Synthesis, docking and biological activity : a novel series of benzimidazole derivatives as potential neuraminidase inhibitors

Abstract

In order to explore the potential of benzimidazole as neuraminidase inhibitors, a series of alkyl benzimidazole carboxylates 5(a-g) and alkyl benzimidazole carboxylic acids 6(a-g) were synthesised by following a four-step strategies involving esterification, nucleophilic aromatic substitution (SNAr), reduction, cyclisation and hydrolysis reactions. The reactions were carried out by both conventional and microwave methods and the modes of heating were compared and studied. Most of the compounds synthesised from the microwave method were found to give better yield in short reaction time although isolated yields were slightly lower compared with conventional method. All isolated compounds obtained were elucidated using 1H NMR, 13C NMR, DEPT-135, HSQC, 19F NMR analysis and ESI-mass spectroscopy. Molecular docking was later performed on both series in order to gain insight of possible binding modes and the preferred orientations/conformations of benzimidazole derivatives complexed in the active site of neuraminidase. Based on docking analysis, 6f was found to interact better in neuraminidase active site compared other compounds due to the presence 3-pentyl at position C2. Only pure compounds of carboxylic acid series 6(a-g) were further evaluated via neuraminidase inhibition assay as they could be dissolved in buffer solution. Although the results showed poor inhibitory activity towards neuraminidase enzyme, it is in good agreement with the docking results where 6f showed good inhibition among tested compounds.