideris, S.; Ultsch, M.; VanderPorten,
E.; Wei, B.; Xu, Q.; Yen, I.; Yue, Q.; Zhang, H.; Zhang, X. Identification of
substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lac-
tate dehydrogenase. Bioorg. Med. Chem. Lett., 2013, 23(11), 3186-3194.
http://dx.doi.org/10.1016/j.bmcl.2013.04.001 PMID: 23628333
[13] Rovnyak, G.C.; Atwal, K.S.; Hedberg, A.; Kimball, S.D.; Moreland, S.;
Gougoutas, J.Z.; O’Reilly, B.C.; Schwartz, J.; Malley, M.F. Dihydropyrimi-
dine calcium channel blockers. 4. Basic 3-substituted-4-aryl-1,4-
dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents. J.
Med. Chem., 1992, 35(17), 3254-3263.
http://dx.doi.org/10.1021/jm00095a023 PMID: 1387168
[14] Sondhi, S.M.; Goyal, R.N.; Lahoti, A.M.; Singh, N.; Shukla, R.; Raghubir, R.
Synthesis and biological evaluation of 2-thiopyrimidine derivatives. Bioorg.
Med. Chem., 2005, 13(9), 3185-3195.
http://dx.doi.org/10.1016/j.bmc.2005.02.047 PMID: 15809154
[15] Bhosle, M.R.; Deshmukh, A.R.; Pal, S.; Srivastava, A.K.; Mane, R.A. Syn-
thesis and antihyperglycemic evaluation of new 2-hydrazolyl-4-
thiazolodinone-5-carboxylic acids having pyrazolyl pharmacophore. Bioorg.
Med. Chem. Lett., 2015, 25, 2442-2446.
http://dx.doi.org/10.1016/j.bmcl.2015.03.068 PMID: 25937008
[16] Luszezki, J.J.; Glowniak, K.; Czuczwar, S.J. Time-curse and dose response
relationship of imperatorin in the mouse maximal electroshock seizure
threshold model. Neurosci. Res., 2007, 562, 53-59.
[17] Diasio, R.B.; Harris, B.E. Clinical pharmacology of 5-fluorouracil. Clin.
Pharmacokinet., 1989, 16(4), 215-237.
http://dx.doi.org/10.2165/00003088-198916040-00002 PMID: 2656050
[18] Dragunow, M. Adenosine receptor antagonism accounts for the seizure-
prolonging effects of aminophylline. Pharmacol. Biochem. Behav., 1990,
36(4), 751-755.
http://dx.doi.org/10.1016/0091-3057(90)90072-P PMID: 2217501
[19] Trivedi, R.; Bhuva, V.R.; Dholariya, B.H.; Dodiya, D.K.; Kataria, V.B.;
Shah, V.H. Synthesis and antitubercular evaluation of some novel 1, 2, 3, 6-
tetrahydropyrimidne-5-carbonitile. Bioorg. Med. Chem. Lett., 2011, 20,
6100-6102.
http://dx.doi.org/10.1016/j.bmcl.2010.08.046 PMID: 20813528
[20] Russowsky, D.; Canto, R.F.; Sanches, S.A.; D’Oca, M.G.; de Fátima, A.;
Pilli, R.A.; Kohn, L.K.; Antônio, M.A.; de Carvalho, J.E. Synthesis and dif-
ferential antiproliferative activity of Biginelli compounds against cancer cell
lines: Monastrol, oxo-monastrol and oxygenated analogues. Bioorg. Chem.,
2006, 34(4), 173-182.
http://dx.doi.org/10.1016/j.bioorg.2006.04.003 PMID: 16765411
[21] Barton, D.H.; Hesse, R.H.; To, H.T.; Pechet, M.M. A convenient synthesis of
5-fluorouracil. J. Org. Chem., 1972, 37(2), 329-330.
http://dx.doi.org/10.1021/jo00967a037 PMID: 5013354
[22] Vitreschak, A.G.; Rodionov, D.A.; Mironov, A.A.; Gelfand, M.S. Regulation
of riboflavin biosynthesis and transport genes in bacteria by transcriptional
and translational attenuation. Nucleic Acids Res., 2002, 30(14), 3141-3151.
http://dx.doi.org/10.1093/nar/gkf433 PMID: 12136096
[23] Prusoff, W.H. Synthesis and biological activities of iododeoxyuridine, an
analog of thymidine. Biochim. Biophys. Acta, 1959, 32(1), 295-296.
http://dx.doi.org/10.1016/0006-3002(59)90597-9 PMID: 13628760
Current Organic Synthesis, 2021, Vol. 18, No. 0 21
[24] Ranise, A.; Bruno, O.; Bondavalli, F.; Schenone, S.; D’Amico, M.; Falciani,
M.; Filippelli, W.; Rossi, F. 5-Substituted 2,3-dihydro-6-mercapto-1,3-
diphenyl-2-thioxo-4(3H)-pyrimidinones and their 6-(acylthio) derivatives
with platelet antiaggregating, antiinflammatory, antiarrhythmic, antihyper-
lipidemic and other activities. Farmaco, 1994, 49(9), 551-558.
PMID: 7811350
[25] Wamberg, M.; Pederson, E. B.; Nielsen, C. Nielsen, Synthesis of furoanellat-
ed analogues of emivirine (MKC-442), Chemlnform. 2004, 35(30)
[26] Senthilkumar, P.; Long, J.; Swetha, R.; Shruthi, V.; Wang, R.R.; Preethi, S.;
Yogeeswari, P.; Zheng, Y.T.; Sriram, D. Synthesis of zidovudine derivatives
with anti-HIV-1 and antibacterial activities. Nucleosides Nucleotides Nucleic
Acids, 2009, 28(2), 89-102.
http://dx.doi.org/10.1080/15257770902736442 PMID: 19219739
[27] Ojo, B.; Findsen, L.A.; Igarashi, N.; Kong, B.; Chowdhury, B.K. Synthesis
and bronchodilatory activity of four new derivatives of deoxyvasicine. Drug
Des. Discov., 1996, 14(1), 1-14.
