Thiohydantoins and hydantoins derived from amino acids as potent urease inhibitors: inhibitory activity and ligand-target interactions

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dc.creatorPriscila Goes Carvalho
dc.creatorMarciéli Fabris
dc.creatorMatheus Yoshimitsu Tatsuta Nakamae
dc.creatorBreno Germano de Freitas Oliveira
dc.creatorCamilo Henrique da Silva Lima
dc.creatorÂngelo de Fátima
dc.creatorMarcelle de Lima Ferreira Bispo
dc.creatorFernando Cesar Macedo Junior
dc.date.accessioned2024-11-05T23:00:21Z
dc.date.accessioned2025-09-09T01:33:01Z
dc.date.available2024-11-05T23:00:21Z
dc.date.issued2022
dc.description.sponsorshipCNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico
dc.description.sponsorshipFAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais
dc.description.sponsorshipCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
dc.format.mimetypepdf
dc.identifier.doihttps://doi.org/10.1016/j.cbi.2022.110045
dc.identifier.issn0009-2797
dc.identifier.urihttps://hdl.handle.net/1843/77842
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofChemico-Biological Interactions
dc.rightsAcesso Aberto
dc.subjectRessonância magnética nuclear
dc.subjectCanavalia ensiformis
dc.subjectUrease - Inibidores
dc.subjectEstereoquimica
dc.subject.otherThiohydantoins
dc.subject.otherHydantoins
dc.subject.otherNMR
dc.subject.otherMolecular docking
dc.subject.otherC. ensiformis
dc.subject.otherSaturation Transfer Difference STD
dc.titleThiohydantoins and hydantoins derived from amino acids as potent urease inhibitors: inhibitory activity and ligand-target interactions
dc.typeArtigo de periódico
local.citation.spage110045
local.citation.volume365
local.description.resumoWe report the investigation of hydantoins and thiohydantoins derived from L and d-amino acids as inhibitors against the Canavalia ensiformis urease (CEU). The biochemical in vitro assay against CEU revealed a promising inhibitory potential for most thiohydantoins with six of them showing %I higher than the reference inhibitor thiourea (56.5%). In addition, thiohydantoin derived from l-valine, 1b, as well as the hydantoin 2d, derived from l-methionine, were identified as the most potent inhibitors with %I = 90.5 and 85.9 respectively. Enzyme kinetic studies demonstrated a mixed and uncompetitive inhibition profile for these compounds with Ki values of 0.42 mM for 1b and 0.99 mM for 2d. These kinetic parameters, obtained from traditional colorimetric assay, were strictly related to the KD values measured spectroscopically by the Saturation Transfer Difference (STD) technique for the urease complex. STD was also used to evince the moieties of the ligands responsible for the binding with the enzyme. Molecular docking studies showed that the thiohydantoin and hydantoin rings can act as a pharmacophoric group due to their binding affinity by hydrogen bonding interactions with critical amino acid residues in the enzyme active and/or allosteric site. These findings agreed with the experimental alpha values, demonstrating that 1b has affinity by free enzyme, and 2d derivative, an uncompetitive inhibitor, has great binding affinity at the allosteric site. The results for the thiohydantoin 1a, derived from d-valine, demonstrated a drastic stereochemical influence on inhibition, kinetics, and binding parameters in comparison to its enantiomer 1b.
local.identifier.orcidhttps://orcid.org/0000-0003-4483-2119
local.identifier.orcidhttps://orcid.org/0000-0001-6763-3046
local.identifier.orcidhttps://orcid.org/0000-0003-4631-389X
local.identifier.orcidhttps://orcid.org/0000-0002-5579-7809
local.identifier.orcidhttps://orcid.org/0000-0003-2344-5590
local.identifier.orcidhttps://orcid.org/0000-0002-6001-360X
local.identifier.orcidhttps://orcid.org/0000-0002-4230-1309
local.publisher.countryBrasil
local.publisher.departmentICX - DEPARTAMENTO DE QUÍMICA
local.publisher.initialsUFMG
local.url.externahttps://www.sciencedirect.com/science/article/pii/S0009279722002502

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