Discovery of novel thioquinazoline- N-aryl-acetamide/ N-arylacetohydrazide hybrids as anti-SARS-CoV-2 agents: Synthesis, in vitro biological evaluation, and molecular docking studies

Heba T Abdel-Mohsen; Mohamed A Omar; Omnia Kutkat; Ahmed M El Kerdawy; Alaa A Osman; Mohamed GabAllah; Ahmed Mostafa; Mohamed A Ali; Hoda I El Diwani

doi:10.1016/j.molstruc.2022.134690

Discovery of novel thioquinazoline- N-aryl-acetamide/ N-arylacetohydrazide hybrids as anti-SARS-CoV-2 agents: Synthesis, in vitro biological evaluation, and molecular docking studies

J Mol Struct. 2023 Mar 15:1276:134690. doi: 10.1016/j.molstruc.2022.134690. Epub 2022 Nov 30.

Authors

Heba T Abdel-Mohsen¹, Mohamed A Omar¹, Omnia Kutkat², Ahmed M El Kerdawy³, Alaa A Osman⁴, Mohamed GabAllah², Ahmed Mostafa², Mohamed A Ali², Hoda I El Diwani¹

Affiliations

¹ Department of Chemistry of Natural and Microbial Products, Pharmaceutical and Drug Industries Research Institute, National Research Centre, El-Buhouth St., Dokki, P.O. Box 12622, Cairo, Egypt.
² Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza 12622, Egypt.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
⁴ Department of Pharmaceutical Chemistry, School of Pharmacy, NewGiza University (NGU), NewGiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.

Abstract

In the current investigation, two novel series of (tetrahydro)thioquinazoline-N-arylacetamides and (tetrahydro)thioquinazoline-N-arylacetohydrazides were designed, synthesized and investigated for their antiviral activity against SARS-CoV-2. The thioquinazoline-N-arylacetamide 17g as well as the tetrahydrothioquinazoline-N-arylacetohydrazides 18c and 18f showed potent antiviral activity with IC₅₀ of 21.4, 38.45 and 26.4 µM, respectively. In addition, 18c and 18f demonstrated potential selectivity toward the SARS-CoV-2 over the host cells with SI of 10.67 and 16.04, respectively. Further evaluation of the mechanism of action of the three derivatives 17g, 18c, and 18f displayed that they can inhibit the virus at the adsorption as well as at the replication stages, in addition to their virucidal properties. In addition, 17g, 18c, and 18f demonstrated satisfactory physicochemical properties as well as drug-likeness properties to be further optimized for the discovery of novel antiviral agents. The docking simulation on M^pro binding site predicted the binding pattern of the target compounds rationalizing their differential activity based on their hydrophobic interaction and fitting in the hydrophobic S2 subsite of the binding site.

Keywords: Molecular docking studies; SARS-CoV-2; Thioquinazoline.