Heteroaryl ether analogues of an antileishmanial 7-substituted 2-nitroimidazooxazine lead afford attenuated hERG risk: In vitro and in vivo appraisal

• DOI: 10.1016/j.ejmech.2020.112914
• Publication Date: 2020-10-10T15:16:28Z
• Authors: Andrew M. Thompson; Patrick D. O’Connor; Andrew J. Marshall; Vanessa Yardley; Louis Maes; Suman Gupta; Delphine Launay; Stephanie Braillard; Eric Chatelain; Baojie Wan; Scott G. Franzblau; Zhenkun Ma; Christopher B. Co...; William A. Denny
• Keywords: Male; 0303 health sciences; Dose-Response Relationship, Drug; Pyridines; Pharmacology. Therapy; Antiprotozoal Agents; Ether; Hydrocarbons, Aromatic; 3. Good health; Disease Models, Animal; Mice; Structure-Activity Relationship; 03 medical and health sciences; Parasitic Sensitivity Tests; Solubility; Cricetinae; Oxazines; Animals; Humans; Leishmaniasis, Visceral; Female; Biology; Leishmania donovani

Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) 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.