Isolation, semi-synthesis, docking-based prediction, and bioassay-based activity ofDolichandrone spathaceairidoids: new catalpol derivatives as glucosidase inhibitors

Abstract

Dolichandrone spathaceairidoids are promising anti-diabetic inhibitors towards α-glucosidase protein (PDB-) and oligo-1,6-glucosidase protein. Five catalpol iridoids(1,2,10,13,14)were isolated from mangrove plantD. spathacea, and their derivatives (3,4,5,6,7,8,9,11,12,15) were obtained from reduction, acetylation,O-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 (inhibitability and physiological compatibility were predicted by molecular docking simulation and prescreened based on Lipinski's rule of five. Experimental α-glucosidase inhibition of1-15was evaluated using enzyme assays. Compounds3,4,5,6, and9are new iridoid derivatives, introduced to the literature for the first time, while all fifteen compounds1-15are studied for molecular docking for the first time. Regarding protein, the five strongest predicted inhibitors assemble in the order2>10>1>9>14. In respect to, the corresponding order is14>2>10>5>1=9. Lipinski's criteria suggest10as the candidate with the most potential for oral administration. Thein vitrobioassay revealed that compound10is the most effective inhibitor with a respective IC50value of 0.05 μM, in the order10>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.