Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India.
Acta Trop. 2010 Jan;113(1):48-51. doi: 10.1016/j.actatropica.2009.09.004. Epub 2009 Sep 19.
Dihydrofolate reductase (DHFR) is a well-known target for antibacterial and anticancer therapy. DHFR inhibitors are useful for protozoan parasites, but are yet to be explored against metazoan species; hence the present work was designed to evaluate the efficacy of DHFR inhibitors against filariasis, one of the major neglected tropical diseases. Molecules from our in-house library of synthetic antifolate agents (biguanide and dihydrotriazine derivatives) were evaluated along with the antimalarial drug pyrimethamine and the antibacterial drug trimethoprim in an in vitro model against Brugia malayi microfilariae (Mf). Three biguanides and two dihydrotriazines were more potent than trimethoprim and pyrimethamine against B. malayi Mf. Trimethoprim, pyrimethamine and four of the five compounds active against Mf were also active against adult worms. To probe the mechanism of action of the compounds, reversal of activity of active compounds by folic acid and folinic acid was studied. In conclusion, DHFR inhibitors could be used as leads for new antifilarial drugs.
二氢叶酸还原酶（DHFR）是一种广为人知的抗菌和抗癌治疗靶点。DHFR 抑制剂对原生动物寄生虫很有用，但尚未针对后生动物物种进行探索；因此，本工作旨在评估 DHFR 抑制剂对丝虫病（一种主要的被忽视热带病）的疗效。我们的合成抗叶酸剂（双胍和二氢三嗪衍生物）库中的分子与抗疟药物乙胺嘧啶和抗菌药物甲氧苄啶一起在体外模型中针对马来丝虫微丝蚴（Mf）进行了评估。三种双胍和两种二氢三嗪对 B. malayi Mf 的活性均强于甲氧苄啶和乙胺嘧啶。对 Mf 具有活性的甲氧苄啶、乙胺嘧啶和五种化合物中的四种对成虫也具有活性。为了探究化合物的作用机制，研究了叶酸和亚叶酸对活性化合物活性的逆转作用。总之，DHFR 抑制剂可用作新型抗丝虫药物的先导化合物。
