A furoxan–amodiaquine hybrid as a potential therapeutic for three parasitic diseases

Bryan T. Mott; Ken Chih-Chien Cheng; Rajarshi Guha; Valerie P. Kommer; David L. Williams; Jon J. Vermeire; Michael Cappello; David J. Maloney; Ganesha Rai; Ajit Jadhav; Anton Simeonov; James Inglese; Gary H. Posner; Craig J. Thomas

doi:10.1039/C2MD20238G

A furoxan–amodiaquine hybrid as a potential therapeutic for three parasitic diseases†

Bryan T. Mott,^ab Ken Chih-Chien Cheng,^b Rajarshi Guha,^b Valerie P. Kommer,^c David L. Williams,^c Jon J. Vermeire,^d Michael Cappello,^d David J. Maloney,^b Ganesha Rai,^b Ajit Jadhav,^b Anton Simeonov,^b James Inglese,^be Gary H. Posner^af and Craig J. Thomas*^b

Author affiliations

* Corresponding authors

^a Department of Chemistry, Zanvyl Krieger School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland, USA

^b Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA
E-mail: craigt@mail.nih.gov

^c Department of Immunology and Microbiology, Rush University Medical Center, 1735 West Harrison Street, Chicago, Illinois, USA

^d Department of Pediatrics, Yale Child Health Research Center, Yale University Medical School, 464 Congress Avenue, New Haven, CT 06520, USA

^e National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA

^f The Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health, Baltimore, Maryland, USA

Abstract

Parasitic diseases continue to have a devastating impact on human populations worldwide. Lack of effective treatments, the high cost of existing ones, and frequent emergence of resistance to these agents provide a strong argument for the development of novel therapies. Here we report the results of a hybrid approach designed to obtain a dual acting molecule that would demonstrate activity against a variety of parasitic targets. The antimalarial drug amodiaquine has been covalently joined with a nitric oxide-releasing furoxan to achieve multiple mechanisms of action. Using in vitro and ex vivo assays, the hybrid molecule shows activity against three parasites – Plasmodium falciparum, Schistosoma mansoni, and Ancylostoma ceylanicum.

MedChemComm

A furoxan–amodiaquine hybrid as a potential therapeutic for three parasitic diseases†

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A furoxan–amodiaquine hybrid as a potential therapeutic for three parasitic diseases

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