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Flexible diaminodihydrotriazine inhibitors of Plasmodium falciparum dihydrofolate reductase: Binding strengths, modes of binding and their antimalarial activities.
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-03-25 , DOI: 10.1016/j.ejmech.2020.112263
Sumalee Kamchonwongpaisan 1 , Netnapa Charoensetakul 1 , Choladda Srisuwannaket 2 , Supannee Taweechai 1 , Roonglawan Rattanajak 1 , Jarunee Vanichtanankul 1 , Danoo Vitsupakorn 1 , Uthai Arwon 1 , Chawanee Thongpanchang 1 , Bongkoch Tarnchompoo 1 , Tirayut Vilaivan 2 , Yongyuth Yuthavong 1
Affiliation  

A series of flexible diaminodihydrotriazines or cycloguanil (Cyc) analogues are developed and shown to inhibit P. falciparum dihydrofolate reductase (PfDHFR) of the wild type or those carrying either single (S108N), double (C59R + S108N and A16V + S108T), triple (N51I + C59R + S108N and C59R + S108N + I164L) or quadruple (N51I + C59R + S108N + I164L) mutations, responsible for antifolate resistance. The flexibility of the side chain at position N1 has been included in the design so as to avoid unfavourable steric interaction with the side chain of residue 108 of the resistant mutants. The inhibition constants of many inhibitors for the mutant enzymes are in the low nanomolar region. Regaining of drug binding efficacies was achieved with both A16V and S108N series of mutants. X-ray studies of some enzyme-inhibitor complexes designed for optimal interaction with the mutant enzymes reveal the modes of binding in line with the Ki values. A number of these compounds show excellent antimalarial activities against resistant P. falciparum bearing the mutant enzymes, and exhibit low cytotoxicity to mammalian cells, making them good candidates for further development as antimalarial drugs.

中文翻译:

恶性疟原虫二氢叶酸还原酶的灵活的二氨基二氢三嗪抑制剂:结合强度,结合方式及其抗疟活性。

已开发出一系列灵活的二氨基二氢三嗪或环鸟嘌呤(Cyc)类似物,并显示可抑制野生型的恶性疟原虫二氢叶酸还原酶(PfDHFR)或携带单个(S108N),携带两个(C59R + S108N和A16V + S108T),携带三个(N51I + C59R + S108N和C59R + S108N + I164L)或四倍(N51I + C59R + S108N + I164L)突变,引起抗叶酸耐药性。设计中已包括位置N1的侧链的柔性,以避免与抗性突变体的残基108的侧链发生不利的空间相互作用。许多抑制剂对突变酶的抑制常数在低纳摩尔区域。用A16V和S108N系列突变体都实现了药物结合效率的重新获得。为与突变型酶最佳相互作用而设计的某些酶抑制剂复合物的X射线研究表明,结合模式与Ki值一致。这些化合物中的许多对具有突变酶的抗性恶性疟原虫显示出优异的抗疟活性,并且对哺乳动物细胞显示出低细胞毒性,使其成为抗疟药物的进一步开发的良好候选者。
更新日期:2020-03-26
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