Synthesis and biological evaluation of N -cyanoalkyl-, N -aminoalkyl-, and N -guanidinoalkyl-substituted 4-aminoquinoline derivatives as potent, selective, brain permeable antitrypanosomal agents
Sola, Irene (Universitat de Barcelona. Institut de Biomedicina)
Artigas, Albert (Universitat de Barcelona. Institut de Biomedicina)
Taylor, Martin C. (London School of Hygiene and Tropical Medicine)
Pérez-Areales, Francisco Javier (Universitat de Barcelona. Institut de Biomedicina)
Viayna, Elisabet (Universitat de Barcelona. Institut de Biomedicina)
Clos, M. Victoria (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Pérez, Belén (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Wright, Colin W. (University of Bradford. Bradford School of Pharmacy)
Kelly, John M. (London School of Hygiene and Tropical Medicine)
Muñoz-Torrero López-Ibarra, Diego (Universitat de Barcelona. Institut de Biomedicina)

Date:	2016
Abstract:	Current drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. The search for novel, effective, brain permeable, safe, and inexpensive antitrypanosomal compounds is therefore an urgent need. We have recently reported that the 4-aminoquinoline derivative huprine Y, developed in our group as an anticholinesterasic agent, exhibits a submicromolar potency against Trypanosoma brucei and that its homo- and hetero-dimerization can result in to up to three-fold increased potency and selectivity. As an alternative strategy towards more potent smaller molecule anti-HAT agents, we have explored the introduction of ω-cyanoalkyl, ω-aminoalkyl, or ω-guanidinoalkyl chains at the primary amino group of huprine or the simplified 4-aminoquinoline analogue tacrine. Here, we describe the evaluation of a small in-house library and a second generation of newly synthesized derivatives, which has led to the identification of 13 side chain modified 4-aminoquinoline derivatives with submicromolar potencies against T. brucei. Among these compounds, the guanidinononyltacrine analogue 15e exhibits a 5-fold increased antitrypanosomal potency, 10-fold increased selectivity, and 100-fold decreased anticholinesterasic activity relative to the parent huprine Y. Its biological profile, lower molecular weight relative to dimeric compounds, reduced lipophilicity, and ease of synthesis, make it an interesting anti-HAT lead, amenable to further optimization to eliminate its remaining anticholinesterasic activity.
Grants:	Ministerio de Economía y Competitividad SAF2014-57094-R Agència de Gestió d'Ajuts Universitaris i de Recerca 2014SGR52
Note:	Altres ajuts: J.M.K. acknowledges funding support from the Wellcome Trust (Grant number WT092573MA). Fellowships from GC to I.S., F.J.P.-A., and E.V. are gratefully acknowledged.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	4-Aminoquinolines ; Side chain modification ; Guanidines ; Antitrypanosomal agents ; Brain permeability
Published in:	Bioorganic & Medicinal Chemistry, Vol. 24 (november 2016) , p. 5162-5171, ISSN 1464-3391

DOI: 10.1016/j.bmc.2016.08.036
PMID: 27591008

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