Aminothiazoles: Hit to lead development to identify antileishmanial agents

European Journal of Medicinal Chemistry
Debnath BhuniyaDenis Martin

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 b...Continue Reading

References

Jan 25, 2002·Special Care in Dentistry : Official Publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry·J JackowskiT Müller
May 31, 2002·Journal of Medicinal Chemistry·Daniel F VeberKenneth D Kopple
Nov 29, 2002·The New England Journal of Medicine·Shyam SundarJonathan Berman
Jul 1, 2004·Comparative Immunology, Microbiology and Infectious Diseases·P Desjeux
Sep 1, 2005·Antimicrobial Agents and Chemotherapy· AshutoshNeena Goyal
Jun 22, 2007·The New England Journal of Medicine·Shyam SundarSujit K Bhattacharya
Oct 17, 2007·Nature Reviews. Microbiology·François ChappuisMarleen Boelaert
Jan 21, 2011·Journal of Medicinal Chemistry·Alejandra Gallardo-GodoyAdam R Renslo
May 10, 2011·Drug Design, Development and Therapy·Eric Chatelain, Jean-Robert Ioset
Jun 22, 2011·Colorectal Disease : the Official Journal of the Association of Coloproctology of Great Britain and Ireland·H-Z QiuG-L Lin
Oct 1, 2013·Bioorganic & Medicinal Chemistry·Anja MeissnerCourtney C Aldrich
Oct 8, 2013·European Journal of Medicinal Chemistry·Vadiraj S GopinathDenis Martin
Dec 1, 2012·International Journal for Parasitology. Drugs and Drug Resistance·Lucio H Freitas-JuniorJair L Siqueira-Neto
Aug 12, 2014·The Lancet Global Health·Belen PedriqueJean-Hervé Bradol

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Citations

Nov 17, 2015·Journal of Medicinal Chemistry·Charles E MowbrayLouis J Maes
Jun 26, 2017·Drug Discovery Today·Bilal ZulfiqarVicky M Avery
Oct 13, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bilal ZulfiqarVicky M Avery
Aug 28, 2020·Acta Crystallographica. Section E, Crystallographic Communications·Andreas BeuchelRüdiger W Seidel
May 13, 2020·Drug Development Research·Myla Lôbo de SouzaPedro José Rolim Neto
Jun 27, 2021·Chemico-biological Interactions·Luiz Alberto Barros FreitasPaulo André Teixeira de Moraes Gomes

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