Aminothiazoles: Hit to lead development to identify antileishmanial agents


As part of Drugs for Neglected Diseases initiative's lead optimization program for the development of new chemical entities to treat visceral leishmaniasis (VL), a series of aminothiazoles were synthesized and screened for in vitro efficacy, solubility and microsomal stability. The primary aim of identifying a lead structure with sub-micromolar activity was achieved. Out of 43 compounds synthesized, 16 compounds showed in vitro activity at less than 1 μM against VL. Compound 32 showed excellent antileishmanial potency (IC50 = 3 nM) and had all the acceptable properties except for metabolic instability. Blocking the metabolic soft spots in compound 32, where the 4-methoxy pyridine substituent was replaced by 5-ethoxy group, led to compound 36 (IC50 = 280 nM) with improved stability. To understand the disposition of 36, in vivo pharmacokinetic study was conducted in a mouse model. Compound 36 showed high clearance (91 mL/min/kg); short half-life (0.48 h) after intravenous administration (1 mg/kg) and exposure (AUC0-24) following oral administration was 362 ng h/mL with absolute bioavailability of 8%. To summarize, 43 analogs were synthesized out of which 15 compounds showed very potent sub-nanomolar efficacy in in vitro systems but the liability of metabolic instability seemed to be the major challenge for this chemical class and remains to be addressed.


Bhuniya, D.; Mukkavilli, R.; Shivahare, R.; Launay, D.; Ravindra, T.; Dere, Deshpande A.; Verma, A.; Vishwakarma, P.; Moger, M.; Pradhan, A.; Pati, H.; Gopinath, V.S.; Puri, S.K.; Martin, D. Aminothiazoles: Hit to lead development to identify antileishmanial agents. European Journal of Medicinal Chemistry (2015) 102: 582-593. [DOI: 10.1016/j.ejmech.2015.08.013]

Aminothiazoles: Hit to lead development to identify antileishmanial agents

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