Collaborative Virtual Screening Identifies a 2-Aryl-4-aminoquinazoline Series with Efficacy in an In Vivo Model of Trypanosoma cruzi Infection

Authors: Tawaraishi, Taisuke; Ochida, Atsuko; Akao, Yuichiro; Itono, Sachiko; Kamaura, Masahiro; Akther, Thamina; Shimada, Mitsuyuki; Canan, Stacie; Chowdhury, Sanjoy (TCGLS Member); Cao, Yafeng; Condroski, Kevin ; Engkvist, Ola ; Francisco, Amanda; Ghosh, Sunil (TCGLS Member); Kaki, Rina; Kelly, John M.; Kimura, Chiaki; Kogej, Thierry; Nagaoka, Kazuya; Naito, Akira; Pairaudeau, Garry; Radu, Constantin; Roberts, Ieuan; Shum, David; Watanabe, Nao-aki; Xie, Huanxu; Yonezawa, Shuji; Yoshida, Osamu; Yoshida, Ryu; Mowbray, Charles ; Perry, Benjamin

Publication: Journal of Medicinal Chemistry (2023), 66(2), 1221-1238

DOI: https://doi.org/10.1021/acs.jmedchem.2c00775

Abstract: Probing multiple proprietary pharmaceutical libraries in parallel via virtual screening allowed rapid expansion of the structure-activity relationship (SAR) around hit compounds with moderate efficacy against Trypanosoma cruzi, the causative agent of Chagas Disease. A potency-improving scaffold hop, followed by elaboration of the SAR via design guided by the output of the phenotypic virtual screening efforts, identified two promising hit compounds 54 and 85, which were profiled further in pharmacokinetic studies and in an in-vivo model of T. cruzi infection. Compound 85 demonstrated clear reduction of parasitemia in the in-vivo setting, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments.

Graphical Abstract: