Structure-based design of multitargeting ChEs-MAO B inhibitors based on phenyl ring bioisosteres: AChE/BChE selectivity switch and drug-like characterization.
Eur J Med Chem
; 274: 116511, 2024 Aug 05.
Article
em En
| MEDLINE
| ID: mdl-38820854
ABSTRACT
A structure-based drug design approach was focused on incorporating phenyl ring heterocyclic bioisosteres into coumarin derivative 1, previously reported as potent dual AChE-MAO B inhibitor, with the aim of improving drug-like features. Structure-activity relationships highlighted that bioisosteric rings were tolerated by hMAO B enzymatic cleft more than hAChE. Interestingly, linker homologation at the basic nitrogen enabled selectivity to switch from hAChE to hBChE. In the present work, we identified thiophene-based isosteres 7 and 15 as dual AChE-MAO B (IC50 = 261 and 15 nM, respectively) and BChE-MAO B (IC50 = 375 and 20 nM, respectively) inhibitors, respectively. Both 7 and 15 were moderately water-soluble and membrane-permeant agents by passive diffusion (PAMPA-HDM). Moreover, they were able to counteract oxidative damage induced by both H2O2 and 6-OHDA in SH-SY5Y cells and predicted to penetrate into CNS in a cell-based model mimicking blood-brain barrier. Molecular dynamics (MD) simulations shed light on key differences in AChE and BChE recognition processes promoted by the basic chain homologation from 7 to 15.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acetilcolinesterase
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Butirilcolinesterase
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Desenho de Fármacos
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Inibidores da Colinesterase
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article