探索3-哌啶-4-基-1H-吲哚骨架作为一种新型抗疟化学类型。
Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype.
作者信息
Santos Sofia A, Lukens Amanda K, Coelho Lis, Nogueira Fátima, Wirth Dyann F, Mazitschek Ralph, Moreira Rui, Paulo Alexandra
机构信息
Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Professor Gama Pinto, 1640-003 Lisbon, Portugal; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
The Broad Institute, Infectious Diseases Initiative, Cambridge, MA 02142, USA; Harvard School of Public Health, Department of Immunology and Infectious Disease, Boston, MA 02115, USA.
出版信息
Eur J Med Chem. 2015 Sep 18;102:320-33. doi: 10.1016/j.ejmech.2015.07.047. Epub 2015 Jul 31.
A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight compounds were obtained following a three-step synthetic approach and evaluated for anti-parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-resistant and sensitive strains (EC50 values ∼ 3 μM), selectivity for malaria parasite and no cross-resistance with chloroquine, thus representing a potential new chemotype for further optimization towards novel and affordable antimalarial drugs.
基于对恶性疟原虫进行高通量全细胞筛选得到的活性化合物，合成了一系列具有结构多样性的3-哌啶-4-基-1H-吲哚。采用三步合成方法得到了38种化合物，并对其抗寄生虫活性进行了评估。构效关系研究表明，3-哌啶-4-基-1H-吲哚对大多数N-哌啶基修饰不兼容。然而，我们能够鉴定出一种具有类先导物性质的新化合物（10d，分子量 = 305；cLogP = 2.42），该化合物对耐药和敏感菌株均显示出抗疟活性（半数有效浓度值约为3 μM），对疟原虫具有选择性且与氯喹无交叉耐药性，因此代表了一种潜在的新化学类型，可用于进一步优化以开发新型且价格低廉的抗疟药物。
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