Pyrimidine-morpholine hybrids as potent druggable therapeutics for Alzheimer's disease: Synthesis, biochemical and in silico analyses.

Autor: Zaib S; Department of Basic and Applied Chemistry, Faculty of Science and Technology, University of Central Punjab, Lahore 54590, Pakistan. Electronic address: sumera.zaib@ucp.edu.pk., Younas MT; Department of Basic and Applied Chemistry, Faculty of Science and Technology, University of Central Punjab, Lahore 54590, Pakistan., Khan I; Department of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester MI 7DN, UK. Electronic address: kimtiaz@hotmail.co.uk., Ali HS; Chemistry Research Laboratory, Department of Chemistry and the INEOS Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK., McAdam CJ; Department of Chemistry, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand., White JM; School of Chemistry and Bio-21 Institute, University of Melbourne, 3052 Parkville, Australia., Jaber F; Department of Biomedical Engineering, Ajman University, Ajman, United Arab Emirates; Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates., Awwad NS; Department of Chemistry, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia., Ibrahium HA; Biology Department, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Dec; Vol. 141, pp. 106868. Date of Electronic Publication: 2023 Sep 16.
DOI: 10.1016/j.bioorg.2023.106868
Abstrakt: The identification of effective and druggable cholinesterase inhibitors to treat progressive neurodegenerative Alzheimer's disorder remains a continuous drug discovery hunt. In this perspective, the present study investigates the design and discovery of pyrimidine-morpholine hybrids (5a-l) as potent cholinesterase inhibitors. Palladium-catalyzed Suzuki-Miyaura cross-coupling reaction was employed to introduce the structural diversity on the pyrimidine heterocyclic core. A range of commercially available boronic acids was successfully coupled showing a high functional group tolerance. In vitro cholinesterase inhibitory potential using Ellman's method revealed significantly strong potency. Compound 5h bearing a meta-tolyl substituent at 2-position of pyrimidine ring emerged as a lead candidate against AChE with an inhibitory potency of 0.43 ± 0.42 µM, ∼38-fold stronger value than neostigmine (IC 50  = 16.3 ± 1.12 µM). Compound 5h also showed the lead inhibition against BuChE with an IC 50 value of 2.5 ± 0.04 µM. The kinetics analysis of 5h revealed the non-competitive mode of inhibition against AChE whereas computational modelling results of potent leads depicted diverse contacts with the binding site amino acid residues. Molecular dynamics simulations revealed the stability of biomolecular system, while, ADME analysis demonstrated druglikeness behaviour of potent compounds. Overall, the investigated pyrimidine-morpholine scaffold presented a remarkable potential to be developed as efficacious anti-Alzheimer's drugs.
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 © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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