PMID: 8854041
[28] Keam, S.J. Telbivudine. Drugs, 2007, 67(13), 1917-1929.
http://dx.doi.org/10.2165/00003495-200767130-00011 PMID: 17722961
[29] Mandala, D.; Watts, P. An improved synthesis of lamivudine and emtricta-
bine. ChemistrySelect, 2017, 2(3), 1102-1105.
http://dx.doi.org/10.1002/slct.201700052
[30] Ciceri, S.; Ciuffreda, P.; Ferrabischi, P. Synthesis of the antitumor nucleoside
capecitabine through a chemo-enzymatic approach. Tetrahedron Lett., 2015,
56(43), 5909-5913.
http://dx.doi.org/10.1016/j.tetlet.2015.09.027
[31] Mandala, D.; Chada, S.; Watts, P. Semi-continuous multi-step synthesis of
lamivudine. Org. Biomol. Chem., 2017, 15(16), 3444-3454.
http://dx.doi.org/10.1039/C7OB00480J PMID: 28362445
[32] Kim, J.; Cowan, A.; Lisek, R.; Raymondi, N.; Rosenthal, A.; Hirsch, D.D.;
Rawls, S.M. Icilin-evoked behavioral stimulation is attenuated by alpha₂-
adrenoceptor activation. Brain Res., 2011, 1384, 110-117.
http://dx.doi.org/10.1016/j.brainres.2011.02.002 PMID: 21315691
[33] Singh, V.; Sapehiyia, V.; Srivastava, V.; Kaur, S. ZrO2-pillared clay: An
efficient catalyst for solventless. Catal. Commun., 2006, 7(8), 571-578.
http://dx.doi.org/10.1016/j.catcom.2005.12.021
[34] Capparelli, E.V.; Holland, D.; Okamoto, C.; Gragg, B.; Durelle, J.; Marquie-
Beck, J.; van den Brande, G.; Ellis, R.; Letendre, S. Lopinavir concentrations
in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV.
AIDS, 2005, 19(9), 949-952.
http://dx.doi.org/10.1097/01.aids.0000171409.38490.48 PMID: 15905676
[35] Grover, GJ.; Dzwonczyk, S.; McMullen, DM.; Normandin, DE.; Parham,
CS.; Sleph, PG.; Moreland, S. Pharmacological profile of the dihydropyrimi-
dine calacium channel blockers SQ32,547 and SQ32,926[correction of
SQ32,946] 1995, 26(2), 289-94.
[36] Mayer, T.U.; Kapoor, T.M.; Haggarty, S.J.; King, R.W.; Schreiber, S.L.;
Mitchison, T.J. Small molecule inhibitor of mitotic spindle bipolarity identi-
fied in a phenotype-based screen. Science, 1999, 286(5441), 971-974.
http://dx.doi.org/10.1126/science.286.5441.971 PMID: 10542155
[37] Rami, C.; Patel, L.; Patel, C.N.; Parmar, J.P. Synthesis, antifungal activity,
and QSAR studies of 1,6-dihydropyrimidine derivatives. J. Pharm. Bioallied
Sci., 2013, 5(4), 277-289.
http://dx.doi.org/10.4103/0975-7406.120078 PMID: 24302836
[38] Economou, C.; Romaire, J.P.; Scott, T.Z.; Parr, B.T.; Herzon, S.B. A con-
vergent approach to batzelladine alkaloids. Total synthesis of (+)-
batzelladine E,(-)-dehydrobatzelladineC, and (+)-batzelladine K. Tetrahe-
dron Lett., 2018, 74(26), 3188-3197.
http://dx.doi.org/10.1016/j.tet.2018.04.050
[39] Huang, R.I.; Patel, P.; Walinsky, P.; Fischman, D.L.; Ogilby, J.D.; Awar, M.;
Frankil, C.; Savage, M.P. Efficacy of intracoronary nicardipine in the treat-
ment of no-reflow during percutaneous coronary intervention. Catheter.
Cardiovasc. Interv., 2006, 68(5), 671-676.
http://dx.doi.org/10.1002/ccd.20885 PMID: 17034064
[40] Busch, M .; Jan, D Substituted fused pyrimidinones and dihydropyrimidi-
nones. AU2011298423A1, 2015.
[41] Essa HHu, Daniel R, Sidler, Ulf H. Dolling, Michael A, Patane. Process for
making dihydropyrimidinones. WO1997021687A1, 1997.
[42] David, B; Hans, H Dihydropyrimidinones for use as bace2 inhibitors.
KR20120061069A, 2014.
[43] Colin, M. Colin M. Tice, Lois M. Bryman, Renee C. Roemmele. 2-aryl-5,6-
dihydropyrimidinones and herbicidal use thereof. US5629264A, 1997.
[44] Essa HHu, Daniel R, Sidler, Ulf H. Dolling, Michael A, Patane.. Process for
making dihydropyrimidinones. US5786472A, 1998.
[45] Nussbaum, F V; Dagmar, K; Sonja, A; Martina, D 4-(4-cyano-2-
thioaryl)dihydropyrimidinones and use thereof. SG186679A1, 2013.
[46] Gnamm, C; Hoesch, H; Peters, S; Oost, T Jörg Ries Uwe. substituted bicy-
clic dihydropyrimidinones, pharmaceutical composition comprising them
and use. BR112015017929A8, 2019.
[47] Nussbaum, FV; Dagmar, K; Sonja, A; Martina, D Sulfonic amide and sul-
foximine-substituted diaryl-dihydropyrimidinones and usage thereof.
HK1171451A1, 2015.
[48] Vincent, E; Claude, G Use of compositions obtained by calcining particular
metal-accumulating plants for implementing catalytical reactions.
AU2014220639A1, 2015.
22 Current Organic Synthesis, 2021, Vol. 18, No. 0
[49] Saturated ring fused dihydropyrimidone or dihydrotrione compound and its
medical use. TW202000652A, 2020.
[50] Zhanq, Liwan Dihydropyrimidinones synthetic method and catalyst.
CN110201714A, 2019.
[51] Heike Gielen-Haertwig, Barbara A, Jörg K, Volkhart Li, Josef P, Karl-Heinz
Schlemmer, Leila T. 1,4-diaryl-dihydropyrimidin-2-ones and their use as
human neutrophil elastase inhibitors. EP1723121B1, 2012.
[52] Gabriela, C; Tony, T; Anna, R 2-(Pyrimidin-5-yl)-thiopyrimidine derivatives
as Hsp70 and Hsc70 modulators for the treatment of proliferative disorders.
EP2467142B1, 2016.
[53] Scott, E. S; Lauren, B; John, C; Ken William, D. Pyridopyrimidinone inhibi-
tors of viruses. US9567331B2, 2017.
[54] Mashooq, A B; Mohamed, A. Dihydropyrimidinone derivatives.
US10047071B1,
[55] Olcay, B; Jeffrey, L. Methods for heat shock protein dependent cancer treat-
ment. US8754094B2, 2011.
[56] Mark Joseph, T; Holly Victoria, A; Craig, A; Steven Mark, B; Mark, K;
Adrian Kotei, K; Nathaniel, J. Heteroaryl Derivatives As Sepiapterin Reduc-
tase Inhibitors. Ep3356345a1, 2018.
[57] Ulrike, D. Spohr, Michael J. Malone, Nathan B. Mantlo. Substituted pyrim-
idinone and pyridone compounds and methods of use. US6096753A, 2006.
