Halo-Substituted Adamantyl Benzamides as Digestive Enzyme Modulators: Synthesis, DFT Analysis, and Biological...

Current research work contains synthesis of novel para-halo substituted adamantane benzamides which were emerged as promising scaffolds in drug discovery by predicting their metabolic stability, broad pharmacological potential and lipophilicity through in silico and in vitro studies. Synthetic route was designed through acylation of adamantaminol with p-halo substituted benzoyl chlorides which resulted in high yields. Characterization analysis was done through spectroscopic methods. The main highlight was the energy gap between HOMO and LUMO energy levels of the novel products which came nearly same for all (i.e., 5.4 eV) found by DFT studies. For drug-likeness and pharmacokinetic analysis, ADME assessments took place which revealed impactful physicochemical profiles, blood-brain barrier permeability, no violation in Lipinski's rule and high gastrointestinal absorption, with low toxicity risks. Molecular docking and digestive enzyme inhibition and activation studies revealed that fluoro substituted benzoyl amide is a promising molecule as its IC₅₀ values were lowest for pepsin (IC₅₀ = 2.51 ± 1.4) and trypsin (IC₅₀ = 3.8 ± 1.2) and the percentage of activation was highest for lipase (% of activation = 60.18 ± 1.6) and α-amylase (% of activation = 57.66 ± 1.5).