Center of Marine Sciences, CCMAR, Gambelas Campus, University of Algarve, UAlg, 8005-139 Faro, Portugal.
Department of Chemistry and Pharmacy, Faculty of Sciences and Technology, FCT, Gambelas Campus, University of Algarve, UAlg, 8005-139 Faro, Portugal.
Molecules. 2022 Aug 24;27(17):5401. doi: 10.3390/molecules27175401.
Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against parasites. This study reports the synthesis and structure of trioxolane-pyrazole (, ) and tetraoxane-pyrazole (, ) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for antileishmanial activity against promastigotes of and , and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of Trioxolane-pyrazole hybrids and exhibited some activity against promastigotes, while tetraoxane-pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound was the most active against both strains of . Such finding was corroborated by the results obtained in assessments of the amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide-pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of . Our preliminary biological findings encourage further optimization of peroxide-pyrazole hybrids to identify a promising antileishmanial lead.
利什曼病是最具影响力的被忽视热带病之一。在尝试重新利用抗疟药物或候选药物时，发现选定的 1,2,4-三恶烷、1,2,4,5-四恶烷和含吡唑的化学型对寄生虫表现出活性。本研究报道了 3(5)-氨基吡唑与含内过氧化物的构建块反应得到的三恶烷-吡唑（、）和四恶烷-吡唑（、）杂合体的合成和结构。有趣的是，只有 3(5)-氨基吡唑的内环胺被发现作为酰胺偶联的亲核试剂。然而，反应的命运受到吡唑杂环的质子互变异构的影响，生成了 3-和 5-氨基吡唑含杂合体，这些杂合体通过不同的技术进行了表征，包括 X 射线晶体学。这些化合物针对 和 前鞭毛体的抗利什曼原虫活性进行了评估，对 THP-1 细胞的细胞毒性进行了评估。选择的化合物还针对 的巨噬细胞内变形体进行了评估。三恶烷-吡唑杂合体 和 对 前鞭毛体表现出一定的活性，而四恶烷-吡唑杂合体则没有活性，这很可能是由于溶解度问题。然后制备了八种盐形式，特别是甲苯磺酸盐、甲磺酸盐和盐酸盐，以提高相应过氧化物杂合体的溶解度，并对其进行了统一测试。在鞭毛体中的生物学评估表明，化合物 对两种 株均表现出最强的活性。在变形体易感性评估中得到的结果证实了这一发现。值得注意的是，过氧化物-吡唑杂合体的盐形式显示出更广泛的作用谱，对两种 株均表现出活性。我们的初步生物学发现鼓励进一步优化过氧化物-吡唑杂合体，以确定有前途的抗利什曼原虫先导化合物。
