Synthesis of 3-hydroxy-2-naphthohydrazide-based hydrazones and their implications in diabetic management via in vitro and in silico approaches

Abstract

Diabetes mellitus (DM) has prevailed as a chronic health condition and has become a serious global health issue due to its numerous consequences and high prevalence. We have synthesized a series of hydrazone derivatives and tested their antidiabetic potential by inhibiting the essential carbohydrate catabolic enzyme, alpha-glucosidase. Several approaches including fourier transform infrared, H-1 NMR, and C-13 NMR were utilized to confirm the structures of all the synthesized derivatives. In vitro analysis of compounds 3a-3p displayed more effective inhibitory activities against alpha-glucosidase with IC50 in a range of 2.80-29.66 mu M as compared with the commercially available inhibitor, acarbose (IC50 = 873.34 +/- 1.67 M). Compound 3h showed the highest inhibitory potential with an IC50 value of 2.80 +/- 0.03 mu M, followed by 3i (IC50 = 4.13 +/- 0.06 mu M), 3f (IC50 = 5.18 +/- 0.10 mu M), 3c (IC50 = 5.42 +/- 0.11 mu M), 3g (IC50 = 6.17 +/- 0.15 mu M), 3d (IC50 = 6.76 +/- 0.20 mu M), 3a (IC50 = 9.59 +/- 0.14 mu M), and 3n (IC50 = 10.01 +/- 0.42 mu M). Kinetics analysis of the most potent compound 3h revealed a concentration-dependent form of inhibition by 3h with K-i value = 4.76 +/- 0.0068 mu M. Additionally, an in silico docking approach was applied to predict the binding patterns of all the compounds, which indicates that the hydrazide and the naphthalene-ol groups play a vital role in the binding of the compounds with the essential residues (i.e., Glu277 and Gln279) of the alpha-glucosidase enzyme.