Nicotinic Acid-Catalyzed Synthesis of Novel Benzothiazoles and Benzimidazoles from Carbohydrate-Derived Furfurals: Structural, Computational, and Antimicrobial Studies

Abstract

Benzothiazole and benzimidazole derivatives represent important heterocyclic scaffolds with well-established pharmacological relevance. In the present study, a sustainable synthetic approach was developed for the preparation of novel benzothiazole and benzimidazole derivatives via the condensation of carbohydrate-derived furaldehydes with 2-aminobenzenethiol and o-phenylenediamine, respectively. Various biogenic carboxylic acids were evaluated as catalysts, among which nicotinic acid exhibited superior catalytic efficiency, reusability, and compatibility with both aqueous and green organic solvents under conventional heating, affording the targeted products in excellent isolated yields (74-95%). The antimicrobial potential of the synthesized compounds was assessed using agar well diffusion and cup-plate methods against selected bacterial and fungal strains, revealing that several derivatives displayed significant inhibitory activity comparable to that of standard drugs. Two representative benzothiazole derivatives (4d and 4g) were further investigated by single-crystal X-ray diffraction to elucidate their molecular and supramolecular architectures. Density functional theory calculations based on experimentally determined geometries showed good electronic stability and comparable reactivity, while Hirshfeld surface analysis highlighted that the molecules in the crystal interact by hydrogen-bonding and π···π interactions. Moreover, in silico ADMET studies indicated favorable drug-like properties and pharmacokinetic profiles, such as favorable oral absorption and moderate blood-brain barrier permeability.