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Facile synthesis and antimycobacterial activity of isoniazid, pyrazinamide and ciprofloxacin derivatives
Author(s) -
Alsayed Shahinda S. R.,
Lun Shichun,
Payne Alan,
Bishai William R.,
Gunosewoyo Hendra
Publication year - 2021
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13836
Subject(s) - isoniazid , pyrazinamide , antimycobacterial , ciprofloxacin , mycobacterium tuberculosis , cytotoxicity , chemistry , bedaquiline , potency , ethambutol , microbiology and biotechnology , vero cell , dna gyrase , tuberculosis , ic50 , pharmacology , in vitro , stereochemistry , antibiotics , biology , medicine , biochemistry , pathology , escherichia coli , gene
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 (IC 50 ≥ 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 .