[58] Heike Gielen-Haertwig, Volkhart M Li, Ulrich R, Karl-Heinz S, Swen Aller-
heiligen, Leila Telan, Lars B, Jörg Keldenich , Mary F. Fitzgerald, Kevin N,
Barbara A, Dirk M.. Pyrimidinone derivatives as therapeutic agents against
acute and chronic, ischemic and remodelling inflammatory processes.
ES2414865T3,
[59] Luiz, B A; Augusto Rocha, B F; Rafique, KJ; Faria Santos, C R; Saba, S; Do
Nascimento, V. dihydropyrimidinone-derived selenoesters, process for ob-
taining dihydropyrimidinone-derived selenoesters and their application as an-
tioxidants and acetylcholinesterase inhibitors in the treatment of alzheimer's
disease. BR102017007303A2, 2018.
[60] Luther, J.M. Is there a new dawn for selective mineralocorticoid receptor
antagonism? Curr. Opin. Nephrol. Hypertens., 2014, 23(5), 456-461.
http://dx.doi.org/10.1097/MNH.0000000000000051 PMID: 24992570
[61] McDonald, T.F.; Pelzer, S.; Trautwein, W.; Pelzer, D.J. Regulation and
modulation of calcium channels in cardiac, skeletal, and smooth muscle cells.
Physiol. Rev., 1994, 74(2), 365-507.
http://dx.doi.org/10.1152/physrev.1994.74.2.365 PMID: 8171118
[62] Tajbakhsh, M.; Mohajerani, B.; Heravi, M.M.; Ahmadi, A.N. Natural HEU
type zeolite catalyzed Biginelli reaction for the synthesis of 3,4-
dihydropyrimidin-2(1H)-one derivatives, J. Mol. Cat. Chem, 2005, 236, 216-
219.
[63] Aswin, K.; Mansoor, S.S.; Logaiya, K.; Sudhan, P.N.; Ahmed, R.N. Facile
synthesis of 3,4-dihydropyrimidin-2(1H)-ones and thiones and indeno[1,2-
d]pyrimidines catalyzed by p-dodecylbenzenesulfonic acid. J. Taib. Uni. Sci.,
2014, 8, 236-247.
http://dx.doi.org/10.1016/j.jtusci.2014.03.005
[64] Stefani, H.A.; Gatti, P.M. 3,4-dihydropyrimidin-2(1H)-ones: fast synthesis
under microwave irradiation in solvent free conditions. Synth. Commun.,
2000, 30, 2165-2173.
http://dx.doi.org/10.1080/00397910008087395
[65] Patil, S.; Jadhavar, Sd.; Mane, S.Y. Pineapple juice as a natural catalyst: An
excellent catalyst for Biginelli reaction. Int. J. Org. Chem. (Irvine), 2011, 11,
25-131.
http://dx.doi.org/10.4236/ijoc.2011.13019
[66] Moosavifar, M.C.R. An appropriate one-pot synthesis of dihydropyrimidi-
nones catalyzed by heteropoly acid supported on zeolite: An efficient and re-
usable for the Biginelli. C. R. Chim., 2012, 15, 444-447.
http://dx.doi.org/10.1016/j.crci.2011.11.015
[67] Silva, L.; Fernandes, S.A.; Fatima, A.A. A P-Sulfonic acid Calix[4]arene as
an efficient catalyst for one-pot synthesis of pharmaceutically significant
Coumarin derivatives under solvent-free condition. Tetrahedron Lett., 2011,
52, 6328-6330.
[68] Chitra, S.; Pandiarajan, K. Calcium fluoride: an efficient and reusable cata-
lyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and their corre-
sponding 2(1H)-thione: an improved high yielding protocol for the Biginelli
reaction. Tetrahedron Lett., 2009, 50(19), 2222-2224.
http://dx.doi.org/10.1016/j.tetlet.2009.02.162
[69] Ghotkar, N.S.; Der Phar, B.N. Biginelli synthesis of 3,4-dihydropyrimidin-
2(1H)-one using layered double hydroxide(LDH) as a eco-friendly catalyst.
Chemi., 2015, 7, 167-172.
[70] Jain, S.L.; Joseph, J.K.; Singhal, S.; Mol, B.J. PEG-assisted solvent and
catalyst free synthesis of 3,4-dihydropyrimidinone under mild reaction con-
dition. Cat. A. Chem., 2007, 26, 8134-8138.
[71] Raju, M. Kalaipriya, R. Uma, R. Sridhar, S. Ramakrishna, Pyridinium tri-
fluoroacetate mediated synthesis of 3,4-dihydropyrimidin-2(1H)-ones and
Tetrazolo[1,5-a]pyrimid ine-6-carboxylates. Curr. Chem. Lett., 2012, 1, 27-
34.
[72] González-Olvera, R.; Román-Rodríguez, V.; Negrón-Silva, G.E.; Espinoza-
Vázquez, A.; Rodríguez-Gómez, F.J.; Santillan, R. Multicomponent synthe-
sis and evaluation of new 1,2,3-triazole derivatives of dihydropyrimidinones
as acidic corrosion inhibitors for steel. Molecules, 2016, 21(2), 250-263.
http://dx.doi.org/10.3390/molecules21020250 PMID: 26907242
[73] Kalita, H.R.; Phukan, P. CuI as reusable catalyst for the Biginelli reaction
Catal. Commun., 2007, 81, 179-182.
Khasimbi et al.
[74] Khosropour, R.; Beygzadeh, M.M.; Jokar, M. A one-pot synthesis of 3,4-
dihydro pyrimidin-2(1H)-one from primary alcohols promoted by
Bi(NO3)3.5H2O in two different media: Organic solvent and ionic liquid.
Heterocycles, 2005, 65, 767.
http://dx.doi.org/10.3987/COM-04-10257
[75] Zhou, H.; Hw, M.; Liu, C.; Luo, H.; Prep, G. One-pot synthesis of 3,4-
dihydropyrimidin-2(1H)-one using CuBr2 as catalyst, Biochem. Biotechnol.
36 (2006) 375. (a).V. A. Chebanov, V. E. Desenko, S. M. Chernenko, V. N.
Knyazeva, I. V. Groth, U. Glasnov, T. N. Kappe, C. O. Tuning of chemo and
regioselectivities in multicomponent condensations of 5-aminopyrazoles
dimedone and aldehyde. J. Org. Chem., 2008, 73, 5110.
