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: Alcione Silva de Carvalho, Kelly Salomão, Solange Lisboa de Castro, Taline Ramos Conde, Helena Pereira da Silva Zamith, Ernesto Raúl Caffarena, Belinda Suzette Hall, Shane Robert Wilkinson, Núbia Boechat
• Journal: Memorias do Instituto Oswaldo Cruz (Mem Inst Oswaldo Cruz) Vol. 109 Issue 3 Pg. 315-23 (Jun 2014) ISSN: 1678-8060 [Electronic] Brazil
• PMID: 24676659 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Thiadiazoles
• Triazoles
• Trypanocidal Agents
• megazol
• 1,2,4-triazole
• Nitroreductases

Topics

• Animals
• Comet Assay
• DNA Damage (drug effects)
• Enzyme Activation (drug effects)
• Humans
• Male
• Mice
• Nitroreductases (drug effects, metabolism)
• Parasitic Sensitivity Tests
• Structure-Activity Relationship
• Thiadiazoles (chemistry, metabolism, pharmacology, toxicity)
• Triazoles (chemistry, metabolism, pharmacology, toxicity)
• Trypanocidal Agents (chemistry, pharmacology, toxicity)
• Trypanosoma brucei brucei (drug effects, enzymology)
• Trypanosoma cruzi (drug effects)