Substituted 2-phenylimidazopyridines: a new class of drug leads for human African trypanosomiasis

Abstract

A phenotypic screen of a compound library for antiparasitic activity on Trypanosoma brucei, the causative agent of human African trypanosomiasis, led to the identification of substituted 2-(3-aminophenyl)oxazolopyridines as a starting point for hit-to-lead medicinal chemistry. A total of 110 analogues were prepared, which led to the identification of 64, a substituted 2-(3-aminophenyl)imidazopyridine. This compound showed antiparasitic activity in vitro with an EC50 of 2 nM and displayed reasonable druglike properties when tested in a number of in vitro assays. The compound was orally bioavailable and displayed good plasma and brain exposure in mice. Compound 64 cured mice infected with Trypanosoma brucei when dosed orally down to 2.5 mg/kg. Given its potent antiparasitic properties and its ease of synthesis, compound 64 represents a new lead for the development of drugs to treat human African trypanosomiasis.

Scheme I

Synthesis of substituted 2-(3-aminophenyl)-oxazolopyridines. (a) 2-Amino-3-hydroxypyridine, polyphosphoric acid, 160 °C, 5 h; (b) SnCl₂.2H₂O, EtOAc, reflux; (c) R²COCl, pyridine, cat. DMAP, rt or R²CO₂H, EDCI, HOBt, CH₂Cl₂, rt.

Scheme II

Synthesis of substituted 2-(3-aminophenyl)-oxazolopyridines containing 6-substituents. (a) N, N′-Disuccinimidyl carbonate, THF, rt; (b) DMF, Br₂, rt; (c) NaOH, H₂O, reflux 5 h; (d) as in Scheme I; (e) K₂CO₃, R³-boronic acid, tetrakis(triphenylphosphine)Pd(0) (catalytic), toluene, ethanol, reflux.

Scheme III