Lagardère Prisca, Mustière Romain, Amanzougaghene Nadia, Hutter Sébastien, Franetich Jean-François, Azas Nadine, Vanelle Patrice, Verhaeghe Pierre, Primas Nicolas, Mazier Dominique, Masurier Nicolas, Lisowski Vincent
Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, ENSCM, UFR des Sciences Pharmaceutiques et Biologiques, 34293 Montpellier, France.
Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 13385 Marseille, France.
Pharmaceuticals (Basel). 2022 Jul 1;15(7):820. doi: 10.3390/ph15070820.
Malaria remains one of the major health problems worldwide. The increasing resistance of to approved antimalarial drugs requires the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Based on the structure of Gamhepathiopine, a 2--butylaminothieno[3,2-]pyrimidin-4(3)-one hit, active on the sexual and asexual stages of the parasite and thanked for the introduction of various substituents at position 4 of the thienopyrimidine core by nucleophilic aromatic substitution and pallado-catalyzed coupling reactions, a series of 4-substituted thieno[3,2-]pyrimidines were identified as displaying in vitro activities against both the erythrocytic stage of and the hepatic stage of Among the 28 compounds evaluated, the chloro analogue of Gamhepathiopine showed good activity against the erythrocytic stage of moderate toxicity on HepG2, and better activity against hepatic parasites, compared to Gamhepathiopine.
疟疾仍然是全球主要的健康问题之一。疟原虫对已批准抗疟药物的耐药性不断增加，这就需要开发能够有效预防和/或治疗这种疾病的新型抗疟原虫药物。基于Gamhepathiopine（一种2-丁基氨基噻吩并[3,2-c]嘧啶-4(3H)-酮活性先导化合物）的结构，该化合物对疟原虫的有性和无性阶段均有活性，通过亲核芳香取代反应和钯催化偶联反应在噻吩并嘧啶核心的4位引入各种取代基后，一系列4-取代噻吩并[3,2-c]嘧啶被鉴定为对疟原虫的红细胞阶段和肝脏阶段均具有体外活性。在评估的28种化合物中，Gamhepathiopine的氯代类似物对疟原虫的红细胞阶段显示出良好活性，对HepG2细胞具有中等毒性，并且与Gamhepathiopine相比，对肝脏阶段的疟原虫具有更好的活性。
