Diversity-Oriented Synthesis Yields a New Drug Lead for Treatment of Chagas Disease

作者：Dandapani Sivaraman^*; Germain Andrew R; Jewett Ivan; le Quement Sebastian; Marie Jean Charles; Muncipinto Giovanni; Duvall Jeremy R; Carmody Leigh C; Perez Jose R; Engel Juan C; Gut Jiri; Kellar Danielle; Siqueira Neto Jair Lage; McKerrow James H; Kaiser Marcel; Rodriguez Ana; Palmer Michelle A; Foley Michael; Schreiber Stuart L; Munoz Benito

来源：ACS Medicinal Chemistry Letters, 2014, 5(2): 149-153.

DOI：10.1021/ml400403u

• Trypanosoma cruzi
• diversity-oriented synthesis
• Chagas disease
• neglected disease
• high-throughput screening
• phenotypic assay
• infectious disease
• Molecular Libraries Probe Production Centers Network

A phenotypic high-throughput screen using similar to 100,000 compounds prepared using Diversity-Oriented Synthesis yielded stereoisomeric compounds with nanomolar growth-inhibition activity against the parasite Trypanosoma cruzi, the etiological agent of Chagas disease. After evaluating stereochemical dependence on solubility, plasma protein binding and microsomal stability, the SSS analogue (5) was chosen for structure-activity relationship studies. The p-phenoxy benzyl group appended to the secondary amine could be replaced with halobenzyl groups without loss in potency. The exocyclic primary alcohol is not needed for activity but the isonicotinamide substructure is required for activity. Most importantly, these compounds are trypanocidal and hence are attractive as drug leads for both acute and chronic stages of Chagas disease. Analogue (5) was nominated as the molecular libraries probe ML341 and is available through the Molecular Libraries Probe Production Centers Network.

• 出版日期2014-2