دورية أكاديمية
أعرض في EDS

Structure-based design of multitargeting ChEs-MAO B inhibitors based on phenyl ring bioisosteres: AChE/BChE selectivity switch and drug-like characterization.

التفاصيل البيبلوغرافية
العنوان: Structure-based design of multitargeting ChEs-MAO B inhibitors based on phenyl ring bioisosteres: AChE/BChE selectivity switch and drug-like characterization.
المؤلفون: La Spada G; Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy., Miniero DV; Dept. of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70125, Bari, Italy., Rullo M; Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy., Cipolloni M; Tes Pharma s.r.l., via Palmiro Togliatti 20, 06073, Corciano, PG, Italy., Delre P; CNR, Institute of Crystallography, 70126, Bari, Italy., Colliva C; Tes Pharma s.r.l., via Palmiro Togliatti 20, 06073, Corciano, PG, Italy., Colella M; Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy., Leonetti F; Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy., Liuzzi GM; Dept. of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70125, Bari, Italy., Mangiatordi GF; CNR, Institute of Crystallography, 70126, Bari, Italy., Giacchè N; Tes Pharma s.r.l., via Palmiro Togliatti 20, 06073, Corciano, PG, Italy., Pisani L; Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: leonardo.pisani@uniba.it.
المصدر: European journal of medicinal chemistry [Eur J Med Chem] 2024 Aug 05; Vol. 274, pp. 116511. Date of Electronic Publication: 2024 May 19.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
مواضيع طبية MeSH: Cholinesterase Inhibitors*/pharmacology , Cholinesterase Inhibitors*/chemistry , Cholinesterase Inhibitors*/chemical synthesis , Acetylcholinesterase*/metabolism , Drug Design* , Butyrylcholinesterase*/metabolism, Humans ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; Molecular Dynamics Simulation ; Coumarins/chemistry ; Coumarins/pharmacology ; Coumarins/chemical synthesis ; Cell Line, Tumor
مستخلص: 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 (IC 50  = 261 and 15 nM, respectively) and BChE-MAO B (IC 50  = 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 H 2 O 2 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
فهرسة مساهمة: Keywords: Acetylcholinesterase; Bioisostere; Butyrylcholinesterase; Monoamine oxidases; Multitarget; Structure-based
المشرفين على المادة: 0 (Cholinesterase Inhibitors)
EC 3.1.1.7 (Acetylcholinesterase)
EC 3.1.1.8 (Butyrylcholinesterase)
0 (Coumarins)
تواريخ الأحداث: Date Created: 20240531 Date Completed: 20240615 Latest Revision: 20240618
رمز التحديث: 20240619
DOI: 10.1016/j.ejmech.2024.116511
PMID: 38820854
قاعدة البيانات: MEDLINE
الوصف
تدمد:1768-3254
DOI:10.1016/j.ejmech.2024.116511