Medicinal Chemistry Research (2020) 29:538–548 MEDICINAL

https://doi.org/10.1007/s00044-020-02505-8
CHEMISTRY
RESEARCH
ORIGINAL RESEARCH

Design, synthesis, and characterization of novel substituted

1,2,4-oxadiazole and their biological broadcast
Paranjay H. Parikh1 Jignesh B. Timaniya1 Mrugesh J. Patel1 Kaushal P. Patel1
● ● ●

Received: 30 August 2019 / Accepted: 8 January 2020 / Published online: 18 January 2020
© Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
In the current study, a novel combinatorial library of substituted 1,2,4-oxadiazoles bearing pyridine and thiazole have been
synthesized via the condensation reaction of amidoxime and carboxylic acids and its derivatives in two way. The titled
compounds were screened for their in vitro antimicrobial activity against three gram positive bacteria and three gram
negative bacteria, In vitro antituberculosis activity against Mycobacterium tuberculosis H37RV and in vitro antimalarial
activity against Plasmodium falciparum. Majority of the compounds were found to be active against gram positive bacteria.
Compounds 6e, 6f, 7e, and 7f elaborate moderate antituberculosis activity against the first-line drug while 6c, 6d, 7c, and 7d
1234567890();,:
1234567890();,:

intricate excellent antimalarial activity against Plasmodium falciparum strain.

Keywords Oxadiazole Pyridine Thiazole Plasmodium falciparum Mycobacterium tuberculosis
● ● ● ●

Introduction is also a major infectious disease affected by Mycobacter-

Malaria remains one of the most vital infectious diseases
around the equator, particularly many parts of Americas,
Asia, and much of the Africa also; however, 85–90%
malaria fatalities occur in sub-Saharan Africa. Plasmodium
falciparum, the most dangerous malarial parasite, is
accountable for about 1 million deaths every year, accord-
ing to the World Health Organization latest report million
documented cases of malaria were reported (The Malaria
Eradication Research Agenda Group 2011; WHO 2018).
During the past few decade research to control the malaria
infection has been carried by various prevalent countries,
donors and global malaria partners gave us strengthened to
control malaria around the world (Karunamoorthi 2014).
Various infectious diseases are influencing the world
through their morbidity and mortality in which tuberculosis
Supplementary information The online version of this article (https://
doi.org/10.1007/s00044-020-02505-8) contains supplementary
material, which is available to authorized users.
* Kaushal P. Patel
kaus_chem@yahoo.com
1 2017; Singh and Chouhan 2014). Oxadiazole have occupied
Department of Advanced Organic Chemistry, P. D. Patel Institute
of Applied Sciences, Charotar University of Science and
Technology, Gujarat 388421, India
ium tuberculosis. Main cause of revival of tuberculosis is
the existence of multidrug-resistant M. tuberculosis strains
(Palomino and Martin 2014). WHO recent survey revealed
that still all do not have the MDR-TB facilely with them.
They also declare TB to be the ‘global emergency’ and
more than 30 million people will be effected by myco-
bacteria in the next 20 years (Sandhu 2011; WHO 2011).
The usually accessible drugs are not sufficient to treat the
Multidrug-resistant TB and extensively drug-resistant TB
(London et al. 2016; Patel et al. 2012). That’s need to
developed the new drugs which has divergent and unique
structure and with a mechanism of action possibly different
from that of existing drugs. In this regard, it was thought
that it is worth design and synthesizing various novel
compounds which may have combined applications as
antimalarial, antituberculosis and antimicrobial agents
(Dramowski et al. 2012).
Oxadiazoles and their derivatives can be considered as
simple five membered heterocycles possessing one oxygen
and two nitrogen atoms. The oxadiazoles exist in different
isomeric forms such as 1,2,4-, 1,2,5-, 1,2,3-, and 1,3,4-
oxadiazoles (Hemming 2001). 1,2,4-, 1,2,5-, and 1,3,4-
oxadiazoles are known but 1,2,3-isomer is quit unstable and
reserve back to the diazoketone tautomer (Salahuddin et al.
unique place in the field of bioorganic and pharmaceutical
chemistry due to their diverse activity like anti-microbial
Medicinal Chemistry Research (2020) 29:538–548
(Bakht et al. 2010; Desai et al. 2013; Karakaya et al. 2019;
Madhu Sekhar et al. 2018; Malladi et al. 2014; Ningaiah
et al. 2014; Padmavathi et al. 2009; Patel et al. 2017; Rane
et al. 2013; Thakkar et al. 2017; Tresse et al. 2019; Zhou
et al. 2017), anti-inflammatory, antitubercular, analgesic,
anticonvulsant, anticancer, antifungal, herbicidal, and anti-
parkinson activities (Kumar et al. 2016; Palit et al. 2016).
The five-member heterocyclic compounds; particu-
larly1,2,4-oxadiazole have been successfully tested against
several diseases and therefore received special attention in
the field of chemistry due to their wide medicinal applica-
tions. Various 1,2,4-oxadiazoles have been found as
potential agonists for cortical muscarinic, benzodiazepine,
and 5-HT1D receptors, and as antagonists for histamine H3
receptors (O Bora et al. 2014). It was thought worthwhile to
incorporate above biological importance and heterocyclic
derivatives in one moiety to find the best biologically active
heterocycle. So, we planned to synthesized 1,2,4-oxadiazole
derivatives and examine their biological potency.
Results and discussion
Chemistry
Synthesis of 1,2,4-oxadiazole involves the condensation
between amidoxime and carboxylic acids and its derivatives
in two way. Coupling between the amidoximes with acti-
vated carboxylic acid derivatives such as acid chlorides,
fluorides, anhydrides, and esters to give 1,2,4-oxadiazole
derivatives or less reactive carboxylic acids in the presence
of some coupling reagents like DCC, EDC, HATU, PyBOP,
TBTU, etc. Other transition metal-catalyzed method include
the reaction of amidoximes with aryl halides in presence of
Pd-Catalyst or with aldehydes and subsequently oxidation
and many other methods also available to synthesize
Scheme 1 Synthesis of 3,5-disubstituted-1,2,4-oxadiazole 6a–f and 7a–f. (i) Et3N (2.0 eq., DCM, rt,4 h, (ii) Hydroxylamine (50% w/w in H2O),
Ethanol, reflux, overnight, and (iii) HATU (1.2 eq.), CH3CN, 150 °C, MW, 20 min
539
3,5-disubstituted 1,2,4-oxadiazoles. Scheme 1 shows the
general reaction conditions and method for the synthesized
the 1,2,4-oxadiazoles. First amide intermediate was pre-
pared from acid chloride and aniline to give intermediate
3a–b in excellent yield. Intermediate 3a–b were treated
with hydroxylamine to provide the required amidoxime
4a–b in good yields. The reaction of amidoxime with var-
ious aryl and alkyl acid in the presence of HATU gave 3,5-
disubstituted-1,2,4-oxadiazole 6a–f and 7a–f with good
yield.
Pharmacology
Antimicrobial activity
The minimal inhibitory concentration (MIC) of all the
synthesized compounds 3a–b, 4a–b, 6a–f, and 7a–f was
resolute by broth microdilution method according to
National Committee for Clinical Laboratory Standards
(NCCLS-2002). The antibacterial activity of all synthesized
compounds 3a–b, 4a–b, 6a–f, and 7a–f was screened for
activity on three Gram positive bacteria Bacillus subtilis
(MTCC 441), Clostridium tetani (MTCC 449) Strepto-
coccus pneumoniae (MTCC 1936) and three Gram negative
bacteria Escherichia coli (MTCC 443), Salmonella typhi
(MTCC 98), Vibrio cholerae (MTCC 3906) by using
ampicillin, norfloxacin and ciprofloxacin as the standard
antibacterial drugs. Antifungal activity was screened against
two fungal species Candida albicans (MTCC 3008) and
Aspergillus fumigatus (MTCC 227) where nystatin and
griseofulvin were used as the standard antifungal drugs. The
outcome of anti-microbial screening is summarized in
Tables 1 and 2.
Upon exploration of antimicrobial screening data (Table 3),
it has been observed that Compounds 3a–b and 4a–b are
less active against gram positive bacteria. While the
540 Medicinal Chemistry Research (2020) 29:538–548

