Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110025, India.
J Med Chem. 2017 Feb 9;60(3):1041-1059. doi: 10.1021/acs.jmedchem.6b01447. Epub 2017 Jan 20.
A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.
一系列吡唑并[二氢]吡啶类化合物被合成并评估了它们对实验性内脏利什曼病（VL）的抗利什曼原虫疗效。在所有化合物中，化合物 6d 和 6j 对细胞内无鞭毛体的活性优于米替福新。化合物 6j（50mg/kg/天）通过腹腔途径进一步在 Leishmania donovani/BALB/c 小鼠中进行了为期 5 天的研究，显示脾脏和肝脏寄生虫负荷分别清除率>91%和>93%。在 BALB/c 小鼠中，6j 与亚治疗剂量米替福新（5mg/kg）联合治疗几乎完全改善了疾病（>97%抑制），通过增加一氧化氮的产生并将免疫反应转向 Th1。此外，研究 6j 对 Leishmania 前鞭毛体的影响表明，它诱导了分子事件，如线粒体膜电位丧失、磷脂酰丝氨酸外化和 DNA 片段化，最终导致寄生虫的程序性细胞死亡。这些结果以及药代动力学研究表明，6j 可能是一种有前途的治疗 VL 的先导化合物，可作为米替福新的辅助治疗药物。
