by Tawaraishi T, Ochida A, Akao Y, Itono S, Kamaura M, Akther T, Shimada M, Canan S, Chowdhury S, Cao Y, Condroski K, Engkvist O, Francisco A, Ghosh S, Kaki R, Kelly JM, Kimura C, Kogej T, Nagaoka K, Naito A, Pairaudeau G, Radu C, Roberts I, Shum D, Watanabe N, Xie H, Yonezawa S, Yoshida O, Yoshida R, Mowbray C, Perry B. Journal of Medicinal Chemistry 2023. doi: 10.1021/acs.jmedchem.2c00775
Summary: There is an urgent need for new treatment options for Chagas disease, but the R&D pipeline is relatively bare. The authors used the ‘NTD Booster’ to probe multiple proprietary pharmaceutical libraries in parallel via virtual screening. This allowed rapid expansion of the structure-activity relationship around hit compounds with moderate efficacy. A potency-improving scaffold hop, followed by elaboration of the SAR, guided by output of the phenotypic virtual screening efforts, identified two promising hit compounds; these were profiled further in pharmacokinetic studies and in an in vivo model of T. cruzi infection. One of these compounds demonstrated clear reduction of parasitemia in vivo, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments.