Development of benzo[d]oxazol-2(3H)-ones derivatives as novel inhibitors of Mycobacterium tuberculosis InhA

Pedgaonkar, Ganesh S.; Sridevi, Jonnalagadda Padma; Jeankumar, Variam Ullas; Saxena, Shalini; Devi, Parthiban Brindha; Renuka, Janupally; Yogeeswari, Perumal; Sriram, Dharmarajan

doi:10.1016/j.bmc.2014.08.031

Cited by 10 publications

(3 citation statements)

References 16 publications

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“…Exemplary mycobacterial inhibition inspired us to investigate the binding pattern of these molecules by using molecular docking studies to understand the molecular requirements for the biological activity. Thus, the structural features and previous reports on pyrazoles [30][31][32][33] and especially amide derivatives [34,35] like rimonabant formed the basis for the design of these molecules.…”

Section: Molecular Docking Studiesmentioning

confidence: 96%

Design, synthesis, in silico, and in vitro evaluation of 3‐phenylpyrazole acetamide derivatives as antimycobacterial agents

Gaikwad

Nirmale

Sahoo

et al. 2020

Archiv der Pharmazie

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Mycobacterium tuberculosis (Mtb) is one of the most dangerous pathogens affecting immunocompetent and immunocompromised patients worldwide. Novel molecules, which are efficient and can reduce the duration of therapy against drug-resistant strains, are an urgent unmet need of the hour. In our current study, a series of new 2-(3-phenyl-1H-pyrazol-1-yl)acetamide and N′-benzylidene-2-(3-phenyl-1H-pyrazol-1yl)acetohydrazide derivatives were designed, synthesized, and evaluated for their antimycobacterial potential. The biological evaluation revealed that 6b, 6m, 6l, 7a, and 7k exhibited selective and potent inhibitory activity against Mtb. Furthermore, compounds 6m and 7h were found to be nontoxic to Vero cells with CC 50 of greater than 20 and 80 mg/ml, respectively, and exhibited promising selectivity indices (SI) of greater than 666 and 320, respectively. All derivatives exhibited excellent ADME (absorption, distribution, metabolism, and excretion) properties in silico. Also, all the derivatives were found compliant with Lipinski's rule of five, showing their druggability profile. Molecular docking insights of these derivatives have shown outstanding binding energies on the mycobacterial membrane protein large transporters. These results indicate that this scaffold may lead to a potential antimycobacterial drug candidate in the discovery of antitubercular agents.Tuberculosis (TB), caused due to Mycobacterium tuberculosis (Mtb), is primarily a lung disease but can attack any part of the body such as the spine, brain, and kidney, hence causing extra-pulmonary tuberculosis. [1] In the majority of the patients, Mtb is present in a latent form (LTBI), which, in turn, transmutes into an active disease as soon as the patient's immunity gets weaker. However, people with LTBI remain a large human pool for TB, which implies that for the decline in the global TB burden, all forms of TB should be eradicated. [2] This is exemplified by the fact that big eight countries tally 67% of the total patients: India (27%), China (9%), Indonesia (8%), Pakistan (6%), Philippines (6%), Bangladesh (4%), Nigeria (4%), and South Africa (3%). WHO announced "The End TB strategy" to

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Section: Molecular Docking Studiesmentioning

confidence: 96%

Design, synthesis, in silico, and in vitro evaluation of 3‐phenylpyrazole acetamide derivatives as antimycobacterial agents

Gaikwad

Nirmale

Sahoo

et al. 2020

Archiv der Pharmazie

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“…Specifically, compound ( 29 ) (Figure 10) exhibited a promising antituberculosis activity against an XDR-TB clinical isolate, with MIC 90 of 11.47 μM. The authors also demonstrated that compound ( 29 ) acts through the inhibition of the mycobacterial 2-trans-enoyl-acyl carrier protein reductase (InhA), a key enzyme involved in the mycolic acid biosynthesis in Mtb [51]. Shuyi Si and coworkers have discovered several disubstituted oxazole analogues as potent antituberculosis agents.…”

Section: Antituberculosis Compoundsmentioning

confidence: 99%

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

2017

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Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is according to the World Health Organization (WHO) the infectious disease responsible for the highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in the coming years. The scenario of drug discovery becomes alarming when it is considered that the number of new drugs does not increase proportionally to the emergence of drug resistance. In this review, we will demonstrate the current advances in antitubercular drug discovery, focusing on the research of compounds with potent antituberculosis activity against MDR-TB strains. Herein, active compounds against MDR-TB with minimum inhibitory concentrations (MICs) less than 11 µM and low toxicity published in the last 4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed.

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“…Docking of these molecules into InhA revealed binding conformation of these molecules and the vital interactions with the target. It was observed that the compounds (35), (36), (37), (38), (39) and (40) 62 . 3D-QSAR analysis and a molecular dynamics simulations study was used to elucidate the underlying structural requirements of diphenyl ether derivatives for inhibition of InhA.…”

Section: Structural Generalizationsmentioning

confidence: 99%

InhA inhibitors as potential antitubercular agents

Hamid¹

2016

Orient. J. Chem

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Infectious diseases pose a potential threat and are responsible for killing more people globally than any other single cause. For six decades, antibiotics have been a bulwark against bacterial infectious diseases. This bulwark is failing due to the appearance of resistant bacterial strains. The biosynthesis pathway of fatty acids in bacteria represents a validated target for antibacterial drug discovery, although it is still relatively unexplored. Bacterial FAS-II is essential for survival of bacterial cells, furthermore as it is distinct from FAS-I pathway in mammals, it constitutes a rational beginning point for the design of novel anti-infective drugs. Tuberculosis (TB) is a potentially serious infectious disease. Several strategies that have been adopted for the development of new therapeutic agents against the strains of tuberculosis which are drug resistant involve not only the design and synthesis of compounds against earlier known targets but also the identification and inhibition of novel drug targets. Isoniazid (INH), the first-line agent used for prevention and treatment of tuberculosis targets the enoyl reductase (InhA) enzyme in fatty acid biosynthesis pathway of the mycobacteria. KatG, is the enzyme which activates isoniazid and mutations in this enzyme lead to the majority of INHresistant clinical strains. Thus only those compounds will work against most of the INH resistant strains of mycobacteria which do not require activation of KatG for InhA inhibition.

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Development of benzo[d]oxazol-2(3H)-ones derivatives as novel inhibitors of Mycobacterium tuberculosis InhA

Cited by 10 publications

References 16 publications

Design, synthesis, in silico, and in vitro evaluation of 3‐phenylpyrazole acetamide derivatives as antimycobacterial agents

Design, synthesis, in silico, and in vitro evaluation of 3‐phenylpyrazole acetamide derivatives as antimycobacterial agents

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

InhA inhibitors as potential antitubercular agents

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