1.

Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are naturally occurring compounds isolated

from various Streptomyces species. The PBDs exert their biological activity through covalent
binding and exhibit cytotoxicity. Extensive studies have been carried out on the synthetic
strategies of PBDs, and a sound understanding of structure activity relationships within this
class of compounds has been developed. The PBDs have shown to interfere with the
interaction of endonuclease enzymes of DNA and block the transcription by inhibiting RNA
polymerase in a sequence specific manner. These processes have been thought to account for
the biological activity of PBDs. The PBDs have also been used as a scaffold to attach
different type of moieties leading to novel sequence selective DNA cleaving and cross-
linking agents. The design and synthesis of C8-linked PBD dimers and other hybrids of PBDs
has given a new insight towards the development of molecules with enhanced DNA binding
affinity and sequence specificity compared to the naturally occurring PBDs. This
improvement in the biological profile has been explained on the basis of certain factors like
DNA cross-linking and doubling of DNA binding sites. There seems to be enough potential
for further changing the substitution pattern and to design structurally modified PBDs by
retaining the PBD core intact. In this review both the synthetic strategies and the structure-
activity relationships, particularly the DNA binding and cytotoxicity studies of PBDs have
been discussed.
2. The [1,4]benzodiazepine is an important class of heterocyclic compounds and clinically
used for many ailments in humans. The [1,4]benzodiazepine has unique structure that mimics
the peptide linkage. This interesting observation completely shifted the interest of medicinal
chemist for [1,4]benzodiazepine from CNS acting drugs to anticancer agents. During last few
decades, a large number of reports have appeared in the literature highlighting the anticancer
activity of [1,4]benzodiazepines. Here, in this article, we have discussed the brief synthesis,
origin of [1,4]benzodiazepines as anticancer agent, their mechanism of action and latest
developments in this field. We have compiled the most important literature reports from last
few decades till date.
3. Benzodiazepines (BZDs), a diverse class of benzofused seven-membered N-heterocycles,
display essential pharmacological properties and play vital roles in some biochemical
processes. They have mainly been prescribed as potential therapeutic agents, which
interestingly represent various biological activities such as anticancer, anxiolytic,
antipsychotic, anticonvulsant, antituberculosis, muscle relaxant, and antimicrobial activities.
The extensive biological activities of BZDs in various fields have encouraged medicinal
chemists to discover and design novel BZD-based scaffolds as potential therapeutic
candidates with thefavorite biological activity through an efficient protocol. Although
certainly valuable and important, conventional synthetic routes to these bicyclic benzene
compounds contain methodologies often requiring multistep procedures, which suffer from
waste materials generation and lack of sustainability. By contrast, multicomponent reactions
(MCRs) have recently advanced as a green synthetic strategy for synthesizing BZDs with the
desired scope. In this regard, MCRs, especially Ugi and Ugi-type reactions, efficiently and
conveniently supply various complex synthons, which can easily be converted to the BZDs
via suitable post-transformations. Also, MCRs, especially Mannich-type reactions, provide
speedy and economic approaches for the one-pot and one-step synthesis of BZDs. As a result,
variouss functionalized-BZDs have been achieved by developing mild, efficient, and high-
yielding MCR protocols. This review covers all aspects of the synthesis of BZDs with a
particular focus on the MCRs as well as the mechanism chemistry of synthetic protocols. The
present manuscript opens a new avenue for organic, medicinal, and industrial chemists to
design safe, environmentally benign, and economical methods for the synthesis of new and
known as BZDs.
4. Benzodiazepines (BZDs) represent a diverse class of bicyclic heterocyclic molecules. In
the last few years, benzodiazepines have emerged as potential therapeutic agents. As a result,
several mild, efficient and high yielding protocols have been developed that offer access to
various functionalized benzodiazepines (BZDs). They are known to possess a wide array of
biological activities such as anxiolytic, anticancer, anticonvulsant, antipsychotics, muscle
relaxant, antituberculosis, and antimicrobial activities. The fascinating spectrum of biological
activities exhibited by BZDs in various fields has prompted the medicinal chemist to design
and discover novel benzodiazepine-based analogs as potential therapeutic candidates with the
desired biological profile. In this review, an attempt has been made by to summarize 1)
Recent advances in the synthetic chemistry of benzodiazepines which enable their synthesis
with desired substitution pattern; 2) Medicinal chemistry of BZDs as therapeutic candidates
with promising biological profile including insight of mechanistic studies; 3) The correlation
of biological data with the structure i.e. structure-activity relationship studies were also
included to provide an insight into the rational design of more active agents.
5. Benzodiazepines (BZDs) represent a class of privilege scaffold in the modern era of
medicinal chemistry as CNS active agents and BZD based drugs are used to treat different
psychotic disorders. Inspired from the therapeutic potential of BZDs as promising CNS active
agents, in the present work three different series of 1,5-benzodiazepines bearing various
substitutions at position 2 and 4 of the benzodiazepine core were synthesized by condensing
different substituted chalcones with o-phenylenediamine in the presence of piperidine as a
base catalyst. Structural characterization of title compounds was done by using various
analytical techniques such as IR, NMR, elemental analysis and mass spectral data. All the
synthesized compounds (9a-d, 10a-e and 11a-c) were subjected to in vivo
neuropharmacological studies to evaluate their CNS depressant and antiepileptic activity.
