Chauhan Kuldeep, Sharma Moni, Shivahare Rahul, Debnath Utsab, Gupta Suman, Prabhakar Yenamandra S, Chauhan Prem M S
Medicinal and Process Chemistry Division and Division of Parasitology, CSIR-Central Drug Research Institute , Lucknow 226031, U.P., India.
ACS Med Chem Lett. 2013 Oct 1;4(11):1108-13. doi: 10.1021/ml400317e. eCollection 2013 Nov 14.
The World Health Organization has classified the leishmaniasis as a major tropical disease. The discovery of new compounds for leishmaniasis is therefore a pressing concern for the anti-infective research program. We have synthesized 19 compounds of triazine dimers as novel antileishmanial agents. Most of the synthesized derivatives exhibited better activity against intracellular amastigotes (IC50 ranging from 0.77 to 10.32 μM) than the control, pentamidine (IC50 = 13.68 μM), and are not toxic to Vero cells. Compounds 14 and 15 showed significant in vivo inhibition of 74.41% and 62.64%, respectively, in L. donovani/hamster model. Moreover, expansion of Th1-type and suppression of Th2-type immune responses proved that compound 14 stimulates mouse macrophages to prevent the progression of leishmania parasite. The molecular docking studies involving PTR1 protein PDB further validated the concepts involved in the design of these compounds. Among the investigated analogues, compound 14 has emerged as the potential one to enlarge the scope of the study.
世界卫生组织已将利什曼病列为一种主要的热带疾病。因此，发现用于治疗利什曼病的新化合物是抗感染研究项目的一个紧迫问题。我们合成了19种三嗪二聚体化合物作为新型抗利什曼原虫剂。大多数合成衍生物对细胞内无鞭毛体的活性（IC50范围为0.77至10.32 μM）优于对照药物喷他脒（IC50 = 13.68 μM），且对Vero细胞无毒。在杜氏利什曼原虫/仓鼠模型中，化合物14和15分别表现出74.41%和62.64%的显著体内抑制作用。此外，Th1型免疫反应的增强和Th2型免疫反应的抑制证明化合物14刺激小鼠巨噬细胞以阻止利什曼原虫寄生虫的进展。涉及PTR1蛋白PDB的分子对接研究进一步验证了这些化合物设计中所涉及的概念。在所研究的类似物中，化合物14已成为扩大研究范围的潜在候选物。
