Total Synthesis and Biological Evaluation of Asterriquinol D Dimethyl Ether, Candidusin D, Kumbicins A–B, and Petromurins C–D as α-Glucosidase Inhibitors

The first total synthesis of asterriquinol D dimethyl ether, candidusin D, kumbicins A-B, and petromurins C-D has been accomplished in a concise fashion. The convergent route featured a key double Suzuki coupling and a set of judicious late-stage functional group transformations. Biological evaluation demonstrated these natural products and their derivatives to be a novel class of α-glucosidase inhibitors with unique structural scaffolds. N-Boc-kumbicin A exhibited the most potent inhibitory activity (IC₅₀ = 8.84 ± 3.38 μM) in comparison to the positive control acarbose (IC₅₀ = 564.28 ± 4.68 μM). Kinetic studies indicated that N-Boc-kumbicin A was a reversible and mixed-type inhibitor of α-glucosidase. CD spectral analysis revealed that the interaction of N-Boc-kumbicin A with α-glucosidase caused significant conformational changes and modifications in the microenvironment of the enzyme's secondary structure, principally through the formation of hydrogen bonds and hydrophobic interactions as demonstrated by molecular docking studies.