Results of in vivo evaluation data showed that analogue 11b exhibited potent CNS depressant
activity which was comparable to the standard drug diazepam. Compounds 10b and 10c
displayed significant antiepileptic activity however they were less potent than the standard
drug phenobarbitone. Molecular docking studies were performed using MOE software to find
the interaction pattern and binding mode at the GABAA receptor (PDB Id: 6HUP). The
results of the docking studies were in good agreement with the observed in vivo activity and
revealed the satisfactory binding mode of the compounds within the binding site of the
protein. The docking scores for the most promising candidates 10c, 11b and Diazepam were
found to be -9.18, -9.46 and -9.88, respectively. Further, the compounds showed compliance
with the Lipinski’s ‘rule of five’ and exhibited favourable drug-likeness scores. The identified
leads can be explored further for the design and development of new BZD based
psychotropic agents.
6. Novel series of diazepam bearing sulfonamide moieties 5a-f and 7a-c were designed,
synthesized and evaluated for anticancer activity against HepG2, HCT-116 and MCF-7 cell
lines. MCF-7 was the most sensitive cell line to the influence of the new derivatives. In
particular, compound 5d was found to be the most potent derivative overall the tested
compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC50 = 8.98
± 0.1, 7.77 ± 0.1 and 6.99 ± 0.1 µM respectively. Compound 5d exhibited higher activity than
sorafenib, (IC50 = 9.18 ± 0.6, 5.47 ± 0.3 and 7.26 ± 0.3 µM respectively), against HepG2 and
MCF-7 but exhibited lower activity against HCT116 cancer cell lines respectively. Also, this
compound displayed lower activity than doxorubicin, (IC50 = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75
± 0.4 µM respectively), against HepG2 and MCF-7 but higher activity against HCT116 cell
lines respectively. Compounds 5b, 5c, 5d, 5e, 5f and 7c are respectively, 5.77, 8.58, 9.54,
5.71, 4.68 and 2.31 fold times more toxic in breast cancer cell lines (MCF-7, the most
sensitive cells) than in VERO normal cells. All the synthesized compounds 5a-f and 7a-c
were evaluated for their inhibitory activities against VEGFR-2. Among them, compound 5d
was found to be the most potent derivative that inhibited VEGFR-2 at IC50 value of 0.10 ±
0.01 µM, which is equipotent to sorafenib IC50 value (0.10 ± 0.02 µM). Compound 5c
exhibited excellent activity with IC50 value of 0.12 ± 0.01 µM which nearly equipotent to
that of sorafenib. Compounds 5b, 5e and 5f exhibited very good activity with the same IC50
value of 0.14 ± 0.02 µM. Also, compounds 7c and 7b possessed good VEGFR-2 inhibition
with IC50 values of 0.16 ± 0.06 and 0.17 ± 0.06 µM respectively which are more than the
half activity of that of sorafenib. The data obtained from docking studies were highly
correlated with that obtained from the biological screening.
9. A Hybrid drug which comprises the incorporation of two drug pharmacophores in one
single molecule are basically designed to interact with multiple targets or to amplify its effect
through action on another bio target as one single molecule or to counterbalance the known
side effects associated with the other hybrid part. The present review article offers a detailed
account of the design strategies employed for the synthesis of anticancer agents via molecular
hybridization techniques. Over the years, the researchers have employed this technique to
discover some promising chemical architectures displaying significant anticancer profiles.
Molecular hybridization as a tool has been particularly utilized for targeting tubulin protein as
exemplified through the number of research papers. The microtubule inhibitors such as taxol,
colchicine, chalcones, combretasatin, phenstatins and vinca alkaloids have been utilized as
one of the functionality of the hybrids and promising results have been obtained in most of
the cases with some of the tubulin based hybrids exhibiting anticancer activity at nanomolar
level. Linkage with steroids as biological carrier vector for anticancer drugs and the inclusion
of pyrrolo [2,1-c] [1,4]benzodiazepines (PBDs), a family of DNA interactive antitumor
antibiotics derived from Streptomyces species in hybrid structure based drug design has also
emerged as a potential strategy. Various heteroaryl based hybrids in particular isatin and
coumarins have also been designed and reported to posses’ remarkable inhibitory potential.
Apart from presenting the design strategies, the article also highlights the structure activity
relationship along with mechanistic insights revealed during the biological evaluation of the
hybrids.
10. Development of drugs for new and persistent diseases will increasingly rely on the
expansion of accessible chemical space to allow exploration of novel molecular targets. Here
we report the synthesis of a library of novel fused heterobicyclic small molecules based on
the 1,4-diazepine and 2,4- pyrrolidinedione scaffolds. Key chemical transformations included
a Mannich-type condensation and chemoselective N-acylation reactions. Screening shows
anti-cancer activity of several library compounds which suggests translational potential of
this novel chemical scaffold.
