Design, Synthesis, SwissADME Profile DFT Studies, in vitro and in silico Anti-diabetic Potential of Novel Amide Derivatives Based on Bis((4-amino-4-oxobutanoyl)oxy) Zinc Scaffold.

AIMS: Synthesis and in silico therapeutic potential of newly synthesized amide derivatives based on bis((4-amino-4-oxobutanoyl)oxy)zinc scaffold and their antidiabetic potential.

BACKGROUND

Indeed, the design and synthesis of coordinated complexes are gaining substantial attention in synthetic chemistry due to their intriguing structures and possible applications in catalysis, molecular magnetism, and biological potentials.

OBJECTIVE

The current study deals with the synthesis of amide derivatives based on bis((4-amino-4- oxobutanoyl)oxy)zinc scaffold C1-C5 followed by Swiss absorption, distribution, metabolism, and elimination (ADME), Density functional theory (DFT) studies, molecular docking and in vitro antidiabetic activity.

METHODS

The structure of newly derived compounds was characterized using physiochemical properties and spectroscopic techniques. SwissADME web service was used to analyze the physicochemical properties of the synthesized compounds. The electronic characteristics of C1-C5 were examined using the Time-dependent density functional theory (TD-DFT) approach. Further α-glucosidase and α-amylase enzymes analyzed the anti-diabetic potentials of the synthesized compounds at various concentrations.

RESULTS

SwissADME analysis of compounds showed deviation from Lipinski's rule of five, which is a critical marker in drug development. It predicated poor permeability and absorption in blood brain barrier, while the bioavailability score indicates a suitable plasma concentration. Compounds are assumed to have straightforward synthesis steps. The TD-DFT study found that the highest occupied molecular orbital and lowest unoccupied molecular orbital (HOMO and LUMO) were concentrated on the π-conjugated system of the substituted rings, indicating a significant delocalization of electrons. The study also found that compounds possess chemical hardness and stability properties, with a lower electrophilicity index indicating higher bioactivity and lower toxicity and thus, potential as drug candidates. In in vitro activity, compound C-2 displayed excellent inhibition against both enzymes with IC50 values 2.23 and 2.63 μM, respectively.

CONCLUSION

In short, the newly synthesized amide derivatives based on bis((4-amino-4- oxobutanoyl)oxy)zinc scaffold C1-C5 possess promising in silico efficacy, stability and safety with variable pharmacokinetic profile and anti-diabetic potentials, therefore, further studies are needed.