Biological and Biochemical Evaluation of Isatin-Isoniazid Hybrids as Bactericidal Candidates against Mycobacterium tuberculosis

Biological and Biochemical Evaluation of Isatin-Isoniazid Hybrids as Bactericidal Candidates against Mycobacterium tuberculosis.

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Item Type: Article
Status: Published
Official URL:
Journal or Publication Title: Antimicrobial Agents and Chemotherapy
Volume: 65
Number: 8
Date: 16 July 2021
Divisions: Tuberculosis
UTS Centre for Inflammation
Depositing User: General Admin
Identification Number: 10.1128/AAC.00011-21
ISSN: 0066-4804
Date Deposited: 08 Dec 2021 01:35

Tuberculosis remains a leading cause of mortality among infectious diseases worldwide, prompting the need to discover new drugs to fight this disease. We report here the design, synthesis, and antimycobacterial activity of isatin-mono/bis-isoniazid hybrids. Most of the compounds exhibited very high activity against Mycobacterium tuberculosis, with MICs in the range of 0.195 to 0.39 μg/ml, and exerted a more potent bactericidal effect than the standard antitubercular drug isoniazid (INH). Importantly, these compounds were found to be well tolerated at high doses (>200 μg/ml) on Vero kidney cells, leading to high selectivity indices. Two of the most promising hybrids were evaluated for activity in THP-1 macrophages infected with M. tuberculosis, among which compound 11e was found to be slightly more effective than INH. Overexpression of InhA along with cross-resistance determination of the most potent compounds, selection of resistant mutants, and biochemical analysis, allowed us to decipher their mode of action. These compounds effectively inhibited mycolic acid biosynthesis and required KatG to exert their biological effects. Collectively, this suggests that the synthesized isatin-INH hybrids are promising antitubercular molecules for further evaluation in preclinical settings.

Keywords: InhA; KatG; Mycobacterium tuberculosis; bactericidal activity; drug resistance; isatin-isoniazid hybrids; mycolic acids.

Johansen, Matt D.
Kumar, Sumit
Raynaud, Clément
Quan, Diana H.
Britton, Warwick J.
Hansbro, Philip M.
Kumar, Vipan
Kremer, Laurent
Last Modified: 08 Dec 2021 01:35

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