Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Marseille, France.
Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, ENSCM, UFR des Sciences Pharmaceutiques et Biologiques, Montpellier, France.
Eur J Med Chem. 2022 Nov 5;241:114619. doi: 10.1016/j.ejmech.2022.114619. Epub 2022 Jul 20.
Gamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series. All the compounds were tested on the K1 multi-resistant strain of Plasmodium falciparum and the human HepG2 cell-line, to evaluate their antiplasmodial activity and their cytotoxicity. Analogues' biological results also highlighted the mandatory presence of a heteroatom at position 5 of the thieno[3,2-d]pyrimidin-4(3H)-one moeity for the antiplasmodial activity. However, modifications at position 7 were detrimental for the antiplasmodial activity. We identified furane bioisostere 3j as a promising candidate, showing good blood stage antiplasmodial activity, better water solubility and highly improved intestinal permeability in the PAMPA assay.
甘美派辛（也称为 M1）是一种多阶段作用的抗疟 2-叔丁基氨噻吩并[3,2-d]嘧啶-4(3H)-酮盐酸盐，于 2015 年首次描述。该化合物的开发受到较差的微粒体稳定性、不足的水溶解度和低肠道通透性的限制。为了获得新的优化衍生物，我们从化合物 M1 进行了支架跳跃策略，导致合成了属于六个化学系列的 20 种新化合物。所有化合物都在恶性疟原虫 K1 多耐药株和人 HepG2 细胞系上进行了测试，以评估它们的抗疟原虫活性和细胞毒性。类似物的生物学结果还强调了在噻吩并[3,2-d]嘧啶-4(3H)-酮部分的 5 位上必须存在杂原子，才能具有抗疟原虫活性。然而，7 位的修饰对抗疟原虫活性是有害的。我们确定呋喃生物等排体 3j 是一个很有前途的候选物，它具有良好的红内期抗疟原虫活性、更好的水溶性和在 PAMPA 测定中显著提高的肠道通透性。