[76] Wipf, P.; Cunningham, A. A solid phase protocol of the Biginelli dihydropy-
rimidine synthesis suitable for combinatorial chemistry. Tetrahedron Lett.,
1995, 36(43), 7819-7822.
http://dx.doi.org/10.1016/0040-4039(95)01660-A
[77] Cepanec, L.; Litvic, M.; Bartolinčić, A.; Lovric, M. Ferric chloride/tetraethyl
orthosilicate as an efficient system for synthesis of dihydropyrimidinones by
Biginelli reaction. Tetrahedron, 2005, 61, 4275-4280.
http://dx.doi.org/10.1016/j.tet.2005.02.059
[78] Wan, J.P.; Wang, C.; Pan, Y. Solvent-free synthesis of 6-unsubstituted
dihydropyrimidine using 2-pyrrolidonium bisulphate as effect catalyst. Tet-
rahedron, 2011, 67, 922.
http://dx.doi.org/10.1016/j.tet.2010.12.011
[79] Tu, S.; Zhang, J.; Zhu, X.; Xu, J.; Zhang, Y.; Wang, Q.; Jia, R.; Jiang, B.;
Zhang, J. New potential inhibitors of cyclin-dependent kinase 4: design and
synthesis of pyrido[2,3-d]pyrimidine derivatives under microwave irradiation.
Bioorg. Med. Chem. Lett., 2006, 16(13), 3578-3581.
http://dx.doi.org/10.1016/j.bmcl.2006.03.084 PMID: 16621547
[80] Yadav, L.D.S.; Awasthi, C.; Rai, V.K.; Rai, A. Biorenewable and mercapto-
acetylating building blocks in the Biginelli reaction: Synthesis of thiosugar-
annulated dihydro pyrimidines. Tetrahedron Lett., 2007, 48(28), 4899-4902.
http://dx.doi.org/10.1016/j.tetlet.2007.05.057
[81] Hazarkhani, H.; Karimi, B. N-Bromosuccinimide as an almost neutral cata-
lyst for efficient synthesis of dihydropyrimidinones under microwave irradia-
tion. Synthesis, 2004, 1239-1242.
[82] Hamid, N.; Hamid, R.K.; Ayoob, B.A. A novel and efficient synthesis of
pyrimido[4,5-d]pyrimidine-2,4,7-trione and pyrido[2,3-d,5-d]dipyrmidine-
2,4,6,8-tetrone derivatives. Tetrahedron, 2007, 63, 1770-1774.
http://dx.doi.org/10.1016/j.tet.2006.12.043
[83] Shujian, T.; Shansha, W.U.; Zhengguo, H.; Wenjuan Chin, H. An efficient
microwave-assisted synthesis of pyrido[2,3-d]pyrimidine derivatives. J.
Chem., 2009, 27, 1148-1152.
[84] Zonouzi, F. Hosseinzadeh, N. Karimi, R. Mirzazadeh, W. N. Seik, Novel
approach for the synthesis of a library of fluorescent chromenopyrimidine
derivatives. ACS Comb. Sci., 2013, 15, 240-246.
http://dx.doi.org/10.1021/co300141j PMID: 23547948
[85] Ryabukhin, S.V.; Plaskon, A.S.; Ostapchuk, E.N.; Volochnyuk, D.M.; Tol-
machev, A.A. N-Substituted urea and thiourea in Biginelli reaction promoted
by Chlorotrimethylsilane: convenient synthesis of N1-alkyl-, N-aryl-
andN1,N3-dialkyl-3,4-dihydropyrimidin-2(1H)-(thio)ones. Synthesis, 2011,
2261-2267.
[86] Sasada, T.; Kobayashi, F.; Sakai, N.; Konakahara, T. An unprecedented
approach to 4,5-disubstituted pyrimidine derivatives by a ZnCl(2)-catalyzed
three-component coupling reaction. Org. Lett., 2009, 11(10), 2161-2164.
http://dx.doi.org/10.1021/ol900382j PMID: 19371078
[87] Davoodnia, M. Rahimizadeh. Rivadeh, M. Bakavoli, M. Roshani, Investiga-
tion in to the reaction of 2-amino-4,5-dimethylthiophene-3-carboxamide with
iso (and thio) cyanates under microwaves irradiation. 2006, 16, 151-154.
[88] Ziarani, G.M.; Faramarzi, S.; Asadi, S.; Badiei, A.; Bazl, R.; Amanlou, M.
Three-component synthesis of pyrano[2,3-d]-pyrimidine dione derivatives
facilitated by sulfonic acid nanoporous silica (SBA-Pr-SO3H) and their
docking and urease inhibitory activity. Daru, 2013, 21(1), 3.
http://dx.doi.org/10.1186/2008-2231-21-3 PMID: 23351402
[89] Aswin, K.; Sheik, S. Triphenylphosphine: An efficient catalyst for the syn-
thesi of 4,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione thermal condition.
Journal of king Saud University- Science, 2013.
[90] Wang, C.; Liu, H.; Song, Z.; Ji, Y.; Xing, L.; Peng, X.; Wang, X.; Ai, J.;
Geng, M.; Zhang, A. Synthesis and structure-activity relationship study of
pyrazolo[3,4-d]pyrimidines as tyrosine kinase RET inhibitors. Bioorg. Med.
Chem. Lett., 2017, 27(11), 2544-2548.
http://dx.doi.org/10.1016/j.bmcl.2017.03.088 PMID: 28404375
[91] Huang, Y.Y.; Wang, L.Y.; Chang, C.H.; Kuo, Y.H.; Kaneko, K.; Takayama,
H.; Kimura, M.; Juang, S.H.; Wong, F.F. Vilsmeier-Haack reagent-promoted
formyloxylation of α–chloro-N-arylacetamides by formamide. Tetrahedron,
2012, •••, 9658-9664.
http://dx.doi.org/10.1016/j.tet.2012.09.054
[92] Hajipour, R.; Ghayeb, Y.; Sheikhan, N.; Ruoho, A.E. Supported Tetra me-
thylammonium nitrate/silica sulphuric acid as a useful reagent for nitration
aromatic compounds under solvent-free condition. Synth. Commun., 2011, 41,
2226-2233.
http://dx.doi.org/10.1080/00397911.2010.501474
[93] Zhi-Yong tian, Gang-jun Du, Song-Qiang Xie, Jin Zhao, Wen-yuan Gao,
Cha-jie wang, Synthesis and Bioevaluation of 5-fluorouracil derivatives.
Molecules, 2007, 12, 2450-2457.
Dihydropyrimidinones Scaffold as a Promising Nucleus for Synthetic Profile
[94] Lu, J.; Bai, Y. Catalysis of the Biginelli reaction by ferric and nickel chloride
Hexahydrates one-pot synthesis of 3, 4-dihydropyrimidin-2(1H)-one. Synthe-
sis, •••, (20002), 466-470.
