Novel Crown Ether-Functionalized Fusidic Acid Butyl Ester: Synthesis, Biological Evaluation, In Silico ADMET, and Molecular Docking Studies.

Crown ethers have gained importance in the field of medicine because of their resemblance to natural ionophores like valinomycin. With the goal of developing new pharmacologically important crown ethers, a novel series of crown ethers linked with Fusidic acid butyl ester 10a-d were synthesized and characterized by means of their (1)H NMR, (13)C NMR DEPT-135, FT-IR, and mass spectrometry. In vitro antioxidant and α-glucosidase inhibition activities of all crown ethers along with the precursor Fusidic acid butyl ester were examined and compared to the standard butylated hydroxyanisole and acarbose, respectively. Compounds (FABE-16-crown-4) 10b and (FABE-19-crown-5) 10c showed high antioxidant potential with the IC(50) = 22.5 ± 0.2 μM and 32.1 ± 0.3 μM, respectively, when compared to the standard BHA (IC(50) = 44.2 ± 0.34 μM). To understand the binding mode of the compounds, molecular docking investigations were performed using human antioxidant protein, peroxiredoxin 5. Molecular docking studies revealed higher docking scores (-6.5 and -6.7 kcal/mol) for the highly active compounds 10c and 10b, respectively, than standard BHA (-5.3 kcal/mol). Synthesized crown ethers exhibited moderate α-glucosidase inhibition with (IC(50) = 23.5 ± 0.2 to 76.5 ± 0.1 μM) when compared to acarbose as standard (IC(50) = 5.2 ± 0.8 μM). The in silico ADMET predictions indicated that the prepared compounds obeyed (bRO5) and Veber's rule for the acceptance as orally administered drugs and indicated that all the prepared crown ethers exhibited calculated values of drug likeness parameters in acceptable ranges that showed good potential of these molecules for further drug development investigations.