Table 1 Synthesized of 3,5-disubstituted-1,2,4-oxadiazole 6a–f and 7a–f

Sr Sr
Substrates Yield Substrates Yield
No No

1 7

6a 7a

2 8

6b 7b

3 9

6c 7c

4 10

6d 7d

5 11

6e 7e

6 12

6f 7f

majority of the compounds showed excellent activity
against gram positive bacteria B. subtilis and C. tetani as
compared with ampicillin (MIC = 250 µg/mL). Com-
pounds 6a, 6b, and 7d against S. pneumoniae showed
identical potency as compared with ampicillin (MIC =
250 µg/mL). Whereas compounds 6c and 7a illustrated
the same activity against B. subtilis as compared with
norfloxacin (MIC = 100 µg/mL). Whereas in inhibiting
gram negative bacteria, the compounds 6a and 7e showed
gleaming activity i.e., 62.5 µg/mL against V. cholera as
Medicinal Chemistry Research (2020) 29:538–548 541

Table 2 In vitro antimicrobial

Compounds Gram positive bacteria Gram negative bacteria Fungi
activity (MIC, µg/mL) of all the
synthesized compounds 3a–b, S.P. B.S. C.T. E.C. S.T. V.C. C.A. A.F.
4a–b, 6a–f, 7a–f MTCC MTCC MTCC MTCC MTCC MTCC MTCC MTCC
1936 441 449 443 98 3906 227 3008

3a 200 500 500 250 250 200 >1000 >1000

3b 125 200 500 200 250 200 >1000 1000
4a 200 500 250 100 250 250 1000 500
4b 250 500 500 200 100 100 1000 500
6a 100 100 500 250 62.5 62.5 100 250
6b 200 100 200 250 100 200 500 200
6c 250 250 100 200 250 200 >1000 200
6d 100 250 125 250 200 200 250 250
6e 250 200 250 100 125 100 500 1000
6f 250 250 200 100 250 200 1000 500
7a 500 500 100 200 200 250 >1000 500
7b 250 500 200 125 250 200 >1000 200
7c 200 250 250 200 100 200 500 500
7d 100 100 200 62.5 100 200 1000 500
7e 125 200 200 200 200 62.5 500 200
7f 100 250 500 100 62.5 100 100 100
A 100 250 250 100 100 100 n.t.a n.t.
B 10 100 50 10 10 10 n.t. n.t.
C 25 50 100 25 25 25 n.t. n.t.
D n.t. n.t. n.t. n.t. n.t. n.t. 100 100
E n.t. n.t. n.t. n.t. n.t. n.t. 500 100
S.P. Streptococcus pneumoniae, B.S. Bacillus subtilis, C.T. Clostridium tetani, E.C. Escherichia coli, S.T.
Salmonella typhi, V.C. Vibrio cholerae, C.A. Candida albicans, A.F. Aspergillus fumigatus, MTCC
microbial type culture collection, A Ampicillin, B Norfloxacin, C Chloramphenicol, D Ciprofloxacin,
E Nystatin, F Griseofulvin
a
n.t. not tested

Table 3 In vitro antituberculosis

Compound % Inhibition Compound % Inhibition
activity (% inhibition) of
compounds 3a–b, 4a–b, 6a–f, 250 µg/mL 100 µg/mL 250 µg/mL 100 µg/mL
and 7a–f against M. tuberculosis
H37Rv (at concentration 3a 16 14 6f 95 92
250 µg/mL and 100 µg/mL) 3b 24 17 7a 42 31
4a 11 5 7b 71 61
4b 36 47 7c 36 25
6a 88 77 7d 78 68
6b 20 17 7e 84 77
6c 74 24 7f 96 91
6d 66 54 Rifampicin 98 98
6e 92 92 Isoniazid 99 99

compared with ampicillin (MIC = 100 µg/mL). Com-
pounds 6a and 7f illustrate excellent activity i.e., 62.5 µg/
mL against Salmonella typhi as well as Compound 7d
showed brilliant activity against E. Coli as compared with
ampicillin (MIC = 100 µg/mL). Compounds 4a, 6e, 6f
and 7f against E. coli showed equal activity as compared
with ampicillin (MIC = 100 µg/mL), while against S.
typhi Compounds 4a, 6b, 7c, and 7d well as compounds
4b and 7f against V. cholerae showed the same potency
as compared with ampicillin (MIC = 250 µg/mL).
542 Medicinal Chemistry Research (2020) 29:538–548

