Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
Eur J Med Chem. 2021 Oct 5;221:113518. doi: 10.1016/j.ejmech.2021.113518. Epub 2021 May 13.
The emergence of Plasmodium falciparum resistance to frontline antimalarials, including artemisinin combination therapies, highlights the need for new molecules that act via novel mechanisms of action. Herein, we report the design, synthesis and antimalarial activity of a series of 2-aminobenzimidazoles, featuring a phenol moiety that is crucial to the pharmacophore. Two potent molecules exhibited IC values against P. falciparum 3D7 strain of 42 ± 4 (3c) and 43 ± 2 nM (3g), and high potency against strains resistant to chloroquine (Dd2), artemisinin (Cam3.II) and PfATP4 inhibitors (SJ557733), while demonstrating no cytotoxicity against human cells (HEK293, IC > 50 μM). The most potent molecule, possessing a 4,5-dimethyl substituted phenol (3r) displayed an IC value of 6.4 ± 0.5 nM against P. falciparum 3D7, representing a 12-fold increase in activity from the parent molecule. The 2-aminobenzimidazoles containing a N-substituted phenol represent a new class of molecules that have high potency in vitro against P. falciparum malaria and low cytotoxicity. They possessed attractive pharmaceutical properties, including low molecular weight, high ligand efficiency, high solubility, synthetic tractability and low in vitro clearance in human liver microsomes.
疟原虫对青蒿素为基础的联合疗法等一线抗疟药物产生耐药性，凸显了研发具有全新作用机制的新分子的必要性。本研究报告了一系列 2-氨基苯并咪唑的设计、合成及抗疟活性，这些化合物均含有一个酚基，这是药效团的关键部分。两种强效分子对 3D7 疟原虫株的 IC 值分别为 42 ± 4（3c）和 43 ± 2 nM（3g），对氯喹（Dd2）、青蒿素（Cam3.II）和 PfATP4 抑制剂（SJ557733）耐药株也具有高活性，而对人细胞（HEK293）无细胞毒性（IC > 50 μM）。活性最强的分子（3r）含有 4,5-二甲基取代的酚，对 3D7 疟原虫的 IC 值为 6.4 ± 0.5 nM，与母体分子相比，活性提高了 12 倍。含有 N-取代酚的 2-氨基苯并咪唑代表了一类新的分子，它们对体外疟原虫具有高活性和低细胞毒性。这些分子具有吸引人的药学性质，包括低分子量、高配体效率、高溶解性、合成可及性和在人肝微粒体中的低体外清除率。
