Chemistry Department, Faculty of Science, Sohag University, Sohag, Egypt.
High Institute of Public Health, Alexandria University, Alexandria, Egypt.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):330-342. doi: 10.1080/14756366.2022.2150763.
New spiro-piperidine derivatives were synthesised via the eco-friendly ionic liquids in a one-pot fashion. The antileishmanial activity against promastigote and amastigote forms highlighted promising antileishmanial activity for most of the derivatives, with superior activity compared to miltefosine. The most active compounds and exhibited sub-micromolar range of activity, with IC values of 0.89 µM and 0.50 µM, respectively, compared to 8.08 µM of miltefosine. Furthermore, the antileishmanial activity reversal of these compounds folic and folinic acids displayed comparable results to the positive control trimethoprim. This emphasises that their antileishmanial activity is through the antifolate mechanism targeting DHFR and PTR1. The most active compounds showed superior selectivity and safety profile compared to miltefosine against VERO cells. Moreover, the docking experiments of and against -PTR1 rationalised the observed activities. Molecular dynamics simulations confirmed a stable and high potential binding to -PTR1.
新型螺环哌啶衍生物通过绿色离子液体在一锅法中合成。抗利什曼原虫活性对前鞭毛体和无鞭毛体形式的研究突出了大多数衍生物具有有希望的抗利什曼原虫活性，其活性优于米替福新。最活性化合物和表现出亚微摩尔范围内的活性，IC 值分别为 0.89µM 和 0.50µM，而米替福新的 IC 值为 8.08µM。此外，这些化合物对叶酸和叶酸盐的抗利什曼原虫活性逆转与阳性对照三甲氧苄氨嘧啶显示出可比的结果。这强调了它们的抗利什曼原虫活性是通过针对 DHFR 和 PTR1 的抗叶酸机制。与米替福新相比，最活性化合物对 VERO 细胞表现出更高的选择性和安全性。此外，对 -PTR1 的对接实验合理地解释了观察到的活性。分子动力学模拟证实了与 -PTR1 的稳定和高潜力结合。