Antifungal activity Table 4 In vitro antimalarial activity of compounds 6a–f and 7a–f
Compound IC50 (µg/mL) Compound IC50 (µg/mL)
The fallout of antifungal study (Table 2) of all the synthesized
3a 1.55 6f 0.198
compounds 3a–b, 4a–b, 6a–f, and 7a–f revealed that all the
compounds have poor activity against A. fumigates, except 3b 1.36 7a 1.54
only one compound 6f which shows the same potency as 4a 1.88 7b 0.97
compared with Griseofulvin and Nystatin i.e., 100 µg/mL. 4b 1.47 7c 0.082
Whereas in dissimilarity with standard fungicidal griseofulvin 6a 0.42 7d 0.096
(MIC = 500 µg/mL), compounds 4b, 6d, and 7f have a say 6b 0.78 7e 0.38
luminous antifungal activity i.e., 100 µg/mL, 250 µg/mL, 6c 0.054 7f 0.47
100 µg/mL against C. albicans. Whereas compounds 6b, 7c, 6d 0.322 Quinine 0.268
and 7e showed the same effect as that of griseofulvin i.e., 6e 0.57 Chloroquine 0.020
500 µg/mL against C. albicans. Other all compounds have
frail antifungal activity than nystatin and griseofulvin.
These compounds elaborate major activity against P. fal-
Antituberculosis activity ciparum strain as compared with quinine IC50 0.268 µg/mL.
Whereas compound 6d was found to possesses sensible
All the synthesized targets 3a–b, 4a–b, 6a–f, and 7a–f were activity i.e., IC50 0.322 µg/mL aligned with chloroquine. All
evaluated for their in vitro antituberculosis activity against other compounds were found to be not as much active as
Mycobacterium tuberculosis H37Rv strain. Primary chloroquine and quinine against P. falciparum strain.
screening of all the newly synthesized compounds 3a–b,
4a–b, 6a–f, and 7a–f was carried out at 100 and 250 µg/mL Structural activity relationship (SAR)
by using Lowenstein–Jensen medium as described by Rat-
tan (Rattan 2000). Isoniazid and Rifampicin were used as The outcome of biological assessment revealed that the
standard drugs. The results of antituberculosis screening activity was meaningfully affected by replacement of various
data are present in Table 3. functional groups at R position in oxadiazole ring. cyclo-
In the present study of screening, compound 6e exhibit propyl group was increased antibacterial activity against S.
better activity and showed 95% inhibition at 250 µg/mL typhi and V. cholera. While moderate active against S.
concentration and 92% inhibition at 100 µg/mL concentra- pneumonia and B.subtilis. and very less active against E. Coli.
tion. Compound 6f found to acquire outstanding activity at While methyl group was increased antibacterial activity
both the concentrations i.e., 92% at 250 and 100 µg/mL. against almost all gram positive bacteria but in case of gram
While compounds 7e and 7f were found to possesses great negative bacteria importance of methyl group is poor. Tert-
potency i.e., 96% inhibition at 250 µg/mL concentration and butyl group was inhibited potent antibacterial activity against
91% inhibition at 100 µg/mL concentration against M. gram positive bacteria M. tuberculosis H37Rv strain B.subtilis
tuberculosis H37Rv. While compounds 6c and 7e were and C. tetani as well as repressed strong antituberculosis
found reasonably active against M. tuberculosis H37Rv. activity against M. tuberculosis H37Rv strain and moderate
Remaining all compounds showed deprived inhibition of M. antimalarial activity Phenyl group having different sub-
tuberculosis growth. From the above results, it can be stituents i.e., nitro group, cyano group and methoxy group
accomplished that, compounds 6e and 7f may turn into an present at fourth position on phenyl ring responsible for
innovative class of antitubercular agents in the future. antimalarial activity compete against P. falciparum strain as
compared with quinine and chloroquine.
Antimalarial activity Phenyl group particularly chloro and iodo enhance the
antibacterial activity against all three gram positive bacteria but
All new oxadiazole derivatives 3a–b, 4a–b, 6a–f, and 7a–f very less active against gram negative bacteria. While phenyl
were tested for their antimalarial activity against P. falci- group having methoxy group at fourth position responsible for
parum strain. The obtained results are presented in Table 4. good antibacterial activity against gram negative bacteria S.
Quinine and Chloroquine were used as the reference stan- typhi. While thiazole ring attached to amide bond responsible
dard drugs. The results of the pharmacological screening are for increased antibacterial activity against S. pneumonia, C.
articulated as the drug concentration resulting in 50% tetani and B. subtilis but not as much active against gram
inhibition (IC50) of parasite growth. negative bacteria and pyridine ring attached to amide bond
The compounds 6c, 7c, and 7d were originated to have responsible for increased antibacterial activity against S.
IC50 in the array of 0.032 to 0.096 µg/mL upon P. falci- pneumoniae and B. subtilis and increased antibacterial activity
parum strain as compared with quinine and chloroquine. against C. tetani and B. subtilis, respectively (Fig. 1).
Medicinal Chemistry Research (2020) 29:538–548
Fig. 1 Structural activity relationship (SAR)
Material and methods
All the reagents were used without further purification and
