Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
Biomedical Research and Study Centre , Ratsupites 1, Riga LV-1067, Latvia.
J Med Chem. 2016 Jan 14;59(1):374-87. doi: 10.1021/acs.jmedchem.5b01558. Epub 2015 Dec 23.
2-Aminoquinazolin-4(3H)-ones were identified as a novel class of malaria digestive vacuole plasmepsin inhibitors by using NMR-based fragment screening against Plm II. Initial fragment hit optimization led to a submicromolar inhibitor, which was cocrystallized with Plm II to produce an X-ray structure of the complex. The structure showed that 2-aminoquinazolin-4(3H)-ones bind to the open flap conformation of the enzyme and provided clues to target the flap pocket. Further improvement in potency was achieved via introduction of hydrophobic substituents occupying the flap pocket. Most of the 2-aminoquinazolin-4(3H)-one based inhibitors show a similar activity against digestive Plms I, II, and IV and >10-fold selectivity versus CatD, although varying the flap pocket substituent led to one Plm IV selective inhibitor. In cell-based assays, the compounds show growth inhibition of Plasmodium falciparum 3D7 with IC50 ∼ 1 μM. Together, these results suggest 2-aminoquinazolin-4(3H)-ones as perspective leads for future development of an antimalarial agent.
2-氨基喹唑啉-4(3H)-酮类化合物被鉴定为一类新型疟原虫消化液质体朊酶抑制剂，通过使用基于 NMR 的片段筛选针对 Plm II 进行筛选。初步的片段优化导致了一种亚毫摩尔抑制剂，该抑制剂与 Plm II 共结晶，产生了复合物的 X 射线结构。该结构表明，2-氨基喹唑啉-4(3H)-酮类化合物结合到酶的张开瓣构象上，并为靶向瓣口袋提供了线索。通过引入占据瓣口袋的疏水取代基，进一步提高了效力。大多数基于 2-氨基喹唑啉-4(3H)-酮的抑制剂对消化液质体 Plms I、II 和 IV 表现出相似的活性，对 CatD 的选择性超过 10 倍，尽管改变瓣口袋取代基导致了一种 Plm IV 选择性抑制剂。在细胞测定中，这些化合物对 Plasmodium falciparum 3D7 的生长抑制作用的 IC50 值约为 1 μM。总之，这些结果表明 2-氨基喹唑啉-4(3H)-酮类化合物是未来抗疟药物开发的有前途的先导化合物。
