Synthesis, DFT investigations, antioxidant, antibacterial activity and SAR-study of novel thiophene-2-carboxamide derivatives

Abstract

Synthetic strategy for the synthesis of thiophene 2-carboxamide derivatives substituted with hydroxyl, methyl and amino groups at position-3 was proposed. The strategy includes the cyclization of the precursor ethyl 2-arylazo-3-mercapto-3-(phenylamino)acrylate derivatives, 2-acetyl-2-arylazo-thioacetanilide derivatives and N-aryl-2-cyano-3-mercapto-3-(phenylamino)acrylamide derivatives with N-(4-acetylphenyl)-2-chloroacetamide in alcoholic sodium ethoxide. IR, 1H NMR, and mass spectroscopic analyses were used to characterize the synthesized derivatives. In addition, molecular, electronic properties of the synthesized products were studied by the density functional theory (DFT) where they exhibited close HOMO–LUMO energy gap (ΔEH-L) in which the amino derivatives 7a-c have the highest while the methyl derivatives 5a-c were the lowest. Using the ABTS method, the antioxidant properties of the produced compounds were evaluated, where amino thiophene-2-carboxamide 7a exhibit significant inhibition activity 62.0% compared to ascorbic acid The antibacterial activity against two pathogenic Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two of pathogenic Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) revealed that 7b records the highest activity index compared to ampicillin 83.3, 82.6, 64.0, 86.9%, respectively. Furthermore, the thiophene-2-carboxamide derivatives were docked with five different proteins with the use molecular docking tools and the results explained interactions between amino acid residue of enzyme and compounds. Compounds 3b and 3c showed the highest binding score with 2AS1 protein. Graphical Abstract

Synthetic and Semisynthetic Compounds as Antibacterials Targeting Virulence Traits in Resistant Strains: A Narrative Updated Review

“…The most recent research of Metwally et al [ 50 ] indicated that thiophene-2-carboxamide ( Figure 7 ) derivatives showed antibacterial properties, with S. aureus , B. subtilis , E. coli , and P. aeruginosa being the most susceptible to the activity of the tested compounds. While the results showed no indication of targeting virulence factors, the very fact that the novel synthesized compounds possessed microbicidal activity with no targeted virulence factors whatsoever suggests that there is still hope for old-fashioned drugs as antimicrobials.…”

New thiazole, thiophene and 2-pyridone compounds incorporating dimethylaniline moiety: synthesis, cytotoxicity, ADME and molecular docking studies

“…Several studies have been carried out using various sulfur and/ or nitrogen-containing heterocyclic compounds, including thiophene, thiazole, and pyridine, directed towards different pathologies. These thiophene, thiazole, and pyridine-containing compounds show anticancer [4][5][6][7][8], anti-inflammatory [9][10][11], antibacterial [12][13][14], antioxidant [15], anti-oxidant [16], anti-fungal [17,18], anti-coronavirus [19,20] properties. Thiazoles were also found to act as anti-Alzheimer [21], anti-tubercular [22], and anti-diabetic [23].…”

Synthesis, Structural Determination, Docking Study and Bioactivity of Novel Thiophene Derivatives

“…When compared to oxygen, nitrogen and sulphur, its electronegativity is lower, which means it interacts favourably with enzymes and receptors inside microorganisms [9,10]. Through its chelating qualities, which enable it to form coordination complexes with metal ions, the sulfur atom can interfere with metal-dependent enzymes that are necessary for microbial growth and metabolism [11,12].…”