Collaborative virtual screening to elaborate an imidazo[1,2- a]pyridine hit series for visceral leishmaniasis

Abstract

An innovative pre-competitive virtual screening collaboration was engaged to validate and subsequently explore an imidazo[1,2-a]pyridine screening hit for visceral leishmaniasis. In silico probing of five proprietary pharmaceutical company libraries enabled rapid expansion of the hit chemotype, alleviating initial concerns about the core chemical structure while simultaneously improving antiparasitic activity and selectivity index relative to the background cell line. Subsequent hit optimization informed by the structure-activity relationship enabled by this virtual screening allowed thorough investigation of the pharmacophore, opening avenues for further improvement and optimization of the chemical series.

Fig. 1. Overview of Booster in silico screening process; first (A) and second (B) round of virtual screening result in data set of compounds with annotated SAR around 1; data set is further annotated via expansive analoguing (C).

Fig. 2. A) Diverse compounds identified from the booster giving confidence in the viability of the chemical series; B) dose response curves for 4; C) high content images of L. donovani infected THP1 cells treated with various concentrations of 4.

Scheme 1. i) ArCOCH₃, I₂, NaOH, H₂O, 110 °C; ii) NBS, MeCN, 20 °C; iii) R3-NC, TsOH, ArCHO, MeOH, 70 °C; iv) R3R4NH, t-BuONa, Brettphos-Pd-G3, t-amylalcohol, 90 °C; v) HCl, MeOH, 20 °C; vi) R7COOH, EDCI, pyridine, 25 °C; vii) BH₃SMe₂, THF, 60 °C; viii) ArX, t-BuONa, Pd₂(dba)₃, XantPhos, PhMe, 110 °C; ix) ix) Ti(i-PrO)₄, NaBH₃CN, dioxane, 60 °C

Fig. 3. Pharmacokinetic profiling of 23 in mouse.