N-Adamantanyl-2-(2-(phenyl)hydrazone)-3-oxobutanamides endowed with dual inhibitors of urease and -glucosidase: Design, synthesis, and computational studies

The conventional approach of drug development, which focused on inhibiting a single target, has been superseded by a more advanced strategy known as multi -target design. In this study, we describe the synthesis of new N-adamantyl-2-(2-(phenyl)hydrazone)-3-oxobutanamide (6a -k). These compounds were designed with the intention of serving as prospective drug like candidates that can target both alpha glucosidase and urease enzymes. For this purpose, both in -vitro and in-silico investigations were performed after synthesis and characterization. The density functional theory calculations were employed to calculate optimized geometries, global reactivity descriptors and frontier molecular orbital (FMO) analysis. All compounds were found reactive and compounds 6b, 6c, 6d and 6e were found the most stable. The synthesized compounds were also tested for their ability to inhibit the enzyme activities of urease and alpha-glucosidase. The compound 6c exhibited strong inhibition of urease enzyme, with IC50 value of 13.10 +/- 0.55 mu M, in comparison to the IC50 value of the standard inhibitor thiourea i.e., 16.4 +/- 1.02 mu M. In addition to this, compounds 6d and 6e demonstrated a significant alpha-glucosidase inhibition with IC50 values of 17.16 +/- 0.91 mu M but found less potent as compared to the standard inhibitor Acarbose, i.e. 9.80 +/- 0.20 mu M. The structure-activity relationship (SAR) was established and the in -vitro results were further supported by the molecular docking investigations and molecular dynamic simulation studies. The in -vitro and in-silico results demonstrated a strong correlation in assessing the drug -like characteristics of all synthesized compounds (6a -k). The in silico investigation confirmed the findings in the search for inhibitors against the listed enzymes by elucidating the binding relationship between most of the active compounds and the active site of urease and alpha-glucosidase.