Anti-Diabetic Activity of 2,3,6-Tribromo-4,5-Dihydroxybenzyl Derivatives from Symphyocladia latiuscula through PTP1B Downregulation and α-Glucosidase Inhibition

Abstract

The marine alga, <i>Symphyocladia latiuscula</i> (Harvey) Yamada, is a good source of bromophenols with numerous biological activities. This study aims to characterize the anti-diabetic potential of 2,3,6-tribromo-4,5-dihydroxybenzyl derivatives isolated from <i>S. latiuscula</i> via their inhibition of tyrosine phosphatase 1B (PTP1B) and α-glucosidase. Additionally, this study uses in silico modeling and glucose uptake potential analysis in insulin-resistant (IR) HepG2 cells to reveal the mechanism of anti-diabetic activity. This bioassay-guided isolation led to the discovery of three potent bromophenols that act against PTP1B and α-glucosidase: 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (<b>1</b>), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (<b>2</b>), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether) (<b>3</b>). All compounds inhibited the target enzymes by 50% at concentrations below 10 μM. The activity of <b>1</b> and <b>2</b> was comparable to ursolic acid (IC₅₀; 8.66 ± 0.82 μM); however, <b>3</b> was more potent (IC₅₀; 5.29 ± 0.08 μM) against PTP1B. Interestingly, the activity of <b>1</b>⁻<b>3</b> against α-glucosidase was 30⁻110 times higher than acarbose (IC₅₀; 212.66 ± 0.35 μM). Again, <b>3</b> was the most potent α-glucosidase inhibitor (IC₅₀; 1.92 ± 0.02 μM). Similarly, <b>1</b>⁻<b>3</b> showed concentration-dependent glucose uptake in insulin-resistant HepG2 cells and downregulated PTP1B expression. Enzyme kinetics revealed different modes of inhibition. In silico molecular docking simulations demonstrated the importance of the 7⁻OH group for H-bond formation and bromine/phenyl ring number for halogen-bond interactions. These results suggest that bromophenols from <i>S. latiuscula</i>, especially highly brominated <b>3</b>, are inhibitors of PTP1B and α-glucosidase, enhance insulin sensitivity and glucose uptake, and may represent a novel class of anti-diabetic drugs.