Design, modification, and bio-evaluation of salazinic acid derivatives

Abstract Data on synthesized derivatives of salazinic acid are scarce, with existing reports addressing only derivative hexaacetyl salazinic acid. This study investigated a set of novel potential antidiabetic agents. Analogs of salazinic acid were designed and synthesized using bromination, nucleophilic addition, Friedel-Crafts alkylation, and esterification. Ten synthetic compounds were prepared and structurally elucidated, including eight new compounds (1a-1c, 2a, 3a, 3b, 4a, 4b) and two known analogs. Under bromination, salazinic acid (1) enabled the following reaction chain: oxidation, decarboxylation, and substitution. This yielded products 1a-1c, which were found to have unprecedented scaffolds. Parmosidone F (5) was prepared from 1 with orsellinic acid via Friedel-Crafts alkylation, confirming a previously reported biosynthesis route. These analogs were evaluated for enzyme inhibition of α-glucosidase, and all showed more potent activity than that of acarbose, a positive control (IC50 332 μM), with IC50 values in the range 9.32-39.96 μM. An in silico molecular docking model confirmed that, in terms of enzyme inhibition, the compounds ranked as follows: 3b> 4b > 4a > 1c > 2a > 1b > 1a > 3a. The kinetics of enzyme inhibition showed 4a and 5 to be a non-competitive-type and mixed-type inhibitors, respectively.