Structure and biological property studies of the fluorinated sulfonic esters derived from 2-hydroxy-4-(hydroxy/methoxy)acetophenone as inhibitors of biochemical targets linked to type 2 diabetes mellitus

Abstract

Small molecule multi-target drugs substituted with fluorine atom/s or fluorine-containing group/s continue to attract considerable interest in medicinal chemistry due to their advantages in the treatment of multifactorial diseases. In this study, fluorine-containing alkyl and benzenesulfonyl chloride building blocks were reacted with 2,4-dihydroxyacetophenone 1a or 2-hydroxy-4-methoxyacetophenone 1b to afford the corresponding sulfonic ester derivatives 2a–f and 2g–j, respectively. Detailed crystallographic characterization was performed on a representative compound from each series. The compounds were evaluated through enzymatic assays in vitro for potential to inhibit biochemical targets linked to type 2 diabetes mellitus. Compound 1a and its 4-(4-fluorophenyl)sulfonyl derivative 2d exhibited strong and significant inhibitory effect in vitro against α-glucosidase (IC₅₀ = 0.97 ± 0.02 μM and 0.81 ± 0.07 μM, respectively) and α-amylase (IC₅₀ = 6.89 ± 0.04 μM and 4.87 ± 0.02 μM, respectively) compared to acarbose (IC₅₀ = 8.60 ± 0.20 μM and 1.96 ± 0.03 μM, respectively). The presence of a 4-fluorophenylsulfonyl moiety resulted in moderate inhibitory activity for 2d (IC₅₀ = 27.05 ± 0.01 μM) against protein tyrosine phosphatase 1 beta (PTP1B) compared to the PTP1B inhibitor, suramin (IC₅₀ = 4.63 ± 0.003 μM). The test compounds exhibited strong to moderate nitric oxide radical scavenging activity in vitro against ascorbic acid (IC₅₀ = 5.53 ± 0.03 μM) with IC₅₀ values in the range 0.05–19.30 μM. Compounds 1a and 2d did not inhibit superoxide dismutase (SOD) activity. Molecular docking revealed the involvement of hydrophobic, hydrophilic and electrostatic interactions with amino acid residues in the active site of the test enzymes.