[95] Sweet, F.; Fissekis, J.D. Synthesis of substituted 3,4-tetrahydro-2(1H)-
pyrimidinones and mechanism of the Biginelli reaction. J. Am. Chem. Soc.,
1973, 95, 8741.
http://dx.doi.org/10.1021/ja00807a040
[96] Reilly, O. B.C, Atwal, K. S, Synthesis of substituted 1,2,3,4-tetrahydro-6-
methyl-2-oxo-5-pyrimidine carboxylic acid esters: Biginelli condensation re-
visited. Hetrocyclic., 1987, 26, 1185.
http://dx.doi.org/10.3987/R-1987-05-1185
[97] Atwal, K.S.; Reilly, B.C.O.; Gougoutas, J.Z.; Malley, M.F. Synthesis of
substituted 1,2,3,4-tetrahydro-6-methyl-2-thioxo-5-pyrimidinecarboxylic ac-
id esters. Hetrocyclic., 1987, 26, 1189.
http://dx.doi.org/10.3987/R-1987-05-1189
[98] Kappe, C.O. A re-examination of the mechanism of the Biginelli dihydropy-
rimidine synthesis support for N-acyliminium ion intermediate. J. Org.
Chem., 1997, 62(21), 7201-7204.
http://dx.doi.org/10.1021/jo971010u PMID: 11671828
[99] Cepanee, L.; Litvic, M.; Filipan-Litvic, M.; Grüngold, I. Antimo-
ny(III)chloride- catalyst Biginelli reaction a versatile method for the synthe-
sis of dihydropyrimidinone through a different reaction mechanism. Tetrahe-
dron, 2007, 63, 11822.
http://dx.doi.org/10.1016/j.tet.2007.09.045
[100] Schauble, J.H.; Trauffe, E.A.; Deshpande, P.P.; Evans, R.D. Trans Dialkoxy-
lation of cyclic alkenes: A Prévost-type reaction. Synthesis, 2005, 1333-1339.
http://dx.doi.org/10.1055/s-2005-865333
[101] Heravi, M.M.; Motamedi, R.; Seifi, N.; Bamoharram, F.F. 12-
Molybdophosphoric acid: A recyclable catalyst for the synthesis of Biginelli-
type 3,4-dihydropyrimidine-2(1H)-ones. J. Mol. Catal. Chem., 2007, 6, 373-
376.
[102] Abdel-latif, E.; Abdel-fattah, S.; Gaffer, H.; Etman, H. Synthesis and anti-
tumor activity of some pyrazolo[3,4-d] pyrimidine and pyrazolo[3,4-
b]pyridine derivatives, Egyptian. J. Basic Appl. Sci., 2016, 3, 118-124.
[103] Roy, S.R.; Jadhavar, P.S.; Seth, K.; Sharma, K.K.; Chakraborti, A.K. Or-
ganocatalytic appilication of ionic liquids [bmim][MeSO4] as a recyclable
organocatalyst in the multicomponent reaction for the preparation dihydropy-
rimidinones and thiones. Synthesis, 2011, 2261-2267.
[104] Brown, A.M.; Kunze, D.L.; Yatani, A. The agonist effect of dihydro-
pyridines on Ca channels. Nature, 1984, 311(5986), 570-572.
http://dx.doi.org/10.1038/311570a0 PMID: 6207438
[105] Colović, M.B.; Krstić, D.Z.; Lazarević-Pašti, T.D.; Bondžić, A.M.; Vasić,
V.M. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr.
Neuropharmacol., 2013, 11(3), 315-335.
http://dx.doi.org/10.2174/1570159X11311030006 PMID: 24179466
[106] Inglis, F. The tolerability and safety of cholinesterase inhibitors in the treat-
ment of dementia. Int. J. Clin. Pract. Suppl., 2002, (127), 45-63.
PMID: 12139367
[107] Arun, S.; Khamkaew, A. Anan, A. Nuttapon, A. Suksamrarn, V. Ajavakom,
Novel racemic tetrahydrocur cuminoid dihydropyrimidinone analogues as
potent acetylcholinesterase inhibitors. Bioorg. Med. Chem. Lett., 2013, 23,
2880-2882.
http://dx.doi.org/10.1016/j.bmcl.2013.03.069 PMID: 23583510
[108] Barbosa, F.A.R.; Canto, R.F.S.; Saba, S.; Rafique, J.; Braga, A.L. Synthesis
and evaluation of dihydropyrimidinone-derived selenoesters as multi-
targeted directed compounds against Alzheimer’s disease. Bioorg. Med.
Chem., 2016, 24(22), 5762-5770.
http://dx.doi.org/10.1016/j.bmc.2016.09.031 PMID: 27681239
[109] Canto, R.F.S.; Barbosa, F.A.; Nascimento, V.; de Oliveira, A.S.; Brighente,
I.M.; Braga, A.L. Design, synthesis and evaluation of seleno-
dihydropyrimidinones as potential multi-targeted therapeutics for Alz-
heimer’s disease. Org. Biomol. Chem., 2014, 12(21), 3470-3477.
http://dx.doi.org/10.1039/C4OB00598H PMID: 24752799
[110] Luthin, D.R. Anti-obesity effects of small molecule melanin-concentrating
hormone receptor 1 (MCHR1) antagonists. Life Sci., 2007, 81(6), 423-440.
http://dx.doi.org/10.1016/j.lfs.2007.05.029 PMID: 17655875
[111] Hervieu, G. Melanin-concentrating hormone functions in the nervous system:
food intake and stress. Expert Opin. Ther. Targets, 2003, 7(4), 495-511.
http://dx.doi.org/10.1517/14728222.7.4.495 PMID: 12885269
[112] Goss, J.M.; Schaus, S.E. Enantioselective synthesis of SNAP-7941: chiral
dihydropyrimidone inhibitor of MCH1-R. J. Org. Chem., 2008, 73(19),
7651-7656.
http://dx.doi.org/10.1021/jo801463j PMID: 18767801
[113] Jiang, Y.; Chen, C.A.; Lu, K.; Daniewska, I.; De Leon, J.; Kong, R.; Forray,
C.; Li, B.; Hegde, L.G.; Wolinsky, T.D.; Craig, D.A.; Wetzel, J.M.; Ander-
sen, K.; Marzabadi, M.R. Synthesis and SAR investigations for novel mela-
nin-concentrating hormone 1 receptor (MCH1) antagonists Part 1. The dis-
covery of arylacetamides as viable replacements for the dihydropyrimidinone
moiety of an HTS hit. J. Med. Chem., 2007, 50(16), 3870-3882.
http://dx.doi.org/10.1021/jm060381c PMID: 17668921
[114] Morano, K.A. New tricks for an old dog: the evolving world of Hsp70. Ann.
N. Y. Acad. Sci., 2007, 1113(1), 1-14.
http://dx.doi.org/10.1196/annals.1391.018 PMID: 17513460
Current Organic Synthesis, 2021, Vol. 18, No. 0 23
[115] Luders, J.; Demand, J.; Hohfeld, J. The ubiquity-related BAG-1 provides a
link between the molecular chaperones. Hsc70/Hsp70 and the proteansome.
The Journal of Biological Chemistry, 275(7), 4613-7.
