Synthesis and molecular docking of new hydrazones derived from ethyl isonipecotate and their biological activities

Abstract

Purpose: To investigate the antibacterial and α-glucosidase inhibitory activities of hydrazone derivatives (8a-h) of ethyl isonipecotate. Methods: The reaction of ethyl isonipecotate (2) with 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (1) in an aqueous basic medium yielded ethyl 1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]piperidin-4-carboxylate (3). Compound 3 was subsequently converted to ethyl 1-[(3,5-dichloro-2-ethoxyphenyl)sulfonyl]piperidin-4-carboxylate (5) via O-alkylation. Compound 5 on reaction with hydrated hydrazine yielded 1-[(3,5-dichloro-2-ethoxyphenyl)sulfonyl]piperidin-4-carbohyrazide (6) in MeOH. Target compounds 8a-h were synthesized by stirring 6 with different aromatic aldehydes (7a-h) in MeOH. All the synthesized compounds were structurally elucidated by proton nuclear magnetic resonance (1H-NMR), electron impact mass spectrometry (EI-MS) and infrared (IR) spectroscopy. For antibacterial activity, solutions of the synthesized compounds were mixed with bacterial strains, and the change in absorbance before and after incubation was determined. For enzyme inhibitory activity, change in the absorbance of mixtures of synthesized compounds and enzyme before and after incubation with substrate was determined. Results: The target compounds were synthesized in appreciable yields and well characterized by spectral data analysis. Salmonella typhi was inhibited by 8e (MIC 8.00 ± 0.54 µM), Escherichia coli by 8f (8.21 ± 0.83 µM), Bacillus subtilis by 8c (8.56 ± 0.63 µM) and Staphylococcus aureus by 8c (8.86 ± 0.29 µM). Two compounds, 8e and 8d, were very effective inhibitors of α-glucosidase with IC50 values of 40.62 ± 0.07 and 48.64 ± 0.08 µM, respectively. Conclusion: Low IC50 values of the synthesized compounds against α-glucosidase demonstrates their potential in type-2 diabetes treatment. Furthermore, these compounds exhibit substantial antibacterial activity against the bacterial strains tested.