Lusardi Matteo, Basilico Nicoletta, Iervasi Erika, Brullo Chiara, Parapini Silvia, Ponassi Marco, Rosano Camillo, Spallarossa Andrea
Department of Pharmacy, Università degli Studi di Genova, viale Benedetto XV, 3, 16132, Genova, Italy.
Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, Via Morego, 30, 16163, Genova, Italy.
ChemMedChem. 2025 Aug 16;20(16):e202500154. doi: 10.1002/cmdc.202500154. Epub 2025 Jun 29.
To further extend the structure-activity relationships of previously reported antimalarial anilino-pyrazoles VI, trisubstituted pyrazoles 13-15, and pyrimidines 16 and 17 are designed and synthesized. The novel derivatives are prepared thorough a divergent, chemo-selective approach starting from N,S-acetal intermediates. Compounds 13-17 are tested for their antimalarial and antileishmanial activity and their cytotoxicity is evaluated against human fibroblast. Pyrazoles 14 d,e and pyrimidine 17e are identified as novel and effective antiplasmodial agents being able to inhibit, at micromolar concentrations, chloroquine(CQ)-sensitive and CQ-resistant Plasmodium falciparum strains, as well as Leishmania infatum and Leishmania tropica protozoa. Additionally, favorable pharmacokinetics and toxicity profiles are predicted for the compounds.
为了进一步拓展先前报道的抗疟苯胺基吡唑VI、三取代吡唑13 - 15以及嘧啶16和17的构效关系，设计并合成了这些化合物。这些新型衍生物是从N,S - 缩醛中间体出发，通过一种发散性的化学选择性方法制备的。对化合物13 - 17进行了抗疟和抗利什曼原虫活性测试，并评估了它们对人成纤维细胞的细胞毒性。吡唑14 d,e和嘧啶17e被鉴定为新型有效的抗疟原虫剂，能够在微摩尔浓度下抑制氯喹（CQ）敏感和CQ耐药的恶性疟原虫菌株，以及婴儿利什曼原虫和热带利什曼原虫。此外，预测这些化合物具有良好的药代动力学和毒性特征。