[116] Chaiang, A.N.; Valderramos, J-C.; Balachandran, R.; Chaovatiya, R.J.; Mead,
B.P.; Schneider, C.; Bell, J.; Michael, G.; Klein, M. Donna, Huryn, S.
Xiaojiang, Chen, W. Billy, Day, A. David, Fidock, Peter Wipf, L. Jeffrey, L.
Brodsky, Select pyrimidinones inhibit the propagation of the malaria parasite
plasmodium falciparum. Bioorg. Med. Chem., 2009, 17(4), 1527-1533.
http://dx.doi.org/10.1016/j.bmc.2009.01.024 PMID: 19195901
[117] Christine, M.; Wright, J. Raj, Chovatiya, E. Jameson, M. David, Turner,
Guangyu Zhu, Stefan Werner, M, Donna, Hurny, M. James, Pipas, W. Billy,
W. Day, Peter Wipfb, L. Jeffrey, L. Brodsky, Pyrimidinone-peptoid hybrid
molecule with distinct effects on molecular chaperone function and cell pro-
liferation. Bioorg. Med. Chem., 2008, 16, 3291-3301.
[118] Vale, R.D. The molecular motor toolbox for intracellular transport. Cell,
2003, 112(4), 467-480.
http://dx.doi.org/10.1016/S0092-8674(03)00111-9 PMID: 12600311
[119] Goshima, G.; Vale, R.D. Cell cycle-dependent dynamics and regulation of
mitotic kinesins in Drosophila S2 cells. Mol. Biol. Cell, 2005, 16(8), 3896-
3907.
http://dx.doi.org/10.1091/mbc.e05-02-0118 PMID: 15958489
[120] Gerson-Gurwitz, A.; Thiede, C.; Movshovich, N.; Fridman, V.; Podolskaya,
M.; Danieli, T.; Lakämper, S.; Klopfenstein, D.R.; Schmidt, C.F.; Gheber, L.
Directionality of individual kinesin-5 Cin8 motors is modulated by loop 8,
ionic strength and microtubule geometry. EMBO J., 2011, 30(24), 4942-4954.
http://dx.doi.org/10.1038/emboj.2011.403 PMID: 22101328
[121] Klein, E.; DeBonis, S.; Thiede, B.; Skoufias, D.A.; Kozielski, F.; Lebeau, L.
New chemical tools for investigating human mitotic kinesin Eg5. Bioorg.
Med. Chem., 2007, 15(19), 6474-6488.
http://dx.doi.org/10.1016/j.bmc.2007.06.016 PMID: 17587586
[122] Bose, D. S.; Kumar, R. K.; Fatima, L. A remarkable rate acceleration of the
one-pot three-component cyclocondensation reaction at room temperature:
An expedient synthesis of mitotic kinesin Eg5 inhibitor monastrol Synlett,
2004, 2, 0279-0282.
[123] Chang, M.H. Hepatitis B virus infection. Semin. Fetal Neonatal Med., 2007,
12(3), 160-167.
http://dx.doi.org/10.1016/j.siny.2007.01.013 PMID: 17336170
[124] Glebe, D.; Urban, S. Viral and cellular determinants involved in hepadnaviral
entry. World J. Gastroenterol., 2007, 13(1), 22-38.
http://dx.doi.org/10.3748/wjg.v13.i1.22 PMID: 17206752
[125] Zhu, X.; Zhao, G.; Zhou, X.; Xu, X.; Xia, G.; Zheng, Z.; Wang, L.; Yang, X.;
Li, S. 2,4-Diaryl-4,6,7,8-tetrahydroquinazolin-5(1H)-one derivatives as anti-
HBV agents targeting at capsid assembly. Bioorg. Med. Chem. Lett., 2010,
20(1), 299-301.
http://dx.doi.org/10.1016/j.bmcl.2009.10.119 PMID: 19897363
[126] Hawn, T.R.; Day, T.A.; Scriba, T.J.; Hatherill, M.; Hanekom, W.A.; Evans,
T.G.; Churchyard, G.J.; Kublin, J.G.; Bekker, L.G.; Self, S.G. Tuberculosis
vaccines and prevention of infection. Microbiol. Mol. Biol. Rev., 2014, 78(4),
650-671.
http://dx.doi.org/10.1128/MMBR.00021-14 PMID: 25428938
[127] Nobel Foundation, the Noble prize in physiology or medicine 1905 archived,
Wayback Machine. 2006.
[128] Singh, K.; Singh, K.; Wan, B.; Franzblau, S.; Chibale, K.; Balzarini, J. Facile
transformation of Biginelli pyrimidin-2(1H)-ones to pyrimidines. In vitro
evaluation as inhibitors of Mycobacterium tuberculosis and modulators of
cytostatic activity. Eur. J. Med. Chem., 2011, 46(6), 2290-2294.
http://dx.doi.org/10.1016/j.ejmech.2011.03.010 PMID: 21450375
[129] Sankar, C.; Pandiarajan, K. Synthesis and anti-tubercular and antimicrobial
activities of some 2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-one N-
isonicotinoylhydrazone derivatives. Eur. J. Med. Chem., 2010, 45(11), 5480-
5485.
http://dx.doi.org/10.1016/j.ejmech.2010.08.024 PMID: 20822833
[130] Trivedi, A.R.; Bhuva, V.R.; Dholariya, B.H.; Dodiya, D.K.; Kataria, V.B.;
Shah, V.H. Novel dihydropyrimidines as a potential new class of antituber-
cular agents. Bioorg. Med. Chem. Lett., 2010, 20(20), 6100-6102.
http://dx.doi.org/10.1016/j.bmcl.2010.08.046 PMID: 20813528
[131] Geijselaers, S.L.C.; Sep, S.J.S.; Claessens, D.; Schram, M.T.; van Boxtel,
M.P.J.; Henry, R.M.A.; Verhey, F.R.J.; Kroon, A.A.; Dagnelie, P.C.;
Schalkwijk, C.G.; van der Kallen, C.J.H.; Biessels, G.J.; Stehouwer, C.D.A.
The role of hyperglycaemia. Insulin resistance and blood pressure in diabe-
tes-associated difference in cognitive performance-the Maastricht study. Di-
abetes Care, 2017, 40(11), 1537-1547.
http://dx.doi.org/10.2337/dc17-0330 PMID: 28842522
[132] Umpierrez, G.E.; Pasquel, F.J. Management of inpatient hyperglcemia and
diabetes in older adults. Diabetes Care, 2017, 40(4), 509-517.
http://dx.doi.org/10.2337/dc16-0989 PMID: 28325798
[133] Walls, Ron John J, Ratey, Robert, Simon, Rosen’s emergency medicine
expert consult premium edition-enhanced online feature and print (Rosen’s
emergency medicine: Concepts & Clinical practice.