were obtained commercially. Thin-layer chromatography
(TLC, on aluminium plates coated with silica gel 60 F254,
0.25 mm thickness, Merck) was used for monitoring the
progress of all reactions. Solvents used were of analytical
grade. Mass and LCMS spectra were recorded on Shimadzu
LCMS 2010 spectrometer (Shimadzu, Tokyo, Japan). The
IR spectra were recorded on Shimadzu FTIR 8401 spectro-
photometer using potassium bromide pellets in the range
4000–400 cm−1 and frequencies of only characteristic peaks
are expressed in cm−1. The elemental analysis was done by
using PerkinElmer 2400 series-II elemental analyzer (Per-
kinElmer, USA) and all compounds are originated within ±
0.4% of the theoretical compositions. 1H-NMR and 13C-
NMR spectra were recorded in DMSO-d6 on a Bruker
Advance 400 (MHz), 500 (MHz) spectrometer using sol-
vent peak as an internal standard at 400, 500 and 101,
126 MHz, respectively. Chemical shifts are reported in parts
per million (ppm). Melting points were recorded in melting
point apparatus µThermoCal10 (Analab Scientific Pvt. Ltd,
India) and are uncorrected.
Experimental procedure
General procedure for Synthesis of N-(3-chloro-4-
cyanophenyl)thiophene-2-carboxamide (3a) and
N-(3-chloro-4-cyanophenyl)nicotinamide (3b)
4-amino-2-chlorobenzonitrile (0.8 g, 5.2 mmol) was dis-
solved in dichloromethane (20 mL), and the mixture was
543
stirred at room temperature for 2 h followed by addition of
2-Thiophenecarbonyl chloride or nicotinoyl chloride
hydrochloride (5.7 mmol) and triethylamine (1.4 mL,
10.4 mmol). On completion, Mixture was added to aqueous
sodium bicarbonate solution, and the mixture was extracted
with (30 mL) chloroform. The organic layer was washed
with saturated brine and dried over anhydrous magnesium
sulfate. The residue obtained upon concentration under
reduced pressure was purified by silica gel column chro-
matography using the solvent system of Ethyl acetate:
n-Hexane (2:3) to give the desired compound.
N-(3-Chloro-4-cyanophenyl)thiophene-2-carboxamide (3a)
Pale yellow solid (MeOH) (This compound was prepared by
the general procedure mentioned for the synthesis of com-
pound 3a & 3b); Yield = 78%; mp 212–214 °C; IR (KBr)
νmax 1620 (amide, C=O), 3150–3290 (NH), 2240 (CN)
(cm−1); 1H NMR (DMSO-d6, 500 MHz): δ = 10.69 (s, 1H,
N-H), 8.16 (s, 1H, H-15), 8.05 (d, J = 3.63 Hz, 1H, H-13),
7.90–7.96 (m, 2H, H-10, 6), 7.83–7.89 (m, 1H, H-7), 7.26 (t,
J = 4.41 Hz, 1H, H-14); 13C NMR (DMSO-d6, 126 MHz):
δ = 160.5 (C-2), 144.2 (C-5), 138.7 (C-1), 135.8 (C-9), 135.1
(C-7), 133.2 (C-15), 130.4 (C-13), 128.3 (C-14), 119.9 (C-6),
118.5 (C-10), 116.2 (C-16), 105.7 (C-8); Anal. Calcd. for
C12H7ClN2OS (262.71): C, 54.86; H, 2.69; Cl, 13.49; N,
10.66; O, 6.09; S, 12.20; found C, 54.88; H, 2.64; N, 10.71.
N-(3-Chloro-4-cyanophenyl)nicotinamide (3b)
Pale yellow solid (MeOH) (This compound was prepared
by the general procedure mentioned for the synthesis of
Compound 3a & 3b); Yield = 67%; mp 222–224 °C; IR
544
(KBr) νmax: 1620 (amide, C=O), 3130–3280 (NH), 2230
(CN) (cm−1); 1H NMR (DMSO-d6, 400 MHz): δ = 10.94 (s,
1H, N-H), 9.08–9.16 (m, 1H, H-16), 8.80 (d, J = 5.09 Hz,
1H, H-14), 8.30 (d, J = 7.83 Hz, 1H, H-12), 8.15–8.22 (m,
1H, H-10), 7.97 (d, J = 8.61 Hz, 1H, H-13), 7.88 (d, J =
8.61 Hz, 1H, H-6), 7.60 (dd, J = 4.89, 8.02 Hz, 1H, H-7); 13C
NMR (DMSO-d6, 126 MHz): δ = 165.0 (C-2), 152.7 (C-14),
148.8 (C-16), 144.3 (C-5), 136.7 (C-9), 135.9 (C-12), 135.7
(C-7), 135.2 (C-1), 129.8;(C-13), 123.6 (C-6), 120.1 (C-10),
118.8 (C-17), 106.1 (C-8) Anal. Calcd for C13H8ClN3O
(257.67): C, 60.60; H, 3.13; Cl, 13.76; N, 16.31; O, 6.21;
found C, 60.56; H, 3.17; Cl, 13.71; N, 16.28; O, 6.24.
General procedure for Synthesis of N-(3-chloro-4-(N-
hydroxycarbamimidoyl)phenyl)thiophene-2-
carboxamide (4a) and N-(3-chloro-4-(N-
hydroxycarbamimidoyl)phenyl)nicotinamide (4b)
N-(3-chloro-4-cyanophenyl)thiophene-2-carboxamide
(0.9 g, 3.5 mmol) or N-(3-chloro-4-cyanophenyl)nicotina-
mide (0.9 g, 3.5 mmol) was suspended in ethanol (100 mL),
and the mixture was added to Hydroxylamine (20 mL, 50%
w/w in H2O) solution. The resulting mixture was refluxed
overnight. On completion of reaction, the solution was
allowed to cool down to room temperature and then up to
0 °C. The separated white crystals were filtered, washed
with cold ethanol and dried. (0.88 g, yield: 86%).
N-(3-chloro-4-(N-hydroxycarbamimidoyl)phenyl)thiophene-
2-carboxamide (4a)
Pale yellow solid (MeOH) (This compound was prepared
by the general procedure mentioned for the synthesis of
Compound 4a & 4b); Yield = 67%; mp: 228–230 °C; IR
(KBr) νmax: 1630 (amide, C=O), 3140–3260 (NH), 1640
(C = N) (cm−1); 1H NMR (DMSO-d6, 500 MHz): δ = 10.64
(s, 1H, O-H), 9.47 (s, 1H, N-H), 9.12 (s, 1H, H-6), 8.78 (d,
J = 4.15 Hz, 1H, H-4), 8.30 (d, J = 7.78 Hz, 1H, H-2), 7.98
(s, 1H, H-18), 7.71 (d, J = 8.82 Hz, 1H, H-15), 7.59 (dd, J
= 5.45, 7.53 Hz, 1H, H-3), 7.41 (d, J = 8.30 Hz, 1H, H-11),
5.80 (s, 1H, H-12); 13C NMR (DMSO-d6, 126 MHz): δ =
163.2 (C-7), 162.7 (C-16), 148.2 (C-6), 147.8 (C-4), 139.8
(C-8), 134.9 (C-2), 130.4 (C-1 and 14), 127.1 (C-12), 124.7
(C-3), 121.8 (C-15), 119.1 (C-11), 117.8 (C-13); Anal.
Calcd for C13H11ClN4O2 (290.70): C, 53.71; H, 3.81; Cl,
12.19; N, 19.27; O, 11.01 found: C, 53.73; H, 3.89; Cl,
