Synthesis of significant nitroimidazole-triazole-pyridine hybrids and their molecular modeling as antimicrobial agents

A series of nitroimidazole-triazole hybrids 7a-d and 10a-d have been synthesized through the Huisgen cycloaddition of 1-(2-azidoacetyl)-2-methyl-5-nitro-1 H -imidazole (3) with 2-((4-propargyloxy)benzylidene)malononitrile (4) or ethyl 2-cyano-3-((4-propargyloxy)phenyl) acrylate (8) , followed by cyclization of imidazole-triazole compounds (5 and 9) with N -aryl cyanoacetamides 6a-d . The DFT calculations for the synthesized nitroimidazole-based hybrids revealed comparable twisted configurations and similar Highest occupied molecular orbitals (HOMO)-lowest unoccupied molecular orbital (LUMO) constructions. Consequently, their energy gap ranged from 2.93 to 3.33 eV, where analogues 7b and 5 exhibited the utmost and least values, respectively. In addition, the antimicrobial effectiveness of the prepared nitroimidazole-based hybrids against Gram(+ve), Gram(-ve), and fungal strains were assessed using MIC and IZ assays. Imidazole-triazole hybrids 7a , 7b , and 10d displayed the highest activity, particularly against S. aureus , B. subtilis , and E. coli (minimum inhibitory concentrations (MIC) = 3.125-6.25 µg.mL -1 ), comparable to the reference antibiotics. However, nitroimidazole-triazole hybrid 9 demonstrated a robust fungicidal effect on C. albicans (MIC = 3.125 µg.mL -1 ), comparable to cycloheximide. The molecular docking study was performed to evaluate interactions of the manufactured series with the target protein (PDB: 1BDD). The hybrids 5 and 10d presented the maximum binding affinities (S = -7.1215 and -7.2123 kcal.mol -1 ). These findings suggest that nitroimidazole-hybrids, particularly 10d and 5 , represented promising scaffolds for further development due to their strong binding affinities and diverse interaction profiles. Furthermore, the Swiss Absorption, distribution, metabolism, and excretion (ADME) study provided an in-depth pharmacokinetic evaluation of the new nitroimidazole hybrids, a robust tool for predicting drug-likeness and bioavailability. Hybrids 5 and 9 exhibited favorable solubility with low molecular weights, while hybrids 7a-d and 10a-d showed moderate solubility but higher molecular weights and increased Lipinski violations. The bioavailability scores showed moderate to low, with nitroimidazole-hybrids 5 and 9 . These pharmacokinetic results offered valuable insights into the drug-likeness and potential therapeutic pertinency of these hybrids.