As a result of our search for new isoniazid derivatives with extended spectra of activity, we evaluated the in vitro antimycobacterial activities of isonicotinohydrazides (compounds 2) and their cyanoborane adducts (compounds 3), both obtained by the reaction of isonicotinoylhydrazones (compounds 1) with sodium cyanoborohydride. Most of the tested compounds displayed moderate to high activity against Mycobacterium tuberculosis H37Rv, with MICs ranging from 0.2 to 12.5 g/ml. In particular, some hydrazides showed activity similar to that of rifampin (MIC ؍ 0.2 g/ml) and rather low cytotoxicity, so that they were generally shown to possess high safety indices. In contrast, the coordination to a cyanoborane (BH 2 CN) group (compounds 3) in general brought about a decrease in antimycobacterial activity, while cytotoxicity increased. Interestingly, selected compounds 1 to 3, mostly hydrazides (compounds 2), were effective in killing M. tuberculosis growing within macrophages at concentrations in culture medium which were much lower than the corresponding MICs. These compounds also displayed good activity against drug-resistant M. tuberculosis strains.Tuberculosis (TB) is still a challenging worldwide health problem, and Mycobacterium tuberculosis remains one of the single most deadly human pathogens. The resurgence of TB over the last 15 years, even in industrialized countries where it was almost eradicated, has been favored by the pathogenic synergy with human immunodeficiency virus infection. In fact, TB and other atypical mycobacterioses are now diseases frequently associated with AIDS; human immunodeficiency virus infection significantly increases the risk that new or latent TB infections will progress to active diseases (5, 10-12).The emergence of TB has also been accompanied by the appearance of single-drug-resistant (SDR) and multidrug-resistant strains of M. tuberculosis which are insensitive to one or more of the first-line anti-TB drugs (isoniazid [INH], rifampin, ethambutol, streptomycin, and pyrazinamide) (27). Indeed, a great amount of work has been done in order to acquire useful knowledge about the mechanisms of action of and resistance to available antitubercular agents (7, 13, 17-20, 22-24, 33). M. tuberculosis often becomes drug resistant as a consequence of spontaneous genetic mutations involving the molecular targets of drugs. The primary mechanism of multidrug resistance in TB is the accumulation of mutations in individual drug target genes (19). However, such knowledge is not sufficient to rationally overcome drug resistance in mycobacteria. In fact, currently, combinations of two or more anti-TB drugs are used to prevent the development of resistant mycobacteria; sometimes it is also necessary to resort to second-line drugs (ciprofloxacin, ethionamide, kanamycin, and aminosalicylic acid, etc.) (15,25). Consequently, the present anti-TB regimen is rather complex and lengthy. In immunosuppressed patients, it is also unsatisfactory. All of these serious concerns require particular attention an...
