Biological and biochemical evaluation of isatin-isoniazid hybrids as bactericidal candidates against <i>Mycobacterium tuberculosis</i>.

Johansen, MD; Shalini,; Kumar, S; Raynaud, C; Quan, DH; Britton, WJ; Hansbro, PM; Kumar, V; Kremer, L

Biological and biochemical evaluation of isatin-isoniazid hybrids as bactericidal candidates against <i>Mycobacterium tuberculosis</i>.

Johansen, MD Shalini, Kumar, S Raynaud, C Quan, DH Britton, WJ Hansbro, PM Kumar, V Kremer, L

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Publisher:: American Society for Microbiology
Publication Type:: Journal Article
Citation:: Antimicrobial agents and chemotherapy, 2021
Issue Date:: 2021-05-10

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Field	Value	Language
dc.contributor.author	Johansen, MD
dc.contributor.author	Shalini,
dc.contributor.author	Kumar, S
dc.contributor.author	Raynaud, C
dc.contributor.author	Quan, DH
dc.contributor.author	Britton, WJ
dc.contributor.author	Hansbro, PM
dc.contributor.author	Kumar, V
dc.contributor.author	Kremer, L
dc.date.accessioned	2021-06-25T05:34:48Z
dc.date.available	2021-06-25T05:34:48Z
dc.date.issued	2021-05-10
dc.identifier.citation	Antimicrobial agents and chemotherapy, 2021
dc.identifier.issn	0066-4804
dc.identifier.issn	1098-6596
dc.identifier.uri	http://hdl.handle.net/10453/149759
dc.description.abstract	Tuberculosis remains a leading cause of mortality among infectious diseases worldwide, prompting the need to discover new drugs to fight this disease. We report herein, the design, synthesis and anti-mycobacterial activity of isatin-mono/bis-isoniazid hybrids. Most of the compounds exhibited very high activity against <i>Mycobacterium tuberculosis</i> with minimal inhibitory concentrations in the range of 0.195-0.39 μg/mL and exerted a more potent bactericidal effect than the standard anti-tubercular 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 <i>M. tuberculosis</i>, among which <b>11e</b> 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 anti-tubercular molecules for further evaluation in pre-clinical settings.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	American Society for Microbiology
dc.relation.ispartof	Antimicrobial agents and chemotherapy
dc.relation.isbasedon	10.1128/aac.00011-21
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0605 Microbiology, 1108 Medical Microbiology, 1115 Pharmacology and Pharmaceutical Sciences
dc.subject.classification	Microbiology
dc.title	Biological and biochemical evaluation of isatin-isoniazid hybrids as bactericidal candidates against <i>Mycobacterium tuberculosis</i>.
dc.type	Journal Article
utslib.location.activity	United States
utslib.for	0605 Microbiology
utslib.for	1108 Medical Microbiology
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access	*
dc.date.updated	2021-06-25T05:34:35Z
pubs.publication-status	Published

Abstract:

Tuberculosis remains a leading cause of mortality among infectious diseases worldwide, prompting the need to discover new drugs to fight this disease. We report herein, the design, synthesis and anti-mycobacterial activity of isatin-mono/bis-isoniazid hybrids. Most of the compounds exhibited very high activity against Mycobacterium tuberculosis with minimal inhibitory concentrations in the range of 0.195-0.39 μg/mL and exerted a more potent bactericidal effect than the standard anti-tubercular 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 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 anti-tubercular molecules for further evaluation in pre-clinical settings.

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http://hdl.handle.net/10453/149759