[134] Dhumaskar, K.L.; Meena, S.N.; Ghadi, S.C.; Tilve, S.G. Graphite catalyzed
solvent free synthesis of dihydropyrimidin-2(1H)-ones/thiones and their an-
tidiabetic activity. Bioorg. Med. Chem. Lett., 2014, 24(13), 2897-2899.
http://dx.doi.org/10.1016/j.bmcl.2014.04.099 PMID: 24835627
 24 Current Organic Synthesis, 2021, Vol. 18, No. 0
[135] Wang, Z.; Peng, S.; Peng, M.; Wang, C. Isolation of polyphenol compounds
from olive waste and inhibition of their derivatives for α-Glucosidase and α-
amylase. Nat. Prod. Res., 2019, 1-5.
PMID: 30600709
[136] Kingston, W. Irish contributions to the origins of antibiotics. Ir. J. Med. Sci.,
2008, 177(2), 87-92.
http://dx.doi.org/10.1007/s11845-008-0139-x PMID: 18347757
[137] Tanwar, J.; Das, S.; Fatima, Z.; Hameed, S. Multidrug resistance: an emerg-
ing crisis. Interdiscip. Perspect. Infect. Dis., 2014, 2014, 541340.
http://dx.doi.org/10.1155/2014/541340 PMID: 25140175
[138] Ashok, M.; Holla, B.S.; Kumari, N.S. Convenient one pot synthesis of some
novel derivatives of thiazolo[2,3-b]dihydropyrimidinone possessing 4-
methylthiophenyl moiety and evaluation of their antibacterial and antifungal
activities. Eur. J. Med. Chem., 2007, 42(3), 380-385.
http://dx.doi.org/10.1016/j.ejmech.2006.09.003 PMID: 17070617
[139] Lal, J.; Gupta, S.K. D. Thavaselvam D, D, Agarwal, Design, Synthesis,
Synergistic antimicrobial activity and cytotoxicity of 4-aryl substituted 3,4-
dihydropyrimidinone of curcumin. Bioorg. Med. Chem. Lett., 2012, 22(8),
2872-2876.
http://dx.doi.org/10.1016/j.bmcl.2012.02.056 PMID: 22440624
[140] Attri, P.; Bhatia, R.; Gaur, J.; Arora, B.; Gupta, A.; Kumar, N.; Choi, E.H.
Triethylammonium actetate ionic liquid assisted one-pot synthesis of dihy-
dropyrimidinones and evaluation of their antioxidant and antibacterial activi-
ties. Arab. J. Chem., 2017, 10(2), 206-214.
http://dx.doi.org/10.1016/j.arabjc.2014.05.007
[141] Brands, M.; Endermann, R.; Gahlmann, R.; Krüger, J.; Raddatz, S. Dihydro-
pyrimidinones--a new class of anti-staphylococcal antibiotics. Bioorg. Med.
Chem. Lett., 2003, 13(2), 241-245.
http://dx.doi.org/10.1016/S0960-894X(02)00880-6 PMID: 12482431
[142] Soliman, A.M.; Mohamed, S.K.; El-Remally, M.A.E.A.A.A.; Abdel-Ghany,
H. Synthesis of pyrimidine, dihydropyrimidinone and dihydroimdazole de-
rivatives under free solvent condition and their antibacterial evaluation. J.
Heterocycl. Chem., 2014, 51(4), 1202-1209.
http://dx.doi.org/10.1002/jhet.1657
[143] Bhuiyan, M.H.; Nessa, H.; Mahmud, M.M. Multicomponent reaction: Mi-
crowave-assisted efficient synthesis of dihydropyrimidinones (thiones) and
quinazolinones under green chemistry protocol as probes for antimicrobial
activities. Jr. Sci. Research., 2012, 4(1), 143-153.
http://dx.doi.org/10.3329/jsr.v4i1.8688
[144] Tale, R.H.; Rodge, A.H.; Hatnapure, G.D.; Keche, A.P. The novel 3,4-
dihydropyrimidin-2(1H)-one urea derivatives of N-aryl urea: synthesis, anti-
inflammatory, antibacterial and antifungal activity evaluation. Bioorg. Med.
Chem. Lett., 2011, 21(15), 4648-4651.
http://dx.doi.org/10.1016/j.bmcl.2011.03.062 PMID: 21737269
[145] Anand, P.; Kunnumakkara, A.B.; Sundaram, C.; Harikumar, K.B.; Tharakan,
S.T.; Lai, O.S.; Sung, B.; Aggarwal, B.B. Cancer is a preventable disease
that requires major lifestyle changes. Pharm. Res., 2008, 25(9), 2097-2116.
http://dx.doi.org/10.1007/s11095-008-9661-9 PMID: 18626751
[146] Hayden, E.C. Cutting off cancer’s supply lines. Nature, 2009, 458(7239),
686-687.
http://dx.doi.org/10.1038/458686b PMID: 19360048
[147] Bagri, A.; Kouros-Mehr, H.; Leong, K.G.; Plowman, G.D. Use of anti-VEGF
adjuvant therapy in cancer: challenges and rationale. Trends Mol. Med., 2010,
16(3), 122-132.
http://dx.doi.org/10.1016/j.molmed.2010.01.004 PMID: 20189876
[148] Mostafa, A.S.; Selim, K.B. Synthesis and anticancer activity of new dihydro-
pyrimidinone derivatives. Eur. J. Med. Chem., 2018, 156, 304-315.
http://dx.doi.org/10.1016/j.ejmech.2018.07.004 PMID: 30015070
[149] Soumyanarayanan, U.; Bhat, V.G.; Kar, S.S.; Mathew, J.A. Monastrol mimic
Biginelli dihydropyrimidinone derivatives: synthesis, cytotoxicity screening
against HepG2 and HeLa cell lines and molecular modeling study. Org. Med.
Chem. Lett., 2012, 2(1), 23.
http://dx.doi.org/10.1186/2191-2858-2-23 PMID: 22691177
[150] Nadjm, B.; Behrens, R.H. Malaria: an update for physicians. Infect. Dis. Clin.
North Am., 2012, 26(2), 243-259.
http://dx.doi.org/10.1016/j.idc.2012.03.010 PMID: 22632637
[151] Chernin, E. Patrick Manson (1844-1922) and the transmission of filariasis.
