Purpose

A number of tetrahydropyrimidines and their bioisosteric dihydropyridines bearing chloro substituent at various positions of phenyl ring in C4 of main scaffolds were designed, synthesized and evaluated for antileishmanial activity.

Methods

The antileishmanial activity of the synthesized compounds was evaluated against promastigote and amastigote forms. Moreover, molecular docking studies of the compounds in pteridine reductase 1 (PTR1) pocket were carried out to describe the results of biological experiments.

Results

The compounds exhibited moderate to good antileishmanial activity against promastigote and amastigote forms. Among the screened compounds, 1d and 2c were found as the most potent compounds against promastigote form with EC₅₀ values of 15.5 and 10.5 µM, respectively. Compounds 2a and 2c were the most potent compounds against amastigote form with EC₅₀ values of 5.4 and 2.2 µM, respectively.

Conclusion

According to structure–activity relationship (SAR) studies, the chloro substituent in different positions of phenyl ring at C4 of 1,2,3,4-tetrahydropyrimidine (THPM) and 1,4-dihydropyridine (DHP) rings and also the length of the chain belonging to the ester groups could be important for antileishmanial activity of these compounds. Most of these compounds exhibited low cytotoxicity against macrophages. Compounds 1 h, 2a, 2b and 2c revealed higher activity than glucantime while all compounds showed lower activity toward amphotericine B. Docking studies showed that the synthesized compounds were fit well in the PTR1 pocket. Compounds 1 h and 2c indicated the highest score docking among screened compounds in PTR1 enzyme.

中文翻译：

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四氢嘧啶和二氢吡啶衍生物抗利什曼原虫的合成及生物学评价

目的

设计、合成了许多四氢嘧啶及其生物等排二氢吡啶，它们在主要支架的 C4 苯环的不同位置上带有氯取代基，并评估了它们的抗杀虫活性。

方法

针对前鞭毛体和无鞭毛体形式评估了合成化合物的杀虫活性。此外，对蝶啶还原酶1（PTR1）口袋中的化合物进行了分子对接研究，以描述生物学实验的结果。

结果

这些化合物对前鞭毛体和无鞭毛体形式表现出中等至良好的抗寄生虫活性。在筛选的化合物中，发现1d和2c是对前鞭毛体形式最有效的化合物，EC ₅₀值分别为 15.5 和 10.5 µM。化合物2a和2c是对无鞭毛体形式最有效的化合物，EC ₅₀值分别为 5.4 和 2.2 µM。

结论

根据构效关系 (SAR) 研究，1,2,3,4-四氢嘧啶 (THPM) 和 1,4-二氢吡啶 (DHP) 环的 C4 苯环不同位置的氯取代基以及属于酯基的链可能对这些化合物的抗寄生虫活性很重要。大多数这些化合物对巨噬细胞表现出低细胞毒性。化合物1 h、2a、2b和2c显示出比葡聚糖高的活性，而所有化合物对两性霉素 B 显示出较低的活性。对接研究表明，合成的化合物很好地适合 PTR1 口袋。化合物1 h和2c表示在 PTR1 酶中筛选的化合物中的最高分数对接。