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

Abstract

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 IC50 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.

Spectroscopic investigation and structural simulation in human serum albumin with hydroxychloroquine/Silybum marianum and a possible potential COVID‐19 drug candidate

“…Multiple drug complexes were docked with the major protease, which is extensively studied in the field. [ 15,50–54 ] Figures 8–10 illustrate the molecular docking process and provide a 2D diagram depicting the interactions between HCQ/SM and all the receptors, while Table 4 presents the data on binding energy. The docking energies for the HCQ/SM mixture were determined to be 6.69 and −7.28 kcal mol −1 .…”

“…Estimated free energy of binding a (kcal/mol) −6.24 docked with the major protease, which is extensively studied in the field. [15,[50][51][52][53][54] TRP62 was observed at a distance of 3.78 Å. A π-donor-H bond between the rings of the complex and GLY103 was found at a distance of 2.37 Å.…”

“…The interactions between HSA were determined using the AutoDock program, UCSF Chimera 1.5.1 software, and Discovery Studio 3.0. [7,8,24,54]…”

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“…Thiazoles and their derivatives also play a significant role in the field of medicinal chemistry where they found to exhibit a wide variety of activities such as, antiviral 1 , antioxidant 2 , antituberculosis 3 , antimicrobial 4 , anticancer 5 , anticonvulsant 6 , anti-inflammatory 7 , anti-infective 8 , antidiabetic 9 , anticonvulsant 10 , antifungal 11 , antiepileptic 12 , antidepressant 13 . Some of the thiazole molecules also showed inhibition against SARS-CoV-2 virus disease 14,15 . Several procedures for synthesizing thiazole derivatives are described in the literature [16][17][18][19][20][21][22][23] .…”

An Effective Docking-Guided Strategy for Rational Tailoring of Fluorescent Aptamer Switches of Dimethylindole Red Analogue

“…Fluorescent functional nucleic acids (FFNAs), which are a class of nucleic acid complexes imparted with fluorescent properties by covalent modification or noncovalent interaction with non-nucleic ligands, have been integrated into new platforms and technologies in biochemistry analysis by providing innovative fluorescent signal strategies . Along with constantly emerging new-type fluorophores and developing FNA screening strategies, light-up aptamer-fluorophore complexes (LAFCs) are becoming powerful signal transduction tools at a rapid pace and have been applied in biosensing, , sequencing, drug selection, , and clinical diagnosis . A host of LAFCs were successively reported, especially the classic representatives such as the spinach aptamer-DFHBI complex, the broccoli aptamer-DFHBI-1T complex, and the mango aptamer-thiazole orange (TO) complex .…”