12.39; N, 19.17; O, 10.88.
N-(3-chloro-4-(N-hydroxycarbamimidoyl)phenyl)
nicotinamide (4b)
Pale yellow solid (MeOH) (This compound was prepared
by the general procedure mentioned for the synthesis of
Medicinal Chemistry Research (2020) 29:538–548
Compound 4a & 4b); Yield = 71%; mp: 218–220 °C; IR
(KBr) νmax: 1625 (amide, C=O), 3160–3280 (NH),
1650 (C = N) (cm−1); 1H NMR (DMSO-d6, 500 MHz): δ
= 10.41 (s, 1H, O-H), 9.44 (s, 1H, N-H), 8.04 (d,
J = 3.63 Hz, 1H, H-19), 7.93 (s, 1H, H-12), 7.89 (d,
J = 4.67 Hz, 1H, H-17), 7.68 (d, J = 8.82 Hz, 1H, H-9),
7.40 (d, J = 8.30 Hz, 1H, H-5), 7.24 (t, J = 4.15 Hz, 1H,
H-6), 5.78 (s, 1H, H-18); 13C NMR (DMSO-d6,
126 MHz): δ = 160.1 (C-10), 150.3 (C-1), 140.1 (C-4),
139.4 (C-15), 132.5 (C-19), 132.1 (C-8), 131.3 (C-17),
129.6 (C-18), 128.7 (C-6), 128.2 (C-9), 120.4 (C-5),
118.2 (C-7); Anal. Calcd for C12H10ClN3O2S (295.74):
C, 48.74; H, 3.41; Cl, 11.99; N, 14.21; O, 10.82; S,
10.84; found: C, 48.79; H, 3.53; Cl, 12.12; N, 14.20; O,
10.89; S, 10.74.
General procedure for Synthesis of N-(3-chloro-4-(5-
aryl-1,2,4-oxadiazol-3-yl)phenyl)thiophene-2-
carboxamide (6a-f) and N-(3-chloro-4-(5-alkyl-1,2,4-
oxadiazol-3-yl)phenyl)nicotinamide (7a-f)
To a suspension of N-(3-chloro-4-(N-hydroxycarbamimidoyl)
phenyl)thiophene-2-carboxamide (150 mg, 0.5 mmol) or
N-(3-chloro-4-(N-hydroxycarbamimidoyl)phenyl)nicoti-
namide (145 mg, 0.5 mmol) and corresponding car-
boxylic acid (0.55 mmol) in acetonitrile (1.5 mL) was
added and the resulting mixture was heated under
microwave reactor at 150 °C for 20 min. The mixture was
cooled to room temperature, concentrated and residue
was purified by column chromatography (DCM: Acet-
one, 5–20%).
N-(3-Chloro-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)
thiophene-2-carboxamide (6a)
Yellow solid (MeOH) (This compound was prepared by
the general procedure mentioned for the synthesis of
Compound 6a–f); Yield = 73%; mp: 241–243 °C; IR
(KBr) νmax: 1660 (amide, C=O), 3120–3220 (NH)
(cm−1); 1H NMR (DMSO-d6, 400 MHz): δ = 10.57 (br.
s., 1H, NH), 8.12 (d, J = 1.56 Hz, 1H, Ar-H), 8.06 (d,
J = 3.91 Hz, 1H, Ar-H), 7.83–7.94 (m, 3H, Ar-H), 7.25
(t, J = 4.30 Hz, 1H, Ar-H), 2.35–2.46 (m, 1H, CH),
1.24–1.33 (m, 2H, CH2), 1.18 (td, J = 3.86, 7.53 Hz, 2H,
CH2); 13C NMR (DMSO-d6, 101 MHz): δ = 181.0 (C-
16), 166.0 (C-10), 160.3 (C-1), 142.0 (C-15), 139.1 (C-
4), 132.7 (C-7), 132.2 (C-8), 132.0 (C-20), 129.9 (C-22),
128.2 (C-21), 121.1 (C-6), 120.1 (C-9), 118.4 (C-5), 10.1
(C-17), 7.1 (C-18 and 19); LC-MS: m/z (pos): 346.21 [M +
H] + C16H12ClN3O2S (345.80); Anal. Calcd for
C16H12ClN3O2S: C, 55.57; H, 3.50; Cl, 10.25; N, 12.15; O,
9.25; S, 9.27; found: C, 55.66; H, 3.61; Cl, 10.35; N, 12.21;
O, 9.32; S, 9.32.
Medicinal Chemistry Research (2020) 29:538–548
N-(3-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)
thiophene-2-carboxamide (6b)
Yellow solid (MeOH) (This compound was prepared by the
general procedure mentioned for the synthesis of Com-
pound 6a–f); Yield = 79%; mp: 247–249 °C; IR (KBr)
νmax: 1665 (amide, C=O), 3160–3240 (NH) (cm−1). 1H
NMR (DMSO-d6, 500 MHz): δ = 10.58 (s, 1H, NH), 8.12
(s, 1H, H-18), 8.07 (s, 1H, H-9), 7.85 - 7.96 (m, 3H, H-5, 6,
20), 7.26 (s, 1H, H-19), 2.68 (s, 3H, –CH3); 13C NMR
(DMSO-d6, 126 MHz): δ = 176.6 (C-16), 166.1 (C-10),
160.3 (C-1), 142.0 (C-15), 139.1 (C-4), 132.8 (C-7), 132.2
(C-8), 132.0 (C-18), 129.9 (C-20), 128.2 (C-19), 121.2 (C-
6), 120.1 (C-9), 118.5 (C-5), 11.9 (C-17); LC-MS m/z
(pos): 320.20 [M + H] + C14H10ClN3O2S (calcd. 319.76);
Anal. Calcd for C14H10ClN3O2S: C, 52.59; H, 3.15; Cl,
11.09; N, 13.14; O, 10.01; S, 10.03; found: C, 52.63; H,
3.21; Cl, 11.13; N, 13.03; O, 9.91; S, 10.15.
N-(3-chloro-4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)
phenyl)thiophene-2-carboxamide (6c)
Yellow solid (This compound was prepared by the general
procedure mentioned for the synthesis of Compound 6a–f);
Yield = 80%; mp: 255–257 °C; IR (KBr) νmax: 1650
(amide, C=O), 3150–3240 (NH) (cm−1); 1H NMR
(DMSO-d6, 400 MHz): δ = 10.61 (s, 1H, NH), 8.83 (s, 1H,
H-18), 8.55 (d, J = 8.22 Hz, 1H, H-22), 8.58 (d, J =
7.82 Hz, 1H, H-23), 8.17 (d, J = 1.56 Hz, 1H, H-25),
8.06–8.11 (m, 2H, H-9,26), 7.96 (t, J = 8.02 Hz, 1H, H-
20), 7.90–7.94 (m, 2H, H-5,6), 7.26 (t, J = 4.30 Hz, 1H, H-
19); 13C NMR (DMSO-d6, 126 MHz): δ = 172.7 (C-16),
166.8 (C-110), 160.2 (C-1), 148.1 (C-24), 142.3 (C-15),
139.0 (C-4), 133.7 (C-7), 132.5 (C-8), 132.3 (C-18), 132.0
(C-22), 131.3 (C-26), 129.8 (C-17), 128.0 (C-20), 127.4
(C-6), 124.5 (C-19), 122.3 (C-23), 121.1 (C-25), 119.3 (C-
9), 118.3 (C-5); LC-MS m/z (pos): 427.36 [M + H] +
C19H11ClN4O4S (calcd. 426.83); Anal. Calcd for
C19H11ClN4O4S: C, 53.47; H, 2.60; Cl, 8.31; N, 13.13; O,
14.99; S, 7.51; found: C, 53.57; H, 2.65; Cl, 8.37; N,
13.19; O, 15.09; S, 7.64.
N-(3-chloro-4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)
phenyl)thiophene-2-carboxamide (6d)
Yellow solid (This compound was prepared by the general
procedure mentioned for the synthesis of Compound 6a–f);
Yield = 61%; mp: 251–253 °C; IR (KBr) νmax: 1640
(amide, C=O), 3160–3250 (NH) (cm−1); 1H NMR (DMSO-
d6, 500 MHz): δ = 10.71 (br. s., 1H, NH), 8.33 (d, J =
7.78 Hz, 2H, H-18, 19), 8.19 (s., 1H, H-20), 8.10–8.16 (m,
2H, H-26, 22), 8.05 (d, J = 8.30 Hz, 1H, H-6), 7.93 (s, 1H,
