Thiazole-based SARS-CoV-2 protease (COV M pro ) inhibitors: Design, synthesis, enzyme inhibition, and molecular modeling simulations.

Autor: Elsayed RW; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., Sabry MA; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., El-Subbagh HI; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., Bayoumi SM; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., El-Sayed SM; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Jazyk: angličtina
Zdroj: Archiv der Pharmazie [Arch Pharm (Weinheim)] 2022 Sep; Vol. 355 (9), pp. e2200121. Date of Electronic Publication: 2022 May 23.
DOI: 10.1002/ardp.202200121
Abstrakt: As an attempt to contribute to the efforts of combating the pandemic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for COVID-19, new analogs of the repurposed drug nitazoxanide which showed promising inhibitory efficacy on a viral protease enzyme were designed, synthesized and evaluated for their inhibitory activity on the main protease of the SARS-CoV-2 virus, using the COV2-3CL protease inhibition assay. The obtained results showed that the N-(substituted-thiazol-2-yl)cinnamamide analogs 19, 20, and 21 were the most active compounds with IC 50 values of 22.61, 14.7, 21.99 µM, respectively, against the viral protease compared to the reference drugs, nitazoxanide, and lopinavir. Molecular modeling studies showed binding interactions of 19, 20, and 21 with hydrogen bonds to Gln189 and Glu166, arene-arene interaction between the thiazole moiety and His41, and other hydrophobic interactions between the ethene spacer moiety and Asn142. Moreover, an extra arene-arene interaction between substituted benzo[d]thiazole and His41 was observed regarding compounds 19 and 21. Surface mapping and flexible alignment proved the structural similarity between the new drug candidates and nitazoxanide. Compliance of the new compounds to Lipinski's rule of five was investigated and absorption, distribution, metabolism, excretion, and toxicology data were predicted. The newly synthesized compounds are promising template ligands for further development and optimization.
(© 2022 Deutsche Pharmazeutische Gesellschaft.)
Databáze: MEDLINE
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