Zobrazit v EDS

Crystallographic and Electroanalytical Analyses of Fexinidazole and Its Major Metabolites

Uloženo v:
Podrobná bibliografie
Název: Crystallographic and Electroanalytical Analyses of Fexinidazole and Its Major Metabolites
Autoři: Abdrrahman S. Surur, Siva S. M. Bandaru, Christian Fischer, Van T. D. Nguyen, Andreas Link, Patrick J. Bednarski, Carola Schulzke
Rok vydání: 2025
Sbírka: Torrens University Australia: Figshare
Témata: Biochemistry, Cell Biology, Genetics, Biotechnology, Cancer, Infectious Diseases, Computational Biology, Chemical Sciences not elsewhere classified, providing valuable insights, predominantly planar geometry, nitroaromatic compound approved, methyl ether bridge, initial concerted transfer, fexinidazole closely resembles, two distinct conformers, conformer ii aligns, aromatic nitro group, activation mechanism required, major metabolites fexinidazole, nitro group, reduction mechanism, absolutely required, fexinidazole showcases, fexinidazole revealed, three protons, three electrons, sulfoxide metabolite, sulfone metabolite, structural intricacies, structural features
Popis: Fexinidazole, a drug active against trypanosomiasis and leishmaniasis, is a rare example of a nitroaromatic compound approved under the contemporary drug discovery framework. In an earlier study, we showed that the nitro group is absolutely required for antileishmanial activity. The current study employed X-ray crystallography to unveil the structural intricacies of fexinidazole and its principal metabolites, as well as electroanalytical analyses to characterize the reduction properties of the aromatic nitro group. Fexinidazole showcases a predominantly planar geometry with two distinct conformers. While most metrical parameters were conserved between fexinidazole and its metabolites, differences in the methyl ether bridge and S -methyl tail indicated distinctive preferences in molecular arrangement: conformer I of fexinidazole closely resembles the sulfone metabolite, while conformer II aligns with the sulfoxide metabolite. On the other hand, electroanalytical analysis of fexinidazole revealed a pH-dependent, two-step nitro group reduction mechanism, involving an initial concerted transfer of an electron and a proton, followed by the uptake of three electrons and three protons to likely form a hydroxylamine species. These findings characterize the molecular architecture and reduction mechanism of fexinidazole, providing valuable insights into its structural features and activation mechanism required for anti-infective activity.
Druh dokumentu: article in journal/newspaper
Jazyk: unknown
Relation: https://figshare.com/articles/journal_contribution/Crystallographic_and_Electroanalytical_Analyses_of_Fexinidazole_and_Its_Major_Metabolites/29906554
DOI: 10.1021/acsomega.5c05115.s001
Dostupnost: https://doi.org/10.1021/acsomega.5c05115.s001
Rights: CC BY-NC 4.0
Přístupové číslo: edsbas.9A50C68F
Databáze: BASE
Popis
Abstrakt:Fexinidazole, a drug active against trypanosomiasis and leishmaniasis, is a rare example of a nitroaromatic compound approved under the contemporary drug discovery framework. In an earlier study, we showed that the nitro group is absolutely required for antileishmanial activity. The current study employed X-ray crystallography to unveil the structural intricacies of fexinidazole and its principal metabolites, as well as electroanalytical analyses to characterize the reduction properties of the aromatic nitro group. Fexinidazole showcases a predominantly planar geometry with two distinct conformers. While most metrical parameters were conserved between fexinidazole and its metabolites, differences in the methyl ether bridge and S -methyl tail indicated distinctive preferences in molecular arrangement: conformer I of fexinidazole closely resembles the sulfone metabolite, while conformer II aligns with the sulfoxide metabolite. On the other hand, electroanalytical analysis of fexinidazole revealed a pH-dependent, two-step nitro group reduction mechanism, involving an initial concerted transfer of an electron and a proton, followed by the uptake of three electrons and three protons to likely form a hydroxylamine species. These findings characterize the molecular architecture and reduction mechanism of fexinidazole, providing valuable insights into its structural features and activation mechanism required for anti-infective activity.
DOI:10.1021/acsomega.5c05115.s001