H-23), 7.96 (s, 1H, H-21), 7.26 (s., 1H, H-19); 13C NMR
545
(DMSO-d6, 126 MHz): δ = 173.3 (C-16), 167.0 (C-10),
160.4 (C-1), 142.4 (C-15), 139.1 (C-4), 133.5 (C-7), 132.8
(C-8), 132.3 (C-23), 132.2 (C-25), 130.1 (C-20), 128.7 (C-
19), 128.2 (C-26), 127.1 (C-22), 121.2 (C-17), 119.5 (C-9),
118.6 (C-5), 117.9 (CN), 115.4 (C-24); LC-MS m/z (pos):
407.09 [M + H] + C20H11ClN4O2S (calcd. 406.84); Anal.
Calcd for C20H11ClN4O2S: C, 59.04; H, 2.73; Cl, 8.71; N,
13.77; O, 7.86; S, 7.88; found: C, 58.79; H, 2.79; Cl, 8.86;
N, 13.92; O, 7.91; S, 7.63.
N-(4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)-3-chlorophenyl)
thiophene-2-carboxamide (6e)
Yellow solid (This compound was prepared by the general
procedure mentioned for the synthesis of Compound
6a–f); Yield = 63%; mp: 259–261 °C; IR (KBr) νmax:
1670 (amide, C=O), 3130–3210 (NH) (cm−1). 1H NMR
(DMSO-d6, 500 MHz): δ = 10.58 (br. s., 1H, NH), 8.15
(s, 1H, H-18), 8.07 (br. s., 1H, H-9), 7.85–7.99 (m, 3H, H-
5, 6, 20), 7.25 (s, 1H, H-19), 1.45 (s, 9H, 3CH3); 13C
NMR (DMSO-d6, 126 MHz): δ = 185.4 (C-16), 165.8 (C-
10), 160.3 (C-1), 142.0 (C-15), 139.1 (C-4), 132.7 (C-7),
132.2 (C-8), 132.0 (C-18), 129.9 (C-20), 128.2 (C-19),
121.2 (C-9), 120.1 (C-5), 118.5 (C-6), 33.2 (C-17), 27.9
(C-22, 23, 24); LC-MS m/z (pos): 362.26 [M + H] +
C17H16ClN3O2S (calcd. 361.84); Anal. Calcd for
C17H16ClN3O2S: C, 56.43; H, 4.46; Cl, 9.80; N, 11.61; O,
8.84; S, 8.86; found: C, 56.57; H, 4.62; Cl, 9.69; N, 11.65;
O, 8.83; S, 8.71.
N-(3-chloro-4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)
phenyl)thiophene-2-carboxamide (6f)
Yellow solid (This compound was prepared by the general
procedure mentioned for the synthesis of Compound 6a–f);
Yield = 59%; mp: 242–244 °C; IR (KBr) νmax: 1645
(amide, C=O), 3160–3250 (NH) (cm−1). 1H NMR (DMSO-
d6, 500 MHz): δ = 10.40 (br, s, 1H, NH), 8.75 (d, J =
4.15 Hz, 1H, H-18), 8.29 (d, J = 7.79 Hz, 1H, H-20), 8.10
−8.19 (m, J = 8.82 Hz, 2H, H-9, 22), 8.12 (s, 1H, H-26),
7.79 (d, J = 8.30 Hz, 1H, H-6), 7.60 (dd, J = 5.20, 7.30 Hz,
1H, H-5), 7.49 (d, J = 8.25 Hz, 1H, H-19), 7.00–7.06 (m,
J = 8.80 Hz, 1H, H-23), 6.91 (s., 1H, H-25), 3.76 (s, 3H,
OCH3); 13C NMR (DMSO-d6, 126 MHz): δ = 165.3 (C-
16), 162.0 (C-10), 161.9 (C-1), 157.7 (C-24), 155.3 (C-15),
149.6 (C-4), 139.9 (C-7), 136.4 (C-8), 133.2 (C-18), 130.5
(C-20), 129.3 (C-19), 128.0, (C-6), 127.8 (C-9), 125.4 (C-
5), 122.6 (C-17), 121.5 (C-22), 117.3 (C-26), 114.4 (C-23,
25), 55.9 (C-28); LC-MS m/z (pos): 412.56 [M + H] +
C20H14ClN3O3S (calcd. 411.86); Anal. Calcd for
C20H14ClN3O3S: C, 58.33; H, 3.43; Cl, 8.61; N, 10.20; O,
11.65; S, 7.78; found: C, 58.47; H, 3.33; Cl, 8.56; N, 10.20;
O, 11.66; S, 7.62.
546
N-(3-chloro-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)
nicotinamide (7a)
Yellow solid (This compound was prepared by the general
procedure mentioned for the synthesis of Compound 7a–f);
Yield = 57%; mp: 237–239 °C; IR (KBr) νmax: 1640
(amide, C=O), 3130–3260 (NH) (cm−1). 1H NMR (DMSO-
d6, 500 MHz): δ = 10.85 (s, 1H, NH), 9.14 (br. s., 1H, H-
20), 8.79 (br. s., 1H, H-18), 8.34 (d, J = 7.79 Hz, 1H, H-
16), 8.18 (s, 1H, H-9), 7.91 (s, 2H, H-6, 5), 7.61 (br. s., 1H,
H-17), 2.42 (br. s., 1H, H-22), 1.30 (d, J = 5.19 Hz, 2H, H-
23), 1.19 (s, 2H, H-24); 13C NMR (DMSO-d6, 126 MHz): δ
= 181.1 (C-21), 166.0 (C-10), 164.6 (C-1), 152.4 (C-20),
148.7 (C-18), 142.0 (C-4), 135.8 (C-16), 132.2 (C-7), 132.0
(C-8), 130.1 (C-15), 123.6 (C-6), 121.3 (C-17), 120.4 (C-9),
118.6 (C-5), 10.1 (C-22), 7.2 (C-23, 24); LC-MS m/z (pos):
341.26 [M + H] + C17H13ClN4O2 (calcd. 340.76); Anal.
Calcd for C17H13ClN4O2: C, 59.92; H, 3.85; Cl, 10.40; N,
16.44; O, 9.39; found: C, 60.01; H, 3.89; Cl, 10.49; N,
16.52; O, 9.27.
N-(3-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)
nicotinamide (7b)
Yellow solid (This compound was prepared by the general
procedure mentioned for the synthesis of Compound 7a–f);
Yield = 71%; mp: 271–273 °C; IR (KBr) νmax: 1650
(amide, C=O), 3150–3280 (NH) (cm−1). 1H NMR (DMSO-
d6, 500 MHz): δ = 10.81 (s, 1H, NH), 9.13 (s, 1H, H-20),
8.79 (d, J = 3.63 Hz, 1H, H-18), 8.32 (d, J = 8.30 Hz, 1H,
H-16), 8.17 (s, 1H, H-9), 7.89–7.99 (m, 2H, H-5, 6), 7.58 -
7.62 (m, 1H, H-17), 2.68 (s, 3H, H-22); 13C NMR (DMSO-
d6, 126 MHz): δ = 176.7 (C-21), 166.1 (C-10), 164.7 (C-1),
152.5 (C-18), 148.8 (C-20), 142.0 (C-4), 135.6 (C-16),
132.2 (C-7), 132.0 (C-8), 130.0 (C-15), 123.5 (C-6), 121.3
(C-17), 120.4 (C-9), 118.6 (C-5), 11.9 (C-22); LC-MS m/z
(pos): 315.21 [M + H] + C15H11ClN4O2 (calcd. 314.72);
Anal. Calcd for C15H11ClN4O2: C, 57.24; H, 3.52; Cl,
11.26; N, 17.80; O, 10.17; found: C, 57.16; H, 3.63; Cl,
11.16; N, 17.83; O, 10.23.
N-(3-chloro-4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)
phenyl)nicotinamide (7c)
Yellow solid (This compound was prepared by the general
procedure mentioned for the synthesis of Compound 7a–f);
Yield = 76%; mp: 260–262 °C; IR (KBr) νmax: 1640
(amide, C=O), 3160–3270 (NH) (cm−1). 1H NMR (DMSO-
d6, 400 MHz): δ = 10.85 (br. s., 1H, NH), 9.10–9.16 (m,
1H, H-20), 8.80 (d, J = 4.70 Hz, 1H, H-18), 8.44 (q, J =
9.00 Hz, 4H, H-23, 24, 26, 27), 8.32 (d, J = 7.82 Hz, 1H, H-
16), 8.20 (d, J = 1.96 Hz, 1H, H-9), 8.08 (d, J = 8.61 Hz,
1H, H-6), 7.92–8.00 (m, 1H, H-5), 7.60 (dd, J = 4.89,
