Synthesis, biological evaluation, and molecular modelling of substituted thiazolyl thiourea derivatives: A new class of prolyl oligopeptidase inhibitors.

Autor: Naseem S; Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan., Oneto A; Department of Pharmaceutical & Medicinal Chemistry, An der Immenburg 4, D-53121 Bonn, Germany., Ullah S; Natural and Medical Sciences Research Centre, University of Nizwa, P.O. Box 33, PC 616, Birkat Al Mauz, Nizwa, Sultanate of Oman., Fatima S; Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan., Mali SN; Department of Pharmaceutical Science and Technology, Birla Institute of Technology, Mesra 835215, India; School of Pharmacy, D.Y. Patil University (Deemed to be University), Sector 7, Nerul 400706, Navi Mumbai, India., Jawarkar RD; Department of Medicinal Chemistry and Drug Discovery, Dr. Rajendra Gode Institute of Pharmacy, University Mardi Road, Amravati 444603, India., Khan A; Natural and Medical Sciences Research Centre, University of Nizwa, P.O. Box 33, PC 616, Birkat Al Mauz, Nizwa, Sultanate of Oman., Alharthy RD; Department of Chemistry, Science & Arts College, Rabigh Branch, King Abdulaziz University, Rabigh 21911, Saudi Arabia., Kashtoh H; Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Gyeongbuk, Republic of Korea., Al-Harrasi A; Natural and Medical Sciences Research Centre, University of Nizwa, P.O. Box 33, PC 616, Birkat Al Mauz, Nizwa, Sultanate of Oman. Electronic address: aharrasi@unizwa.edu.om., Shafiq Z; Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan; Department of Pharmaceutical & Medicinal Chemistry, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: zahidshafiq@bzu.edu.pk., Boshta NM; Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Koam 32511, Egypt.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 Aug; Vol. 275 (Pt 1), pp. 133571. Date of Electronic Publication: 2024 Jul 01.
DOI: 10.1016/j.ijbiomac.2024.133571
Abstrakt: Prolyl oligopeptidase (POP) is a compelling therapeutic target associated with aging and neurodegenerative disorders due to its pivotal role in neuropeptide processing. Despite initial promise demonstrated by early-stage POP inhibitors, their progress in clinical trials has been halted at Phase I or II. This impediment has prompted the pursuit of novel inhibitors. The current study seeks to contribute to the identification of efficacious POP inhibitors through the design, synthesis, and comprehensive evaluation (both in vitro and in silico) of thiazolyl thiourea derivatives (5a-r). In vitro experimentation exhibited that the compounds displayed significant higher potency as POP inhibitors. Compound 5e demonstrated an IC 50 value of 16.47 ± 0.54 μM, representing a remarkable potency. A meticulous examination of the structure-activity relationship indicated that halogen and methoxy substituents were the most efficacious. In silico investigations delved into induced fit docking, pharmacokinetics, and molecular dynamics simulations to elucidate the intricate interactions, orientation, and conformational changes of these compounds within the active site of the enzyme. Moreover, our pharmacokinetic assessments confirmed that the majority of the synthesized compounds possess attributes conducive to potential drug development.
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 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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