Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai, India.
J Enzyme Inhib Med Chem. 2010 Jun;25(3):331-9. doi: 10.3109/14756360903179443.
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 12 nM activity against tgDHFR. The most striking observation was that B2-07 showed similar potency to trimetrexate, approximately 233-fold improved potency over trimethoprim and approximately 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.
合成了 21 种双胍和二氢三嗪衍生物，并将其评估为机会性微生物二氢叶酸还原酶 (DHFR) 的抑制剂：卡氏肺孢子虫 (pc)、刚地弓形虫 (tg)、鸟分枝杆菌 (ma) 和大鼠肝脏 (rl)。该系列中最有效的化合物是 B2-07，对 tgDHFR 的活性为 12 nM。最引人注目的观察结果是，B2-07 对 trimetrexate 具有相似的效力，与 trimethoprim 相比，其效力提高了约 233 倍，与 trimetrexate 相比，对 tgDHFR 的选择性提高了约 7 倍。在刚地弓形虫 DHFR 的同源模型中进行的分子对接研究解释了 B2-07 的观察到的效力。该分子可以作为进一步设计具有更好选择性和更高效力的分子的良好先导物。