Medicinal Chemistry Research (2020) 29:538–548
8.02 Hz, 1H, H-17); 13C NMR (DMSO-d6, 101 MHz): δ =
173.4 (C-21), 167.4 (C-10), 165.0 (C-1), 152.9 (C-20),
150.4 (C-18), 149.1 (C-4), 142.8 (C-16), 136.0 (C-7), 132.7
(C-8), 132.6 (C-15), 130.3 (C-23), 129.8 (C-27), 128.9 (C-
6), 125.0 (C-24), 123.9 (C-26), 121.7 (C-17), 120.1 (C-9),
119.0 (C-5); LC-MS m/z (neg): 420.41 [M-H]-
C20H12ClN5O4 (calcd. 421.79); Anal. Calcd for
C20H12ClN5O4: C, 56.95; H, 2.87; Cl, 8.40; N, 16.60; O,
15.17; found: C, 57.02; H, 2.93; Cl, 8.37; N, 16.50;
O, 15.18.
N-(3-chloro-4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)
phenyl)nicotinamide (7d)
Yellow solid (This compound was prepared by the general
procedure mentioned for the synthesis of Compound 7a–f);
Yield = 70%; mp: 241–243 °C; IR (KBr) νmax: 1630
(amide, C=O), 3180–3270 (NH) (cm−1). 1H NMR (DMSO-
d6, 500 MHz): δ = 10.31 (br, s, 1H, NH), 8.32 (d, J =
7.80 Hz, 2H, H-18, 20), 8.20 (s, 1H, 16), 8.06–8.14 (m, 3H,
H-9, 23, 27), 8.10 (d, J = 8.24 Hz, 1H, H-6), 7.95 (s, 1H, H-
24), 7.98 (s, 1H, H-26), 7.28 (s, 1H, H-17); 13C NMR
(DMSO-d6, 126 MHz): δ = 175.3 (C-21), 169.0 (C-10),
165.4 (C-1), 140.4 (C-18), 138.1 (C-20), 135.5 (C-4), 134.8
(C-16), 133.3 (C-7), 131.2 (C-8), 129.1 (C-15), 128.5 (C-22),
128.0 (C-23), 127.8 (C-27), 123.2 (C-17), 118.5 (C-9),
117.6 (C-5), 116.9 (CN), 114.4 (C-25); LC-MS m/z (pos):
402.26 [M + H] + C21H12ClN5O2 (calcd. 401.81); Anal.
Calcd for C21H12ClN5O2: C, 62.77; H, 3.01; Cl, 8.82; N,
17.43; O, 7.96; found: C, 62.87; H, 2.96; Cl, 8.81; N, 17.53;
O, 7.96%.
N-(4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)-3-chlorophenyl)
nicotinamide (7e)
Yellow solid (This compound was prepared by the general
procedure mentioned for the synthesis of Compound 7a–f);
Yield = 79%; mp: 252–254 °C; IR (KBr) νmax: 1680
(amide, C=O), 3130–3240 (NH) (cm−1). 1H NMR
(DMSO-d6, 400 MHz): δ = 10.91 (s, 1H, NH), 9.18 (d, J =
1.96 Hz, 1H, H-20), 8.83 (d, J = 3.52 Hz, 1H, H-18), 8.42
(d, J = 7.82 Hz, 1H, H-16), 8.20 (d, J = 1.96 Hz, 1H, H-9),
7.98 (d, J = 8.61 Hz, 1H, H-6), 7.91–7.95 (m, 1H, H-17),
7.68 (dd, J = 4.89, 8.02 Hz, 1H, H-5), 1.46 (s, 3H, H-22);
13
C NMR (DMSO-d6, 101 MHz): δ = 185.4 (C-21), 165.8
(C-10), 163.8 (C-1), 150.3 (C-20), 147.0 (C-18), 142.0 (C-
4), 138.1 (C-16), 132.2 (C-7), 132.1 (C-8), 130.7 (C-15),
124.4 (C-6), 121.4 (C-17), 120.6 (C-9), 118.7 (C-5), 27.9
(C-22); LC-MS m/z (pos): 357.31 [M + H] +
C18H17ClN4O2 (calcd. 356.81); Anal. Calcd for
C15H11ClN4O2: C, 57.24; H, 3.52; Cl, 11.26; N, 17.80; O,
10.17; found: C, 57.16; H, 3.63; Cl, 11.16; N, 17.83;
O, 10.23.
Medicinal Chemistry Research (2020) 29:538–548
N-(3-chloro-4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)
phenyl)nicotinamide (7f)
Yellow solid (This compound was prepared by the general
procedure mentioned for the synthesis of Compound 7a–f);
Yield = 79%; mp: 264–266 °C; IR (KBr) νmax: 1650 (amide,
C=O), 3130–3210 (NH) (cm−1). 1H NMR (DMSO-d6,
500 MHz): δ = 10.66 (s, 1H, NH), 9.15 (s, 1H, H-20), 8.79 (d,
J = 4.15 Hz, 1H, H-18), 8.33 (d, J = 7.79 Hz, 1H, H-16),
8.13–8.21 (m, J = 8.82 Hz, 2H, H-23, 27), 8.06 (s, 1H, H-9),
7.79 (d, J = 8.30 Hz, 1H, H-6), 7.59 (dd, J = 5.19, 7.27 Hz,
1H, H-5), 7.53 (d, J = 8.30 Hz, 1H, H-17), 7.01–6.96 (m, 2H,
H-24, 26), 3.86 (s, 1H, H-29); 13C NMR (DMSO-d6,
126 MHz): δ = 164.3 (C-21), 163.0 (C-10), 162.9 (C-1), 155.7
(C-25), 152.3 (C-20), 148.6 (C-18), 140.9 (C-4), 135.4 (C-16),
132.2 (C-7), 131.5 (C-8), 131.3 (C-15), 130.0 (C-6), 127.1 (C-
17), 123.4 (C-9), 121.6 (C-5), 120.5 (C-22), 118.3 (C-23, 27),
113.7 (C-24), 55.4 (C-26); LC-MS m/z: Not supported
C21H15ClN4O3 (calcd. 406.82); Anal. Calcd for C21H15ClN4O3
(406.82): C, 62.00; H, 3.72; Cl, 8.71; N, 13.77; O, 11.80;
found: C, 62.09; H, 3.92; Cl, 8.59; N, 13.78; O, 11.99.
Conclusion
All the novel oxadiazole derivatives bearing thiazole and
pyridine core have been synthesized by the three-step reaction
process using a conventional method. All the new synthesized
targets were screened for their antimalarial, antituberculosis,
antibacterial and antifungal activities with the expectation of
ascertained some new structural leads hopeful as potent
antimicrobial, antimalarial and antituberculosis components.
It can be fulfilled that the compounds 6c, 6d, 6e, 6f, 7c, 7d,
7e, and 7f were found to be mainly skillful members of the
series. Majority of the compounds were found to be active
against C. tetani and B. subtilis. In the antifungal activity, as
compared with griseofulvin compounds 6a, 6d and 7f have
shown exceptional activity against C. albicans. While in
antituberculosis activity, compounds 6f, 7e and 7f displayed
marvelous antituberculosis activities. Whereas in anti-
malarial activity, four compounds (6c, 6d, 7d, and 7f) have
shown admirable activity against strains of P. falciparum as
compared with quinine. The presence of oxadiazole core in
the synthesized compounds are predicted to be liable for the
good biological activity.
Acknowledgements The author gratefully acknowledges the research
facilities provided by the P. D. Patel Institute of Applied Sciences,
CHARUSAT.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
547
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
References
