New 1,2,4-triazole potential inhibitors of mycobacterial imidazoleglycerol-phosphate dehydratase (IGPD)

Mycobacterium tuberculosis, especially its multi-resistant strains, poses a serious threat to human health, and therefore, the development of new anti-tuberculosis agents is an important trend in new biologically active compounds search. 1,2,4-Triazole is a privileged fragment of antibacterial drugs, including anti-tuberculosis agents. A number of macromolecular targets are known for M. tuberculosis, among which special attention deserves imidazoleglycerol-phosphate dehydratase (IGPD) – the enzyme catalyzing the sixth reaction of histidine bacterial biosynthesis. This enzyme can be considered a selective target of anti-tuberculosis therapy due to the lack of human orthologs. Some researchers previously shown that some of compounds with 1,2,4-triazole fragments inhibits IGPD. According to those authors, 1,2,4-triazole is able to mimic the heterocycle of IGPD substrate – imidazole glycerol phosphate. In the proposed work, a number of high model affinity to the IGPD catalytic site new derivatives of 5-aminomethyl-1,2,4-triazole-3-carboxamides were synthesized. The antimicrobial potential of these compounds was tested against the M. smegmatis. Non-pathogenic M. smegmatis were used as a model of M. tuberculosis due to the high conservativeness of IGPD and similarities in cell wall structure and metabolism in the genus Mycobacterium. According to the primary results a number of 5-aminomethyl-1,2,4-triazole-3-carboxamide derivatives show the inhibition of the M. smegmatis microbial growth. Moreover, experimental data showed that the greatest activity was shown by those compounds whose affinity for the model of the catalytic center of the enzyme was higher. This suggests that the new compounds may be active by binding to the catalytic site of IGPD.