title: Megazol and its bioisostere 4H-1,2,4-triazole: comparing the trypanocidal, cytotoxic and genotoxic activities and their in vitro and in silico interactions with the Trypanosoma brucei nitroreductase enzyme.
abstract: Megazol (7) is a 5-nitroimidazole that is highly active against Trypanosoma cruzi and Trypanosoma brucei, as well as drug-resistant forms of trypanosomiasis. Compound 7 is not used clinically due to its mutagenic and genotoxic properties, but has been largely used as a lead compound. Here, we compared the activity of 7 with its 4H-1,2,4-triazole bioisostere (8) in bloodstream forms of T. brucei and T. cruzi and evaluated their activation by T. brucei type I nitroreductase (TbNTR) enzyme. We also analysed the cytotoxic and genotoxic effects of these compounds in whole human blood using Comet and fluorescein diacetate/ethidium bromide assays. Although the only difference between 7 and 8 is the substitution of sulphur (in the thiadiazole in 7) for nitrogen (in the triazole in 8), the results indicated that 8 had poorer antiparasitic activity than 7 and was not genotoxic, whereas 7 presented this effect. The determination of Vmax indicated that although 8 was metabolised more rapidly than 7, it bounds to the TbNTR with better affinity, resulting in equivalent kcat/KM values. Docking assays of 7 and 8 performed within the active site of a homology model of the TbNTR indicating that 8 had greater affinity than 7.
authors.affiliation: Departamento de Síntese de Fármacos, Farmanguinhos, Fiocruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Alcione Silva de
authors.initials: AS
authors.lastname: Carvalho
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Kelly
authors.initials: K
authors.lastname: Salomão
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Solange Lisboa de
authors.initials: SL
authors.lastname: Castro
authors.affiliation: Departamento de Farmacologia e Toxicologia, Instituto Nacional de Controle de Qualidade em Saúde, Fiocruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Taline Ramos
authors.initials: TR
authors.lastname: Conde
authors.affiliation: Departamento de Farmacologia e Toxicologia, Instituto Nacional de Controle de Qualidade em Saúde, Fiocruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Helena Pereira da Silva
authors.initials: HP
authors.lastname: Zamith
authors.affiliation: Programa de Computação Científica, Fiocruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Ernesto Raúl
authors.initials: ER
authors.lastname: Caffarena
authors.affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, London, UK.
authors.forename: Belinda Suzette
authors.initials: BS
authors.lastname: Hall
authors.affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, London, UK.
authors.forename: Shane Robert
authors.initials: SR
authors.lastname: Wilkinson
authors.affiliation: Departamento de Síntese de Fármacos, Farmanguinhos, Fiocruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Núbia
authors.initials: N
authors.lastname: Boechat
mesh_terms: D000818:Animals; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009601:Nitroreductases / Q000187:drug effects* / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology*; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D013830:Thiadiazoles; D014230:Triazoles; D014344:Trypanocidal Agents; C013378:megazol; C045575:1,2,4-triazole; D009601:Nitroreductases