Twenty-one biguanide and dihydrotriazine derivatives were synthesized and evaluated as inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms: Pneumocystis carinii (pc), Toxoplasma gondii (tg), Mycobacterium avium (ma), and rat liver (rl). The most potent compound in the series was B2-07 with 12nM activity against tgDHFR. The most striking observation was that B2-07 showed similar potency to trimetrexate, ∼233-fold improved potency over trimethoprim and ∼7-fold increased selectivity as compared to trimetrexate against tgDHFR. Molecular docking studies in the developed homology model of tgDHFR rationalized the observed potency of B2-07. This molecule can act as a good lead for further design of molecules with better selectivity and improved potency.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Enzyme Inhibition and Medicinal Chemistry|
|State||Published - 2010|
- Dihydrofolate reductase
ASJC Scopus subject areas
- Drug Discovery