Isolation, semi-synthesis, docking-based prediction, and bioassay-based activity of iridoids: new catalpol derivatives as glucosidase inhibitors.

iridoids are promising anti-diabetic inhibitors towards α-glucosidase protein (PDB-3W37) and oligo-1,6-glucosidase protein (PDB-3AJ7). Five catalpol iridoids (1, 2, 10, 13, 14) were isolated from mangrove plant , and their derivatives (3, 4, 5, 6, 7, 8, 9, 11, 12, 15) were obtained from reduction, acetylation, -alkylation, acetonisation, or hydrolysation starting from naturally isolated compounds. They were identified by spectral methods such as IR, MS, and 1D and 2D NMR. Their glucosidase-related (3W37 and 3AJ7) inhibitability and physiological compatibility were predicted by molecular docking simulation and prescreened based on Lipinski's rule of five. Experimental α-glucosidase inhibition of 1-15 was evaluated using enzyme assays. Compounds 3, 4, 5, 6, and 9 are new iridoid derivatives, introduced to the literature for the first time, while all fifteen compounds 1-15 are studied for molecular docking for the first time. Regarding protein 3W37, the five strongest predicted inhibitors assemble in the order 2 > 10 > 1 > 9 > 14. In respect to 3AJ7, the corresponding order is 14 > 2 > 10 > 5 > 1 = 9. Lipinski's criteria suggest 10 as the candidate with the most potential for oral administration. The bioassay revealed that compound 10 is the most effective inhibitor with a respective IC value of 0.05 μM, in the order 10 > 2 > 14 > 13 > 1. The computational and experimental results show good consistency. The study opens an alternative approach for diabetes treatment based on inhibitability of natural and semi-synthesised catalpol iridoid derivatives towards carbohydrate-hydrolases.