Novel arylazo nicotinate derivatives as effective antibacterial agents: Green synthesis, molecular modeling, and structure-activity relationship studies

Abstract

A series of novel arylazo nicotinates compounds, denoted as (3a-k and 5a-d) were synthesized and characterized through the reaction of 3-oxo-arylhydrazonals with various active methylene nitriles using microporous zeolite as a green catalyst. The structure of the newly prepared heterocycles was determined using various spectral techniques such as MS, IR, NMR, and elemental analysis. The antibacterial activity of these compounds against Escherichia coli (E. coli) and Bacillus subtilis (B. subtilis) was evaluated, and it was found that all arylazo nicotinate compounds were highly effective against both gram-negative (E. coli) and gram-positive (B. subtilis) bacterial strains. The efficacy of the developed arylazo nicotinate derivatives as antimicrobial agents against E. coli and B. subtilis was evaluated using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values. Density-functional theory (DFT) was employed to investigate the structure–activity relationships of recently synthesized compounds. Gaussian 09 software was utilized to compute various molecular properties, including the distribution of frontier molecular orbitals (FMO), the energy levels of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), the energy gap (Eg), as well as several biological activity descriptors such as ionization potential (IP), electron affinity (EA), chemical potential (μ), chemical hardness (η), electronegativity (χ), global softness (S), and electrophilicity index (ω). The results of the FMO calculations revealed that the arylazo nicotinates had effective charge separation and distinct HOMO/LUMO energy levels for each compound, as reflected by the different Eg values. The Eg values were found to have a strong correlation with the antibacterial efficacy against E. coli and B. subtilis. The highest and lowest efficacy among the molecules (3a-k) were observed for compounds 3b (Eg = 3.36 eV) and 3 k (Eg = 2.27 eV), respectively, while the highest and lowest efficacy among the molecules (5a-d) were observed for compounds 5d (Eg = 3.33 eV) and 5c (Eg = 2.94 eV), respectively.