Identification of benzoylisoquinolines as potential anti-Chagas agents

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• 作者：Kendall G. Byler^a ; Marco Brito-Arias^b ; ; Adrian Marquez-Navarro^c ; Benjamin Nogueda-Torres^c ; Luis G. Torres-Bustillos^b ; Karina Mart&iacute ; nez-Mayorga^a ; ^{kmartinez@tpims.org}
• 关键词：Benzoyl isoquinolones ; Trypanosoma cruzi ; Chemical space ; Structural similarity
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 April, 2012
• 卷：20
• 期：8
• 页码：2587-2594
• 文件大小：3608 K

摘要

A set of three 3-benzoyl substituted isoquinolones was synthesized in good yields and assayed for in vitro trypanocidal activity against Trypanosoma cruzi, the protozoan parasite that causes Chagas鈥?disease. Depending on the concentration evaluated, a greater or equivalent reduction in the number of bloodborne trypomastigotes compared to that observed with benznidazole, a drug currently used to attack the parasite, was observed for two of the samples. In order to assess the potential of the 3-benzoylisoquinolone nucleus as a possible scaffold in the design of novel anti-trypanosomal lead structures, a computational analysis was performed using structural and inhibition information from both functional and target assays archived in the online database, ChEMBL. Chemical space projection of the synthesized compounds along with 3067 structures with known activities against T. cruzi shows that the isoquinolones occupy a sparsely-populated region of chemical space, indicating their potential for development as a novel class of trypanocidals. In addition, 2D and 3D structural similarity analyses revealed micromolar and submicromolar inhibitors of T. cruzi in ChEMBL with high similarity to the synthesized structures.