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

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, "α-glucosidase." Several approaches including fourier transform infrared, ¹ H NMR, and ¹³ C 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 α-glucosidase with IC₅₀ in a range of 2.80-29.66 µM 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 µM, followed by 3i (IC₅₀ = 4.13 ± 0.06 µM), 3f (IC₅₀ = 5.18 ± 0.10 µM), 3c (IC₅₀ = 5.42 ± 0.11 µM), 3g (IC₅₀ = 6.17 ± 0.15 µM), 3d (IC₅₀ = 6.76 ± 0.20 µM), 3a (IC₅₀ = 9.59 ± 0.14 µM), and 3n (IC₅₀ = 10.01 ± 0.42 µM). 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 µM. 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 α-glucosidase enzyme.