Molaei Soheila, Shiran Jafar Abbasi, Shakour Neda, Baradaran Majid, Malihi Zahra, Rahimi Mohammad Reza, Zal Yasamin Abedini, Sepehri Saghi
Zoonoses Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
Sci Rep. 2025 Jul 10;15(1):24867. doi: 10.1038/s41598-025-10545-6.
Leishmaniasis is one of the infectious diseases caused by protozoa and is considered the second most significant parasitic disease after malaria. In this research, thiosemicarbazone Schiff base derivatives were synthesized via a one-pot, two-step, three-component reaction. Then, the effectiveness of the compounds against the two forms of Leishmania major and Leishmania tropica called amastigote and promastigote, was tested. All synthesized compounds displayed weak to good anti-amastigote and anti-promastigote activities. Notably, compounds 5g and 5p were the most potent compounds against amastigote and promastigote forms, respectively, of Leishmania major, with IC = 26.7 µM and 12.77 µM. Analogues 5e and 5g were the most potent compounds against amastigote and promastigote forms of Leishmania tropica, with IC = 92.3 µM and 12.77 µM, respectively. The cytotoxicity activity of the compounds was also evaluated using the J cell lines. Some of the screened derivatives displayed low cytotoxicity to macrophage infection. Among compounds, 5p and 5e showed the highest SI (95.4 and 34.6) against L. major and L. tropica, respectively. In the next phase, the most effective thiosemicarbazone derivatives were examined for their ability to induce apoptosis in promastigotes. According to the results, these compounds displayed different early and late apoptosis as well as necrotic effects on promastigotes of Leishmania major and Leishmania tropica. Furthermore, the compounds' drug-likeness and pharmacokinetic parameters were predicted in silico. All compounds showed acceptable drug-likeness and pharmacokinetic profiles. Furthermore, the most likely sites of the compounds metabolized by the major cytochromes were identified. Additionally, the in silico compounds' cardiotoxicity potential was assessed. This investigation showed compounds 5m-p were cardiotoxic. Lastly, molecular docking and molecular dynamics simulations were performed to explore the potential mechanisms of anti-leishmanial activity in the LmPRT1 active site.
利什曼病是由原生动物引起的传染病之一，被认为是仅次于疟疾的第二大重要寄生虫病。在本研究中，通过一锅两步三组分反应合成了硫代氨基脲席夫碱衍生物。然后，测试了这些化合物对两种利什曼原虫（即硕大利什曼原虫和热带利什曼原虫）的无鞭毛体和前鞭毛体形式的有效性。所有合成化合物均表现出从弱到良好的抗无鞭毛体和抗前鞭毛体活性。值得注意的是，化合物5g和5p分别是对硕大利什曼原虫的无鞭毛体和前鞭毛体形式最有效的化合物，IC值分别为26.7 μM和12.77 μM。类似物5e和5g分别是对热带利什曼原虫的无鞭毛体和前鞭毛体形式最有效的化合物，IC值分别为92.3 μM和12.77 μM。还使用J细胞系评估了化合物的细胞毒性活性。一些筛选出的衍生物对巨噬细胞感染显示出低细胞毒性。在这些化合物中，5p和5e分别对硕大利什曼原虫和热带利什曼原虫表现出最高的SI值（95.4和34.6）。在下一阶段，研究了最有效的硫代氨基脲衍生物诱导前鞭毛体凋亡的能力。根据结果，这些化合物对硕大利什曼原虫和热带利什曼原虫的前鞭毛体表现出不同的早期和晚期凋亡以及坏死作用。此外，通过计算机模拟预测了化合物的类药性和药代动力学参数。所有化合物均显示出可接受的类药性和药代动力学特征。此外，确定了化合物被主要细胞色素代谢的最可能位点。此外，评估了计算机模拟化合物的心脏毒性潜力。该研究表明化合物5m - p具有心脏毒性。最后，进行了分子对接和分子动力学模拟，以探索LmPRT1活性位点抗利什曼活性的潜在机制。
