Design, synthesis, stereochemical characterization, in vitro α-glucosidase, and α-amylase inhibition and in silico studies of novel pyrazole-hydrazide hydrazones

In this work, a novel series of fifteen pyrazole-linked hydrazide-hydrazone derivatives (4a-o) were designed, synthesized, characterized, and evaluated for their antihyperglycemic activity against α-amylase and α-glucosidase. In vitro results revealed that all synthesized compounds (4a-o) showed good to excellent antihyperglycemic activity with IC₅₀ in the range of 30.58 ± 0.56–290.70 ± 2.77 μM for α-glucosidase and in the range of 29.08 ± 0.56–160.70 ± 0.80 μM, as compared to the standard inhibitor acarbose (IC_{50(α-glucosidase)} = 98.12 ± 2.10 µM and IC_{50(α-amylase)} = 126.50 ± 2.01 µM). Among the series, compound 4m with hydroxy group in para position at phenyl ring was also found as the most potent inhibitor of α-amylase and α-glucosidase with IC₅₀ values of 29.08 ± 0.86 and 30.58 ± 0.56 μM, respectively, indicating their better potency than the standard acarbose. In silico molecular docking and molecular dynamic simulations further confirmed the binding modes and binding affinities of compound 4m and acarbose. The Structure-Activity Relationship (SAR) analysis of the effects of some functional groups in the co-structure of 4m were confirmed by IFD and MDS for both α-amylase and α-glucosidase inhibitor recognition.