SYNTHESIS OF 4,6-DIAMINO-1,2-DIHYDRO-1,3,5-TRIAZINES AS POTENTIAL BACTERIAL DIHYDROFOLATE REDUCTASE INHIBITORS

Abstract

Treatment for infectious diseases caused by bacteria remains a challenge due to the emergence of microbial resistance. Dihydrofolate reductase (DHFR), a key enzyme in the folate pathway, has been identified as a druggable target for antibacterial drug discovery. In this dissertation, six series of compounds were designed and synthesized via scaffold-based hybridization of 1,2,3-triazole with an anchoring heterocycle containing the 2,4-diamino-1,3-diaza fragment. Side chain modifications were also attempted to optimize their antibacterial and DHFR inhibition activity. All the synthesized compounds went through a phenotype-oriented screening, followed by enzymatic study, on-target activity validation, as well as in silico molecular modeling. As a result, the work of this dissertation has successfully generated potent and selective M. tuberculosis DHFR inhibitors that demonstrated antimycobacterial activity and lesser toxicity. These findings provided insights on the development of antifolates as antitubercular agents.