Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
Molecular Parasitology & Immunology Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh, 201 002, India.
Eur J Med Chem. 2021 Oct 5;221:113516. doi: 10.1016/j.ejmech.2021.113516. Epub 2021 May 4.
The current therapeutic regimen for visceral leishmaniasis is inadequate and unsatisfactory due to toxic side effects, high cost and emergence of drug resistance. Alternative, safe and affordable antileishmanials are, therefore, urgently needed and toward these we synthesized a series of arylpiperazine substituted pyranone derivatives and screened them against both in vitro and in vivo model of visceral leishmaniasis. Among 22 synthesized compounds, 5a and 5g showed better activity against intracellular amastigotes with an IC of 11.07 μM and 15.3 μM, respectively. In the in vivo, 5a significantly reduced hepatic and splenic amastigotes burden in Balb/c mice model of visceral leishmaniasis. On a mechanistic node, we observed that 5a induced direct Leishmania killing via mitochondrial dysfunction like cytochrome c release and loss of membrane potential. Taken together, our results suggest that 5a is a promising lead for further development of antileishmanial drugs.
目前的内脏利什曼病治疗方案由于毒性副作用、成本高和耐药性的出现而不够理想和令人满意。因此，迫切需要替代的、安全且负担得起的抗利什曼原虫药物，为此我们合成了一系列芳基哌嗪取代的吡喃酮衍生物，并对其进行了体内和体外内脏利什曼病模型的筛选。在合成的 22 种化合物中，化合物 5a 和 5g 对细胞内无鞭毛体的活性较好，IC 分别为 11.07μM 和 15.3μM。在体内，化合物 5a 显著降低了内脏利什曼病 Balb/c 小鼠模型的肝和脾内无鞭毛体负担。在机制节点上，我们观察到 5a 通过类似于细胞色素 c 释放和膜电位丧失的线粒体功能障碍直接诱导利什曼原虫的杀伤。总之，我们的研究结果表明，5a 是进一步开发抗利什曼原虫药物的有前途的先导化合物。
