title: Aminothiazoles: Hit to lead development to identify antileishmanial agents.
abstract: 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.
authors: Advinus Therapeutics Ltd., Bengaluru 560 058, India.
authors: Debnath
authors: D
authors: Bhuniya
authors: Advinus Therapeutics Ltd., Bengaluru 560 058, India.
authors: Rao
authors: R
authors: Mukkavilli
authors: Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors: Rahul
authors: R
authors: Shivahare
authors: Drugs for Neglected Diseases initiative (DNDi), 15 Chemin Louis Dunant, 1202 Geneva, Switzerland.
authors: Delphine
authors: D
authors: Launay
authors: Advinus Therapeutics Ltd., Bengaluru 560 058, India.
authors: Ravindra T
authors: RT
authors: Dere
authors: Advinus Therapeutics Ltd., Bengaluru 560 058, India.
authors: Anil
authors: A
authors: Deshpande
authors: Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors: Aditya
authors: A
authors: Verma
authors: Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors: Preeti
authors: P
authors: Vishwakarma
authors: Advinus Therapeutics Ltd., Bengaluru 560 058, India.
authors: Manjunath
authors: M
authors: Moger
authors: Advinus Therapeutics Ltd., Bengaluru 560 058, India.
authors: Ashok
authors: A
authors: Pradhan
authors: Advinus Therapeutics Ltd., Bengaluru 560 058, India.
authors: Hari
authors: H
authors: Pati
authors: Advinus Therapeutics Ltd., Bengaluru 560 058, India.
authors: Vadiraj S
authors: VS
authors: Gopinath
authors: Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226 031, India. Electronic address: gupta_suman@yahoo.com.
authors: Suman
authors: S
authors: Gupta
authors: Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors: Sunil K
authors: SK
authors: Puri
authors: Drugs for Neglected Diseases initiative (DNDi), 15 Chemin Louis Dunant, 1202 Geneva, Switzerland.
authors: Denis
authors: D
authors: Martin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007624:KB Cells; D007893:Leishmania donovani / Q000187:drug effects*; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D013844:Thiazoles
keywords: Aminothiazoles; Leishmania donovani; Metabolic stability; Pharmacokinetics; Visceral leishmaniasis