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6‐Methyl‐7‐Aryl‐7‐Deazapurine Nucleosides as Anti‐ Trypanosoma cruzi Agents: Structure‐Activity Relationship and in vivo Efficacy
Author(s) -
Lin Cai,
Ferreira de Almeida Fiuza Ludmila,
Cardoso Santos Camila,
Ferreira Nunes Daniela,
Cruz Moreira Otacílio,
Bouton Jakob,
Karalic Izet,
Maes Louis,
Caljon Guy,
Hulpia Fabian,
Nazaré C. Soeiro Maria,
Van Calenbergh Serge
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100144
Subject(s) - benznidazole , trypanosoma cruzi , chagas disease , parasitemia , nucleoside , in vivo , pyrimidine , purine , biology , purine metabolism , benzamidine , drug , aryl , purine analogue , pharmacology , nucleoside analogue , trypanocidal agent , plasmodium falciparum , biochemistry , chemistry , malaria , virology , immunology , parasite hosting , alkyl , microbiology and biotechnology , organic chemistry , world wide web , computer science , enzyme
Chagas disease is a tropical infectious disease resulting in progressive organ‐damage and currently lacks efficient treatment and vaccine options. The causative pathogen, Trypanosoma cruzi , requires uptake and processing of preformed purines from the host because it cannot synthesize these de novo , instigating the evaluation of modified purine nucleosides as potential trypanocides. By modifying the pyrimidine part of a previously identified 7‐aryl‐7‐deazapurine nucleoside, we found that substitution of a 6‐methyl for a 6‐amino group allows retaining T. cruzi amastigote growth inhibitory activity but confers improved selectivity towards mammalian cells. By keeping the 6‐methyl group unaltered, and introducing different 7‐aryl groups, we identified several analogues with sub‐micromolar antitrypanosomal activity. The 7‐(4‐chlorophenyl) analogue 14 , which was stable in microsomes, was evaluated in an acute mouse model. Oral administration of 25 mg/kg b.i.d. suppressed peak parasitemia and protected mice from infection‐related mortality, gave similar reductions as the reference drug of blood parasite loads determined by qPCR, but as benznidazole failed to induce sterile cure in the short time period of drug exposure (5 days).