Design, synthesis and spectral characterization of quinazoline and benzoxazine derivatives as novel DNA gyrase inhibitors.
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Date
2020
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Abstract
Tuberculosis (TB) has remained one of the leading causes of the death worldwide and recently
surpassed HIV/AIDS as lethal disease caused by a single infectious agent. Further, development
of resistance against frontline anti-tubercular drugs has worsened the existing alarming
condition. Therefore, there is an urgent need to develop novel, more effective, inexpensive and
accessible antitubercular agents possessing broad spectrum of potency short duration of drug
regimen, less side effects, which can counter the drug resistant TB and reduce the burden on the
society. Global scientific communities and pharmaceutical industries are aggressively involved
in research to develop a novel broad spectrum anti-tubercular agent to address this rising threat
to human kind. In continuation of our work, focused in developing new anti-TB agents, we have
attempted to develop some potential quinazoline based DNA gyrase and topoisomerase IV
inhibitors as potential anti-tubercular agents. In addition, we have developed novel green and
efficient catalyst-free, mild one-pot tandem synthetic strategy to synthesize benzoxazine
derivatives, that can be further exploited as building blocks for the synthesis of multifaceted
molecular structures, especially for anti-tuberculosis agents.
Chapter 1 gives a brief overview on drug discovery and medicinal chemistry, history of
antibiotic expansion, development of resistance in bacteria, history of anti-TB drugs discovery,
line of treatment for TB, anti-tubercular drugs and their specific targets, classification of TB
drugs, DNA gyrase and topoisomerase IV as a key target for anti-tubercular agents, marketed
drugs and recently reported DNA gyrase inhibitors, importance of benzoxazine and quinazoline
scaffold as well as significance of fluorine containing heterocycles in medicinal chemistry.
Chapter 2 describes, the development of a novel methodology which is green, efficient
catalyst-free and is a mild one-pot, multicomponent synthetic strategy to construct substituted
3,4-dihydro-2H-benzo[b][1,4]oxazine. The reaction proceeds via in-situ formation of Schiffbase followed by base mediated alkylation with phenacyl bromide/substituted phenacyl
bromide, finally leading to intramolecular cyclization to give a mixture of diastereomers with
excellent diastereoselectivity (up to dr = 99:1), which were isolated as single diastereomer in
moderate to excellent yields (41-92%). Besides, this new versatile methodology provides a wide
scope for the synthesis of different functionally substituted benzoxazine scaffolds and can be
further exploited as building blocks for the synthesis of multifaceted molecular structures,
especially for pharmaceutical applications.
In Chapter 3, 15 novel fluorinated quinazoline derivatives have been synthesized and
characterized with Infrared (IR) and Nuclear Magnetic Resonance (NMR) spectroscopic
methods. This chapter also describes the influence of various substituents on the core scaffold
(Fluorinated quinazoline) on its molecular conformations, intermolecular interactions and on the
photoluminescent properties. Hirshfeld surfaces was used to investigate the structure-directing
effects of functional groups in controlling their solid-state behaviour.
In Chapter 4, a total 21 novel quinazoline derivatives (10a-q and 17a-c) were synthesized in
good to moderate yields. The synthesized compounds were well-characterized by spectroscopic
studies (IR and NMR) and evaluated for their preliminary in vitro screening against
Mycobacterium tuberculosis H37Rv strain, which was conducted at TB Discovery Research,
Infectious Disease Research Institute (IDRI), USA. The only notable % zone of inhibition was
observed against Mycobacterium tuberculosis strain H37Rv for compounds 10m which showed
33% inhibition after 24 h incubation which can be considered for further study which includes
MIC, MBC etc.
In Chapter 5, total 23 novel N/O-methylated quinazoline derivatives (10a-o, 16a-d and 16aaad) were synthesized in good to moderate yields. All synthesized compounds were wellcharacterized by spectroscopic studies (IR and NMR) and evaluated for preliminary in-vitro
screening for anti-mycobacterium activity at 20 µM concentration against Mycobacterium
tuberculosis H37Rv strain at TB Discovery Research, Infectious Disease Research Institute
(IDRI), USA. The % zone of inhibition for compounds 16a, against Mycobacterium
tuberculosis strain H37Rv was found to be 34% after 24 h incubation.
Chapter 6 describes, the development of novel quinazoline based DNA gyrase inhibitors as
potential antibacterial agents. Bacterial type II topoisomerase (DNA gyrase and topoisomerase
IV) control the topological state of DNA during replication and are validated targets for
antibacterial agents. Type II topoisomerase is essential in all bacteria. It is also present in
eukaryotic cells but unlike the prokaryotic enzymes eukaryotic topoisomerase II is
homodimeric, this difference in structure makes highly attractive targets in antibacterial drug
discovery. Fluoroquinolones are an example of very active gyrase-based drugs, but the rise in
bacterial resistance to these agents alarm the risk. We have replaced the central core quinolone
with quinazoline ring and synthesized 22 derivatives and evaluated against DNA gyrase and
topoisomerase IV enzyme of Escherichia coli. The most potent compound (10l) displayed
balanced IC50 value of 0.49 and 13.22 μM for DNA Gyrase and topoisomerase IV of
Escherichia coli respectively. This result is intresting for the further studies as it showed
promising well-balanced duel inhibiton in the low micromolar range against DNA gyrase and
topoisomerase IV in E. coli.
Description
Doctoral Degree. University of KwaZulu-Natal, Durban.