Activity of a new class of isonicotinoylhydrazones used alone and in combination with isoniazid, rifampicin, ethambutol, para-aminosalicylic acid and clofazimine against Mycobacterium tuberculosis.
The activities of six derivatives of a new class of isonicotinoylhydrazones were investigated in vitro against Mycobacterium tuberculosis H37Rv ATCC 27294, isoniazid-resistant M. tuberculosis ATCC 35822, rifampicin-resistant ATCC 35838, pyrazinamide-resistant ATCC 35828, streptomycin-resistant ATCC 35820 and 16 clinical isolates of M. tuberculosis. Several compounds showed interesting antimycobacterial activity against both ATCC strains and clinical isolates, but were less active against isoniazid-resistant M. tuberculosis. Combinations of five isonicotinoylhydrazone derivatives and rifampicin, ethambutol, para-aminosalicylic acid, isoniazid and clofazimine were also investigated against M. tuberculosis H37Rv ATCC 27294 and against ATCC drug-resistant strains. Addition of sub-MICs of some isonicotinoylhydrazone derivatives resulted in a four- to 16-fold reduction in MICs of ethambutol, para-aminosalicylic acid and rifampicin with fractional inhibitory concentrations (FICs) ranging between 0.17 and 0.37, suggesting a synergic interaction against M. tuberculosis H37Rv. Increased activity was also observed with other combinations (FICs 0.53-0.75), including isoniazid, and a synergic interaction between one of the isonicotinoylhydrazone derivatives and isoniazid (FIC 0.26) was shown against isoniazid-resistant M. tuberculosis ATCC 35822, whereas no effects were observed on combining the isonicotinoylhydrazones with clofazimine. The ability of isonicotinoylhydrazones to inhibit specifically the growth of M. tuberculosis, the high selectivity index and their ability to enhance the activity of standard antituberculous drugs in vitro indicate that they may serve as promising lead compounds for future drug development for the treatment of M. tuberculosis infections.
De Logu
Alessandro
A
Sezione di Microbiologia e Virologia, Dipartimento di Scienze Chirurgiche e Trapianti d'Organo, Università di Cagliari, Viale Frà Ignazio 38, 09123 Cagliari, Italy. adelogu@unica.it
Onnis
Valentina
V
Saddi
Barbara
B
Congiu
Cenzo
C
Schivo
Maria Laura
ML
Cocco
Maria Teresa
MT
D010131:Aminosalicylic Acid / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D002991:Clofazimine / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000706:statistics & numerical data; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests / Q000706:statistics & numerical data; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D012293:Rifampin / Q000737:chemistry / Q000494:pharmacology; D014709:Vero Cells
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000995:Antitubercular Agents; D006835:Hydrazones; D010131:Aminosalicylic Acid; D004977:Ethambutol; D002991:Clofazimine; D007538:Isoniazid; D012293:Rifampin