Preliminary investigations of the effect of lipophilic analogues of the active metabolite of isoniazid toward bacterial and plasmodial strains.

ABSTRACT

Five lipophilic analogues 1-5 of the active metabolite of the antitubercular drug isoniazid (INH), selected as inhibitors of Mycobacterium smegmatis and Mycobacterium tuberculosis growth, were evaluated for their activity against Corynebacterium glutamicum (lacking in InhA activity), Escherichia coli (to test mycobacteria selectivity), and Plasmodium falciparum (as possible parasite target). Compound 3 was the only one that did not inhibit C. glutamicum growth. The poor InhA inhibitors 1 and 2 were able to inhibit C. glutamicum and their anti(myco)bacterial mechanisms of action involve targets other than InhA. For the effective InhA inhibitors 4 and 5, also active against C. glutamicum and M. tuberculosis strains, more than one pathway should be envisaged to explain their actions. Pyridine-base ring analogues (1, 2, and 3) have no ability to inhibit the growth of E. coli even at a high concentration. Compound 3 thus exhibited a selective inhibitory action toward M. tuberculosis, while it was inactive on C. glutamicum and on E. coli growth. It presented an activity profile similar to that of INH suggesting InhA inhibition as one of the possible mechanisms of action. Finally, although a homologue of the reductase InhA exists in the FAS-II system of P. falciparum, 3 was unable to display antiplasmodial activity.