Optimization of Physicochemical Properties and ADME for 2,4-Substituted 1H‑Pyrrolo[2,3b]pyridines Inhibitors of Trypanosome Proliferation

Neglected tropical diseases, such as human African trypanosomiasis (HAT), require novel treatments that can populate the clinical pipeline in the event of rising resistance and treatment recrudescence. Following a high-throughput screen of almost 42,000 human kinase inhibitor chemotypes, we identified a 2,4-disubstituted azaindole that had good antiparasitic activity, selectivity, and predicted brain exposure, but that failed to meet our criteria for advancement into an efficacy study. Following hit-to-lead optimization, we arrived at 18a, which offered the best combination of potency, properties, and pharmacokinetic parameters, and, while not curative, this work leads to opportunities for continued optimization for HAT and cutaneous leishmaniasis.