A Rattan (2000) In: BI Churchill (ed), Antimicrobials in laboratory
medicine. Livingstone, New Delhi, p 85–108
Bakht MA, Yar MS, Abdel-Hamid SG, Al Qasoumi SI, Samad A
(2010) Molecular properties prediction, synthesis and anti-
microbial activity of some newer oxadiazole derivatives. Eur J
Med Chem 45:5862–5869
Desai NC, Bhatt N, Somani H, Trivedi A (2013) Synthesis, anti-
microbial and cytotoxic activities of some novel thiazole clubbed
1,3,4-oxadiazoles. Eur J Med Chem 67:54–59
Dramowski A, Morsheimer MM, Jordaan AM, Victor TC, Donald PR,
Schaaf HS (2012) Rifampicin-monoresistant Mycobacterium
tuberculosis disease among children in Cape Town, South Africa.
Int J Tuberc Lung Dis 16:76–81
Hemming K (2001) Recent developments in the synthesis, chemistry
and applications of the fully unsaturated 1,2,4-Oxadiazoles. J
Chem Res 209–216
Karakaya S, Yilmaz-Oral D, Kilic CS, Gur S (2019) Umbelliferone
isolated from Zosima absinthifolia roots partially restored erectile
dysfunction in streptozotocin-induced diabetic rats. Med Chem
Res 28:1161–1167
Karunamoorthi K (2014) Malaria vaccine: a future hope to curtail the
global malaria burden. Int J Prev Med 5:529–538
Kumar B, Kumar A, Beheraand AK, Raj V (2016) Latest update on
pharmacological activities of 1,3,4-oxadiazole derivatives. J Cell
Sci Ther 7:233–249
London L, Cox H, Coomans F (2016) Multidrug-resistant TB:
implementing the right to health through the right to enjoy the
benefits of scientific progress. Health Hum Rights 18:25–41
Madhu Sekhar M, Nagarjuna U, Padmavathi V, Padmaja A, Reddy
NV, Vijaya T (2018) Synthesis and antimicrobial activity of
pyrimidinyl 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-tria-
zoles. Eur J Med Chem 145:1–10
Malladi S, Isloor AM, Peethambar SK, Fun HK (2014) Synthesis and
biological evaluation newer analogues 2,5-disubstituted 1,3,4-
oxadiazole containing pyrazole moiety antimicrobial agents. Arab
J Chem 7:1185–1191
NCCLS (National Committee for Clinical Laboratory Standards)
(2002) Performance Standards for Antimicrobial Susceptibility
Testing. Twelfth Informational Supplement, 1-56238-454-6
M100-S12, M7
Ningaiah S, Bhadraiah UK, Doddaramappa SD, Keshavamurthy S,
Javarasetty C (2014) Novel pyrazole integrated 1,3,4-oxadia-
zoles: Synthesis, characterization and antimicrobial evaluation.
Bioorg Med Chem Lett 24:245–248
O Bora R, Dar B, Pradhan V, Farooqui M (2014) [1, 2, 4]-oxadiazoles:
synthesis and biological applications. Mini-Rev Med Chem
14:355–369
Padmavathi V, Sudhakar Reddy G, Padmaja A, Kondaiah P, Ali S
(2009) Synthesis, antimicrobial and cytotoxic activities of 1,3,4-
oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles. Eur J Med
Chem 44:2106–2112
Palit R, Saraswat N, Sahoo J (2016) Review on substituted 1,3,4-
oxadiazole and its biological activities. Int Res J Pharm 7:1–7.
Palomino JC, Martin A (2014) Drug resistance mechanisms in
Mycobacterium tuberculosis. Antibiotics (Basel) 3:317–340
Patel NB, Patel JN, Purohit AC, Patel VM, Rajani DP, Moo-Puc R,
Lopez-Cedillo JC, Nogueda-Torres B, Rivera G (2017) In vitro
and in vivo assessment of newer quinoxaline–oxadiazole hybrids
as antimicrobial and antiprotozoal agents. Int J Antimicrob
Agents 50:413–418
548
Patel RV, Patel PK, Kumari P, Rajani DP, Chikhalia KH (2012)
Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl
(benzothiazolyl) acetamides as antibacterial, antifungal and anti-
tuberculosis agents. Eur J Med Chem 53:41–51
Rane RA, Bangalore P, Borhade SD, Khandare PK (2013) Synthesis
and evaluation of novel 4-nitropyrrole-based 1,3,4-oxadiazole
derivatives as antimicrobial and anti-tubercular agents. Eur J Med
Chem 70:49–58
Salahuddin, Mazumder A, Yar MS, Mazumder R, Chakraborthy GS,
Ahsan MJ, Rahman MU (2017) Updates on synthesis and biological
activities of 1,3,4-oxadiazole: a review. Synth Comm 47:1805–1847
Sandhu GK (2011) Tuberculosis: current situation, challenges and over-
view of its control programs in India. J Glob Infect Dis 3:143–150
Singh R, Chouhan A (2014) Various approaches for synthesis of 1,3,4-
Oxadiazole derivatives and their pharmacological activity. World
J Pharm Pharm Sci 3, 10:1474–1505
Thakkar SS, Thakor P, Doshi H, Ray A (2017) 1,2,4-Triazole and
1,3,4-oxadiazole analogues: Synthesis, MO studies, in silico
Medicinal Chemistry Research (2020) 29:538–548
molecular docking studies, antimalarial as DHFR inhibitor and
antimicrobial activities. Bioorg Med Chem 25:4064–4075
Tresse C, Radigue R, Gomes Von Borowski R, Thepaut M, Hanh Le
H, Demay F, Georgeault S, Dhalluin A, Trautwetter A, Ermel G,
Blanco C, van de Weghe P, Jean M, Giard J-C, Gillet R (2019)
Synthesis and evaluation of 1,3,4-oxadiazole derivatives for
development as broad-spectrum antibiotics. Bioorg Med Chem
27:115097
malERA Consultative Group on Drugs (2011) A research agenda for
malaria eradication: drugs. PLOS Med 8:e1000402
WHO (2011) The sixteenth global report on tuberculosis. WHO,
Geneva, Switzerland
WHO (2018) World malaria report. https://www.who.int/malaria/
publications/world-malaria-report-2018/en/
Zhou L, Wang P-Y, Zhou J, Shao W-B, Fang H-S, Wu Z-B, Yang S
(2017) Antimicrobial activities of pyridinium-tailored pyr-
azoles bearing 1,3,4-oxadiazole scaffolds. J Saudi Chem Soc
21:852–860