Synthesis of benzimidazole-based hydrazones as potential anticarbonic anhydrase agents: a theoretical and experimental investigations

In this research, a series of new hydrazone-Schiff bases of benzimidazole were synthesized in good yields through three step reactions, and the structures were confirmed by means of modern spectroscopic techniques (HR-ESI-MS, ¹H-, and ¹³C NMR). These compounds have been assessed for their <i>in vitro</i> carbonic anhydrase (CA) inhibitory activity, 12 derivatives showed potent inhibition (IC₅₀ = 13.29 ± 0.46 to 30.74 ± 1.28 µM) comparing to the acetazolamide as a standard (IC₅₀ = 18.20 ± 0.43 µM). Molecular docking studies exposed vital binding interactions and robust affinities with the CA active site. Electronic properties and structural stability were examined through DFT (B3LYP/6-311++G(d,p)), and intramolecular interactions were evaluated by means of DFT-D3 and reduced density gradient analysis. Furthermore, TD-DFT (CAM-B3LYP/6-311++G(d,p)) calculations provided insights into the electronic transitions and reactivity parameters like electron affinity, electronegativity, ionization energy, and chemical hardness, offering a deeper understanding of the compounds' inhibitory mechanisms.