2-Phenoxyacetamide derivatives as SARS-CoV-2 main protease inhibitor: In silico studies

Abstract

2-Phenoxyacetamide group has been identified as one of markers in the discovery and development of SARS-CoV-2 antiviral agent through its main protease (M pro ) inhibition pathway. This study aims to study a series of 2-phenoxyacetamide derivatives using in silico method toward SARS-CoV-2 M pro as the protein target. The study was initiated by employing structure-based pharmacophore to virtually screen and to select the ligands, which have the best fit score (hits) along with the common pharmacophore features being matched. The result shows that from the 11 ligands designed, four ligands are selected as the hits by demonstrating fit score in the range of 56.20 to 65.53 to the pharmacophore model, employing hydrogen bond acceptor (HBA) and hydrophobic (H) as the common features. The hits were then docked into the binding site of the M pro to see the binding mode of the corresponding hits as well as its affinity. The docking results free energy of binding (ΔG bind ) of the hits are in agreement with the pharmacophore fit score, in the range of -6.83 to -7.20 kcal/ mol. To gain the information of the hits as a potential drug to be developed, the in silico study was further proceed by predicting the mutagenic potency, toxicity and pharmacokinetic profiles. Based on the efficiency percentage, all hits meet the criteria as drug candidates by showing 84-88% leading to a conclusion that 2-phenoxyacetamide derivatives are beneficial to be marked as the lead compound for SARS-CoV-2 M pro inhibitor.

Synthesis and Phytocytogenotoxic Activity of N-Phenyl-2-phenoxyacetamides Derived from Thymol

“…, 35); 197 (7); 183 (100); 135 (36); 106 (33); 92 (33); 65 (12); 32 (4). (20); 133 (13); 105 (13); 91 (15); 41 (4.5); 32 (10).…”

“…These compounds have garnered attention from researchers due to their diverse range of biological activities, including antiinflammatory effects, 13 anticancer properties, 14,10 analgesic effects, 8 antimicrobial properties, 9 and potential against SARS-CoV-2. 15 The herbicidal potential of N-phenyl-2-phenoxyacetamides was reported in the study by Wu et al, 16 demonstrating that these compounds may have significant phytotoxic potential. In that study, 13 compounds from the class of N-(2-fluoro-5-(3methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)phenyl)-2-phenoxy)acetamides were synthesized and evaluated for herbicidal activity.…”

“…Phenols can be utilized to synthesize N -phenyl-2-phenoxyacetamide compounds, as shown in Figure . These compounds have garnered attention from researchers due to their diverse range of biological activities, including anti-inflammatory effects, anticancer properties, , analgesic effects, antimicrobial properties, and potential against SARS-CoV-2 …”

SARS‐CoV‐2 main protease mutation analysis via a kinematic method

“…For example, 4'-O-methylscutellarein binds the active site, sequestering the catalytic dyad. [20][21][22] In addition, both testosterone and progesterone are Mpro inhibitors. 23 Molecular modeling and simulation results also suggested that insect protease 1KJ0-7 and 2ERW-9 are promising candidates as antivirals against SARS-CoV-2, they do not possess any mutagenic and carcinogenic properties and appear safe for humans.…”

“…Methylated derivatives of Scutellarein are potential inhibitors of Mpro. For example, 4'‐O‐methylscutellarein binds the active site, sequestering the catalytic dyad 20–22 . In addition, both testosterone and progesterone are Mpro inhibitors 23 .…”