New 1,2,3-Triazole Scaffold Schiff Bases as Potential Anti-COVID-19: Design, Synthesis, DFT-Molecular Docking, and Cytotoxicity Aspects

Abstract

Schiff bases encompassing a 1,2,3-triazole motif were synthesized using an efficient multi-step synthesis. The formations of targeted Schiff base ligands were confirmed by different spectroscopic techniques (FT-IR, 1H NMR, 13C NMR, and CHN analysis). The spectral data analysis revealed that the newly designed hydrazones exist as a mixture of trans-E and cis-E diastereomers. Densityfunctional theory calculations (DFT) for the Schiff bases showed that the trans-trans form has the lowest energy structure with maximum stability compared to the other possible geometrical isomers that could be present due to the orientation of the amidic NH–C=O group. The energy differences between the trans-trans on one side and syn-syn and syn-trans isomers on the other side were 9.26 and 5.56 kcal/mol, respectively. A quantitative structure-activity relationship investigation was also performed in terms of density functional theory. The binding affinities of the newly synthesized bases are, maybe, attributed to the presence of hydrogen bonds together with many hydrophobic interactions between the ligands and the active amino acid residue of the receptor. The superposition of the inhibitor N3 and an example ligand into the binding pocket of 7BQY is also presented. Further interesting comparative docking analyses were performed. Quantitative structure-activity relationship calculations are presented, illustrating possible inhibitory activity. Further computer-aided cytotoxicity analysis by Drug2Way and PASS online software was carried out for Schiff base ligands against various cancer cell lines. Overall, the results of this study suggest that these Schiff base derivatives may be considered for further investigation as possible therapeutic agents for COVID-19.

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

“…1,2,3-triazole–based Schiff bases 64 ( Supplementary Figure S7 ) showed considerable binding affinities (−7.4 to −9.1 kcal/mol) with 7BQY, indicating their potential prospect as therapeutics for COVID-19 ( Supplementary Figure S7 ) ( Said et al, 2021 ).…”

Design, Synthesis and Molecular Docking of Novel Acetophenone-1,2,3-Triazoles Containing Compounds as Potent Enoyl-Acyl Carrier Protein Reductase (InhA) Inhibitors

“…Moreover, several drugs on the market, such as rufinamide (anticonvulsant), cetirizine (antibiotic), and tazobactam (antibacterial agent) have inserted a 1,2,3 triazole core into their framework [24] (Figure 1). In the literature, there are numerous 1,2,3-triazoles tethered to bioactive heterocyclic moieties, such as (Figure 2A-D), that have been documented as promising antitubercular agents [25][26][27][28][29][30][31]. In particular, the 1,4-disubstituted 1,2,3-triazole derivatives were identified and proven to have high efficacy against Mycobacterium tuberculosis.…”

“…The importance of the phenoxy methyl moiety in the development of the new candidate with significant antimycobacterium activity is represented by the lead structure (Figure 3B), which exerts its activity through inhibition of the enoyl-acyl carrier protein reductase InhA enzyme, IC50 = 0.38 µM [33]. In the literature, there are numerous 1,2,3-triazoles tethered to bioactive heterocyclic moieties, such as (Figure 2A-D), that have been documented as promising antitubercular agents [25][26][27][28][29][30][31]. In particular, the 1,4-disubstituted 1,2,3-triazole derivatives were identified and proven to have high efficacy against Mycobacterium tuberculosis.…”

“…In the literature, there are numerous 1,2,3-triazoles tethered to bioactive heterocyclic moieties, such as ( Figure 2 A–D), that have been documented as promising antitubercular agents [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. In particular, the 1,4-disubstituted 1,2,3-triazole derivatives were identified and proven to have high efficacy against Mycobacterium tuberculosis.…”

Synthesis, crystal structure elucidation, DFT analysis, drug‐likeness and ADMET evaluation and molecular docking studies of triazole derivatives: Binary inhibition of spike protein and ACE2 receptor protein of COVID‐19

“…A literature survey revealed that 1,2,3 triazole derivatives may act as potential inhibitors against Covid -19 proteins. [19,20] In the current study, three 1,2,3 triazole derivatives, namely, (E)-1-(1-benzyl-5-methyl-4,5-dihydro-1H-1,2,3-triazol-4-yl)-3-phenylprop-2-en-1-one (BMTPP), (E)-1-(1-benzyl-5-methyl-4,5-dihydro-1H-1,2,3-triazol-4-yl)-3-(p-tolyl) prop-2-en-1-one(BMTTP) and (E)-1-(1-benzyl-5-methyl-4,5-dihydro-1H-1,2,3-triazol-4-yl)-3-(4-isopropylphenyl) prop-2-en-1-one (BMTIP) were synthesized and their drug-likeness has been evaluated. The single crystal X-ray diffraction studies have been investigated for compound 2.…”