by Thompson AM, O’Connor PD, Marshall AJ, Yardley V, Maes L, Gupta S, Launay D, Braillard S, Chatelain E, Wan B, Franzblau SG, Ma Z, Cooper CB, Denny WA. European Journal of Medicinal Chemistry 2021; 209:112914. doi: 10.1016/j.ejmech.2020.112914
Summary: Clinical candidate for visceral leishmaniasis, DNDI-0690, resulted from investigation of 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains. As part of the visceral leishmaniasis lead optimization programme, the authors aimed to identify several efficacious backup candidates with diverse product profiles to mitigate development risks. They report the results of a follow-up structure-activity relationship study of a 7-substituted 2-nitroimidazooxazine. They incorporated new aryl or heteroaryl side chains with the intention of improving solubility and safety profiles, whilst maintaining suitable efficacy in animal models. One promising compound displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.