Am. J. Trop. Med. Hyg., 1977, 26(5 Pt 2)(Suppl.), 1065-1070.
http://dx.doi.org/10.4269/ajtmh.1977.26.1065 PMID: 20786
[152] Rogerio, K.R.; Carvalho, L.J.M.; Domingues, L.H.P.; Neves, B.J.; Moreira
Filho, J.T.; Castro, R.N.; Bianco Júnior, C.; Daniel-Ribeiro, C.T.; Andrade,
C.H.; Graebin, C.S. Synthesis and molecular modelling studies of pyrimidi-
nones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial com-
pounds. Mem. Inst. Oswaldo Cruz, 2018, 113(8), e170452.
http://dx.doi.org/10.1590/0074-02760170452 PMID: 29924131
[153] Radini, I.A.; Elsheikh, T.M.; El-Telbani, E.M.; Khidre, R.E. New potential
antimalarial agents: Design, synthesis and biological evaluation of some
View publication stats
Khasimbi et al.
novel quinoline derivatives as antimalarial agents. Molecules, 2016, 21(7),
909.
http://dx.doi.org/10.3390/molecules21070909 PMID: 27428939
[154] de Araujo Furtado, M.; Rossetti, F.; Chanda, S.; Yourick, D. Exposure to
nerve agents: from status epilepticus to neuroinflammation, brain damage,
neurogenesis and epilepsy. Neurotoxicology, 2012, 33(6), 1476-1490.
http://dx.doi.org/10.1016/j.neuro.2012.09.001 PMID: 23000013
[155] Lewis, R.W.; Mabry, J.; Polisar, J.G.; Eagen, K.P.; Ganem, B.; Hess, G.P.
Dihydropyrimidinone positive modulation of δ-subunit-containing gamma-
aminobutyric acid type A receptors, including an epilepsy-linked mutant var-
iant. Biochemistry, 2010, 49(23), 4841-4851.
http://dx.doi.org/10.1021/bi100119t PMID: 20450160
[156] Trelle, S.; Reichenbach, W.; Simon, H. pius, Tschannen, Beatrice, Villiger,
Peter, M. Egger, Matthias, Juni, Peter, Cardiovascular safety of non-steroidal
anti-inflammatory drugs: network meta-analysis. Br. Med. J. (Clin. Res. Ed.),
2011, 342, 7086.
http://dx.doi.org/10.1136/bmj.c7086
[157] Bhateware, A.; Jetti, S. R.; Kadre, T.; Paliwal, P.; Jain, S. Microwave-
assisted synthesis and biological evaluation of dihydropyrimidinone deriva-
tives as anti-inflammatory, antibacterial and antifungal agents International
Jr. Med. Chem., 2013, 1-5.
[158] Mokale, S.N.; Shinde, S.S.; Elgire, R.D.; Sangshetti, J.N.; Shinde, D.B.
Synthesis and anti-inflammatory activity of some 3-(4,6-disubtituted-2-
thioxo-1,2,3,4-tetrahydropyrimidin-5-yl) propanoic acid derivatives. Bioorg.
Med. Chem. Lett., 2010, 20(15), 4424-4426.
http://dx.doi.org/10.1016/j.bmcl.2010.06.058 PMID: 20594837
[159] Viveka, S.; Dinesha, G.K. Nagaraja, P. Shama, G. Baavarajaswamy, K.P.
Rao, & M. Yanjarappa Sreenivasa, One pot synthesis of thiazolo[2,3-
b]dihydropyrimidinone possessing pyrazole moiety and evaluation of their
anti-inflammatory activities. Med. Chem. Res., 2017, 27(1), 171-185.
http://dx.doi.org/10.1007/s00044-017-2058-8
[160] Musini, V.M.; Tejani, A.M.; Bassett, K.; Wright, J.M. Pharmacotherapy for
hypertension in the elderly. Cochrane Database Syst. Rev., 2009, (4),
CD000028.
PMID: 19821263
[161] Hiren, M.; Maryvaniya, K. Palak, Parikh & Dhrubo Jyoti Sen, Synthesis and
in-vitro screening of 3,4-dihydropyrimidin-2(1H)-one derivatives for antihy-
pertensive and calcium channel blocking activity. 2011, 01(05), 109-113.
[162] Priya, N.; Singh, P.; Bhatia, S.; Medhi, B.; Prasad, A.K.; Parmar, V.S.; Raj,
H.G. Characterization of a unique dihydropyrimidinone, ethyl 4-(4′-
heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate,
as an effective antithrombotic agent in a rat experimental model. J. Pharm.
Pharmacol., 2011, 63(9), 1175-1185.
http://dx.doi.org/10.1111/j.2042-7158.2011.01316.x PMID: 21827490
[163] Mansouri, M.; Movahedian, A.; Rosrami, M.; Fassihi, A. Synthesis and
antioxidant evaluation of 4-(furan-2yl)-6-methyl-2thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate esters. 2012, 7(4), 257-264.
[164] Vijay Kotra, V. Venkata Rami Reddy, K. Sri Harika, B. Hari babu,
A.Jayashree & Ravi Varala, Synthesis of Novel 5-carboxynathanilide dihy-
dropyrimidinone derivatives and evaluation of their biological activities.
2014, 3(4), 915-921.
[165] Manos-Turvey, A.; Al-Ashtal, H.A.; Needham, P.G.; Hartline, C.B.; Prichard,
M.N.; Wipf, P.; Brodsky, J.L. Dihydropyrimidinones and -thiones with im-
proved activity against human polyomavirus family members. Bioorg. Med.
Chem. Lett., 2016, 26(20), 5087-5091.
http://dx.doi.org/10.1016/j.bmcl.2016.08.080 PMID: 27624078
[166] Bhat, M. A.; Naglah, M. A.; Kalmouch, A.; Al-Dhfyan, A. Synthesis and
characterization of novel Biginelli dihydropyrimidinones derivatives contain-
ing Imidazole moiety. Jr. Chem., 2019, 1-7.
[167] Kaur, A.; Pathak, D.P.; Sharma, V.; Wakode, S. Synthesis, biological evalua-
tion and docking study of a new series of di-substituted benzoxazole deriva-
tives as selective COX-2 inhibitors and anti-inflammatory agents. Bioorg.
Med. Chem., 2018, 26(4), 891-902.
http://dx.doi.org/10.1016/j.bmc.2018.01.007 PMID: 29373271
[168] Sarkar, K.; Khasimbi, S.; Mandal, S.; Dastidar, P. Rationally development
Metallogelators derivatives from Pyridyl deriva-tives of NSAIDs display an-
ti-inflammatory and anti-cancer activities. ACS Appl. Mater. Interfaces, 2018,
10(36), 30649-30661.
http://dx.doi.org/10.1021/acsami.8b09872 PMID: 30118200
[169] Kaur, A.; Wakode, S.R.; Pathak, D.P.; Shakya, A.K. Synthesis COX-2
inhibition, anti-inflammatory evaluation and docking study of substituted-N-
93,4,5-trimethoxypheny)-benzo[d]oxazole derivatives. Med. Chem., 2018, 14,
660-673.
http://dx.doi.org/10.2174/1573406414666180322091832 PMID: 29564981
[170] Dastidar, P.; Roy, R.; Parveen, P.; Sarkar, K. Supramolecular synthon ap-
proach in designing molecular gels for advanced therapeutics. Adv. Ther.,
2018, 1800061.