Repurposing 1,2,4-oxadiazoles as SARS-CoV-2 PLpro inhibitors and investigation of their possible viral entry blockade potential.
| Autor: | Ayoup MS; Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, 21321, Egypt. Electronic address: Mohamed.salah@alexu.edu.eg., ElShafey MM; Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, 21321, Egypt., Abdel-Hamid H; Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, 21321, Egypt., Ghareeb DA; Bio‑screening and preclinical trial lab, Biochemistry Department, Faculty of Science, Alexandria University, P.O. Box 21511, Alexandria, Egypt., Abu-Serie MM; Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Egypt., Heikal LA; Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt., Teleb M; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. |
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| Jazyk: | angličtina |
| Zdroj: | European journal of medicinal chemistry [Eur J Med Chem] 2023 Apr 05; Vol. 252, pp. 115272. Date of Electronic Publication: 2023 Mar 13. |
| DOI: | 10.1016/j.ejmech.2023.115272 |
| Abstrakt: | Although vaccines are obviously mitigating the COVID-19 pandemic diffusion, efficient complementary antiviral agents are urgently needed to combat SARS-CoV-2. The viral papain-like protease (PLpro) is a promising therapeutic target being one of only two essential proteases crucial for viral replication. Nevertheless, it dysregulates the host immune sensing response. Here we report repositioning of the privileged 1,2,4-oxadiazole scaffold as promising SARS-CoV-2 PLpro inhibitor with potential viral entry inhibition profile. The design strategy relied on mimicking the general structural features of the lead benzamide PLpro inhibitor GRL0617 with isosteric replacement of its pharmacophoric amide backbone by 1,2,4-oxadiazole core. Inspired by the multitarget antiviral agents, the substitution pattern was rationalized to tune the scaffold's potency against other additional viral targets, especially the spike receptor binding domain (RBD) that is responsible for the viral invasion . The Adopted facial synthetic protocol allowed easy access to various rationally substituted derivatives. Among the evaluated series, the 2-[5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl]aniline (5) displayed the most balanced dual inhibitory potential against SARS-CoV-2 PLpro (IC 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 Masson SAS. All rights reserved.) |
| Databáze: | MEDLINE |
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