11. The synthesis of organometallic compounds with potential pharmacological activity has
attracted the attention of many research groups, aiming to take advantage of aspects that the
presence of the metal-carbon bond can bring to the design of new pharmaceutical drugs. In
this context, we have gathered studies reported in the literature in which psychoactive
benzodiazepine drugs were used as ligands in the preparation of organometallic and metal
complexes and provide details on some of their biological effects. We also highlight that most
commonly known benzodiazepine-based drugs display molecular features that allow the
preparation of metallacycles via C-H activation. These organometallic compounds merit
further attention regarding their potential biological effects, not only in terms of psychoactive
drugs but also in the search for drug replacements, for example, for cancer treatments.
12. By employing an intramolecular Pd(0)-mediated ring opening of an acylnitroso-derived
cycloadduct, new hydroxamic acid containing benzodiazepines have been synthesized and
have demonstrated biological activity in MCF-7 and PC-3 tumor cell lines. Subsequent N-O
bond reduction of the hydroxamate has provided access to amide analogues for SAR studies.
During the course of our syntheses, an intermediate oxazoline N-oxide was isolated and gave
insight into the mechanism of the key Pd(0)-mediated reaction.
13. The [1,4]benzodiazepine is an important class of heterocyclic compounds and clinically
used for many ailments in humans. The [1,4]benzodiazepine has unique structure that mimics
the peptide linkage. This interesting observation completely shifted the interest of medicinal
chemist for [1,4]benzodiazepine from CNS acting drugs to anticancer agents. During last few
decades, a large number of reports have appeared in the literature highlighting the anticancer
activity of [1,4]benzodiazepines. Here, in this article, we have discussed the brief synthesis,
origin of [1,4]benzodiazepines as anticancer agent, their mechanism of action and latest
developments in this field. We have compiled the most important literature reports from last
few decades till date.
14. Novel racemic indeno[1,2-e]pyrimido[4,5-b][1,4]diazepine-5,11-diones 3–29 were
obtained regioselectivily from the reaction of 5,6-diamino-3,4-dihydropyrimidin-4-ones 1 and
2-arylideneindandiones 2 as reagents. These compounds have been evaluated at the US
National Cancer Institute (NCI) for their ability to inhibit approximately 60 different human
tumor cell lines, where 5 and 6 presented remarkable activity against 57 and 48 cancer cell
lines, respectively, with the most important GI50 values ranging from 0.49 to 1.46 lM, in
vitro assay.
15. A series of resorcinaren-PAMAM dendrimers with benzodiazepines in the periphery were
synthesized and their anticancer properties studied. The synthesized dendrimers showed
potential anticancer activities, which were enhanced in the presence of a chloro-substituent in
the second ring of the 5- aryl-1,4-benzodiazepine. The dendrimers were characterized by IR,
1 H and 13C NMR, UV–vis absorption, electrospray (ES) and/or MALDI-TOF mass
spectrometries.
16. The combination of two pharmacological entities in a single compound has been utilized
as a promising drug design strategy for site-specificity. So two nitrogen mustard agents were
synthesized by conjugating mustard with the benzodiazepine nucleus in the hope to obtain
central nervous system (CNS) antitumor agents. The benzodiazepine part is aimed to serve as
a CNS active carrier enabling the alkylating moiety to cross the BBB by altering its
physicochemical properties. Structures of all the synthesized compounds were confirmed by
IR, NMR (1 H & 13C), mass spectral and elemental studies. The benzodiazepine-mustard
conjugates are oily at room temperature and quite stable when stored in refrigerator for 2
months. Both compounds when evaluated for NBP alkylating activity against chlorambucil,
proved to be active alkylating agents. The compounds were markedly active when subjected
to in vitro biological evaluation using an MTT colorimetric assay against four human cancer
cell lines (A-549, COLO 205, U-87 MG and IMR-32). The physicochemical ADME studies
were also analyzed using Qikprop 2.5 tools of Schodinger software which further indicates
that both compounds can be potential candidates for the treatment.
17. The combination of two pharmacological entities in a single compound has been utilized
as a promising drug design strategy for site-specificity. So two nitrogen mustard agents were
synthesized by conjugating mustard with the benzodiazepine nucleus in the hope to obtain
central nervous system (CNS) antitumor agents. The benzodiazepine part is aimed to serve as
a CNS active carrier enabling the alkylating moiety to cross the BBB by altering its
physicochemical properties. Structures of all the synthesized compounds were confirmed by
IR, NMR (1 H & 13C), mass spectral and elemental studies. The benzodiazepine-mustard
conjugates are oily at room temperature and quite stable when stored in refrigerator for 2
months. Both compounds when evaluated for NBP alkylating activity against chlorambucil,
proved to be active alkylating agents. The compounds were markedly active when subjected
to in vitro biological evaluation using an MTT colorimetric assay against four human cancer
cell lines (A-549, COLO 205, U-87 MG and IMR-32). The physicochemical ADME studies
were also analyzed using Qikprop 2.5 tools of Schodinger software which further indicates
that both compounds can be potential candidates for the treatment