Novel 1,2,3‐Triazole Derivatives as Potential Inhibitors against Covid‐19 Main Protease: Synthesis, Characterization, Molecular Docking and DFT Studies

Abstract

The highly contagious nature of Covid-19 attracted us to this challenging area of research, mainly because the disease is spreading very fast and until now, no effective method of a safe treatment or a vaccine is developed. A library of novel 1,2,3-triazoles based 1,2,4-triazole, 1,3,4-oxadiazole and/or 1,3,4-thiadiazole scaffolds were designed and successfully synthesized. Different spectroscopic tools efficiently characterized all the newly synthesized hybrid molecules. An interesting finding is that some of the newly designed compounds revealed two isomeric forms. The ratio is affected by the size of the attached group as well as the type of the heteroatom forming the side ring attached to the central 1,2,3-triazole ring. The experimental spectroscopic data is in agreement with the DFT calculations at B3LYP 6-31G (d,p) with regard to the geometrical conformation of the prepared compounds. The DFT results revealed that the stability of one isomeric form over the other in the range of 0.057-0.161 Kcal mol À 1 . A docking study was performed using PyRx and AutoDockVina to investigate the activity of the prepared 1,2,3-triazoles as antiviral agents. Bond affinity scores of the 1,2,3-triazole derivatives were detected in the range of À 6.0 to À 8.8 kcal/ mol showing binding to the active sites of the 6LU7 protease and hence could be anticipated to inhibit the activity of the enzyme. Verification of the docking results was performed using the M pro alignment of coronaviruses substrate-binding pockets of COVID-19 against the ligands. As per these results, it can be proposed that the title hybrid molecules are acceptable candidates against COVID-19 for possible medicinal agents.

Discovery of a Series of Theophylline Derivatives Containing 1,2,3-Triazole for Treatment of Non-Small Cell Lung Cancer

“…Tazobactam is also used as an antibacterial agent ( Karlowsky et al, 2020 ; Lob et al, 2020 ; Los-Arcos et al, 2020 ). 1, 2, 3-Triazole can hybridize with other anticancer pharmacophores or act as a linker connecting two anticancer pharmacophores, which make it in the design and synthesis of antitumor compounds widely ( Bozorov et al, 2019 ; Aouad et al, 2021 ; Liang et al, 2021 ).…”

Triazoles and Their Derivatives: Chemistry, Synthesis, and Therapeutic Applications

“…For example, combined 1,2,3-triazole and tetrazole moieties as in ( 61) ( Supplementary Figure S7 ) are found to inhibit the main protease (M PRO , PDB ID: 6LU7) of SARS-CoV-2 having higher ligand–target interactions ( Cortés-García et al, 2020 ). Several functionalized 1,2,3-triazole derivatives ( 62) also showed good binding affinities (−6.0 to −8.8 kcal/mol) against the same protease 6LU7 ( Aouad et al, 2021 ), and 1,2,3-triazoles ( 63) conjugated with quinolone also showed high potency against M PRO 6LU7 ( Seliem et al, 2021 ). The antiviral results of ( 63) are also supported by their IC 50 values (0.060–0.204 mM).…”

Benchmarking the ability of novel compounds to inhibit SARS-CoV-2 main protease using steered molecular dynamics simulations

“…Several in-silico investigations have proposed prospective inhibitors from diverse source against distinct proteins of SARS-CoV-2 [ 5 , [13] , [14] , [15] , [16] , [17] ]. In earlier studies, the 1,2,3-triazole scaffolds were identified to possess antiviral, anti-inflammatory, antibacterial, and anti-cancerous properties [ [18] , [19] , [20] , [21] ]. In addition, the 1,2,3-triazole scaffolds were also shown to have an antiviral effect on the M pro in experimental studies [ [22] , [23] , [24] ].…”