Facile synthesis and antimycobacterial activity of isoniazid, pyrazinamide and ciprofloxacin derivatives

Shahinda S.R. Alsayed; Shichun Lun; Alan Payne; William R. Bishai; Hendra Gunosewoyo

doi:10.1111/cbdd.13836

Facile synthesis and antimycobacterial activity of isoniazid, pyrazinamide and ciprofloxacin derivatives

Shahinda S.R. Alsayed, Shichun Lun, Alan Payne, William R. Bishai, Hendra Gunosewoyo

School of Medicine

Research output: Contribution to journal › Letter › peer-review

Abstract

Several rationally designed isoniazid (INH), pyrazinamide (PZA) and ciprofloxacin (CPF) derivatives were conveniently synthesized and evaluated in vitro against H37Rv Mycobacterium tuberculosis (M. tb) strain. CPF derivative 16 displayed a modest activity (MIC = 16 µg/ml) and was docked into the M. tb DNA gyrase. Isoniazid-pyrazinoic acid (INH-POA) hybrid 21a showed the highest potency in our study (MIC = 2 µg/ml). It also retained its high activity against the other tested M. tb drug-sensitive strain (DS) V4207 (MIC = 4 µg/ml) and demonstrated negligible cytotoxicity against Vero cells (IC₅₀ ≥ 64 µg/ml). Four tested drug-resistant (DR) M. tb strains were refractory to 21a, similar to INH, whilst being sensitive to CPF. Compound 21a was also inactive against two non-tuberculous mycobacterial (NTM) strains, suggesting its selective activity against M. tb. The noteworthy activity of 21a against DS strains and its low cytotoxicity highlight its potential to treat DS M. tb.

Original language	English (US)
Pages (from-to)	1137-1150
Number of pages	14
Journal	Chemical Biology and Drug Design
Volume	97
Issue number	6
DOIs	https://doi.org/10.1111/cbdd.13836
State	Published - Jun 2021

Keywords

ciprofloxacin
hybrid molecules
indoleamides
isoniazid
pyrazinamide
tuberculosis

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Drug Discovery
Organic Chemistry

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10.1111/cbdd.13836

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title = "Facile synthesis and antimycobacterial activity of isoniazid, pyrazinamide and ciprofloxacin derivatives",

abstract = "Several rationally designed isoniazid (INH), pyrazinamide (PZA) and ciprofloxacin (CPF) derivatives were conveniently synthesized and evaluated in vitro against H37Rv Mycobacterium tuberculosis (M. tb) strain. CPF derivative 16 displayed a modest activity (MIC = 16 µg/ml) and was docked into the M. tb DNA gyrase. Isoniazid-pyrazinoic acid (INH-POA) hybrid 21a showed the highest potency in our study (MIC = 2 µg/ml). It also retained its high activity against the other tested M. tb drug-sensitive strain (DS) V4207 (MIC = 4 µg/ml) and demonstrated negligible cytotoxicity against Vero cells (IC50 ≥ 64 µg/ml). Four tested drug-resistant (DR) M. tb strains were refractory to 21a, similar to INH, whilst being sensitive to CPF. Compound 21a was also inactive against two non-tuberculous mycobacterial (NTM) strains, suggesting its selective activity against M. tb. The noteworthy activity of 21a against DS strains and its low cytotoxicity highlight its potential to treat DS M. tb.",

keywords = "ciprofloxacin, hybrid molecules, indoleamides, isoniazid, pyrazinamide, tuberculosis",

author = "Alsayed, {Shahinda S.R.} and Shichun Lun and Alan Payne and Bishai, {William R.} and Hendra Gunosewoyo",

note = "Funding Information: SSRA is grateful for the support of Curtin International Postgraduate Research Scholarship (CIPRS). WRB is thankful for the support of NIH grants AI 37856 and HL 133190. HG acknowledges the ARC Discovery Early Career Researcher Award DE160100482. Publisher Copyright: {\textcopyright} 2021 John Wiley & Sons Ltd.",

year = "2021",

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language = "English (US)",

volume = "97",

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AU - Alsayed, Shahinda S.R.

AU - Lun, Shichun

AU - Payne, Alan

AU - Bishai, William R.

AU - Gunosewoyo, Hendra

N1 - Funding Information: SSRA is grateful for the support of Curtin International Postgraduate Research Scholarship (CIPRS). WRB is thankful for the support of NIH grants AI 37856 and HL 133190. HG acknowledges the ARC Discovery Early Career Researcher Award DE160100482. Publisher Copyright: © 2021 John Wiley & Sons Ltd.

PY - 2021/6

Y1 - 2021/6

N2 - Several rationally designed isoniazid (INH), pyrazinamide (PZA) and ciprofloxacin (CPF) derivatives were conveniently synthesized and evaluated in vitro against H37Rv Mycobacterium tuberculosis (M. tb) strain. CPF derivative 16 displayed a modest activity (MIC = 16 µg/ml) and was docked into the M. tb DNA gyrase. Isoniazid-pyrazinoic acid (INH-POA) hybrid 21a showed the highest potency in our study (MIC = 2 µg/ml). It also retained its high activity against the other tested M. tb drug-sensitive strain (DS) V4207 (MIC = 4 µg/ml) and demonstrated negligible cytotoxicity against Vero cells (IC50 ≥ 64 µg/ml). Four tested drug-resistant (DR) M. tb strains were refractory to 21a, similar to INH, whilst being sensitive to CPF. Compound 21a was also inactive against two non-tuberculous mycobacterial (NTM) strains, suggesting its selective activity against M. tb. The noteworthy activity of 21a against DS strains and its low cytotoxicity highlight its potential to treat DS M. tb.

AB - Several rationally designed isoniazid (INH), pyrazinamide (PZA) and ciprofloxacin (CPF) derivatives were conveniently synthesized and evaluated in vitro against H37Rv Mycobacterium tuberculosis (M. tb) strain. CPF derivative 16 displayed a modest activity (MIC = 16 µg/ml) and was docked into the M. tb DNA gyrase. Isoniazid-pyrazinoic acid (INH-POA) hybrid 21a showed the highest potency in our study (MIC = 2 µg/ml). It also retained its high activity against the other tested M. tb drug-sensitive strain (DS) V4207 (MIC = 4 µg/ml) and demonstrated negligible cytotoxicity against Vero cells (IC50 ≥ 64 µg/ml). Four tested drug-resistant (DR) M. tb strains were refractory to 21a, similar to INH, whilst being sensitive to CPF. Compound 21a was also inactive against two non-tuberculous mycobacterial (NTM) strains, suggesting its selective activity against M. tb. The noteworthy activity of 21a against DS strains and its low cytotoxicity highlight its potential to treat DS M. tb.

KW - ciprofloxacin

KW - hybrid molecules

KW - indoleamides

KW - isoniazid

KW - pyrazinamide

KW - tuberculosis

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Facile synthesis and antimycobacterial activity of isoniazid, pyrazinamide and ciprofloxacin derivatives

Abstract

Keywords

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