Novel prenyloxy chalcones as potential leishmanicidal and trypanocidal agents: Design, synthesis and evaluation.

Autor: Espinoza-Hicks JC; Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua, Circuito Universitario, Campus Universitario, Apartado Postal 669, Chihuahua, Chih., Mexico., Chacón-Vargas KF; Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, 11340, Ciudad de México, Mexico; Departamento de Parasitología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, 11340, Ciudad de México, Mexico., Hernández-Rivera JL; Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua, Circuito Universitario, Campus Universitario, Apartado Postal 669, Chihuahua, Chih., Mexico., Nogueda-Torres B; Departamento de Parasitología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, 11340, Ciudad de México, Mexico., Tamariz J; Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, 11340, Ciudad de México, Mexico., Sánchez-Torres LE; Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, s/n, 11340, Ciudad de México, Mexico. Electronic address: luviasanchez@hotmail.com., Camacho-Dávila A; Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua, Circuito Universitario, Campus Universitario, Apartado Postal 669, Chihuahua, Chih., Mexico. Electronic address: acamach@uach.mx.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2019 Apr 01; Vol. 167, pp. 402-413. Date of Electronic Publication: 2019 Feb 12.
DOI: 10.1016/j.ejmech.2019.02.028
Abstrakt: The available drugs for treating Leishmaniasis and American trypanosomiasis have high toxicity and multiple side effects, among other problems. More effective and less toxic treatments are urgently needed. A series of chalcones that contained a prenyloxy or geranyloxy substituent was synthesized and characterized. Each substituent was attached to the A ring in some compounds and to the B ring in others, with additional substituents placed on the chalcone moiety. The present aim was to evaluate the effect of the substitution pattern on leishmanicidal and trypanocidal activity. When tested at a single concentration, the compounds exerting a metabolic inhibition close to or exceeding 50% for Leishmania mexicana were 11, 17 and 12, and for Trypanosoma cruzi were 11, 17, 15 and 26. Upon determining the selectivity index (SI =IC 50 /CC 50 ), the values were 80.9, 1.24 and 55.12 for 11, 17 and 12 (respectively) versus L. mexicana, and 75.1, 1.43, 27.36 and 33.52 for 11, 17, 15 and 26 (respectively) versus T. cruzi. Structural isomers 11 and 17 showed activity for both the L. mexicana and T. cruzi strains, though the greater cytotoxic activity of 17 led to a lower SI. Compounds 12, 15 and 26 were species specific. For T. cruzi, the SI was higher for 11, 15 and 26 than for the reference drugs nifurtimox and benznidazole. The examination of promastigote morphology after exposing L. mexicana and T. cruzi to 11 revealed a decrease in cell density. The current findings suggest that 11 could be a useful lead compound for further SAR studies.
(Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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