Chemical modification of ascorbic acid and evaluation of its lipophilic derivatives as inhibitors of secretory phospholipase A₂ with anti-inflammatory activity

The halo 6-fatty acid esters of l-ascorbic acid 3a, 3b and 6-fatty acid esters of l-ascorbic acid 5a-g were achieved from l-ascorbic acid 1. Compounds 3a, 3b and 5a-g were evaluated for anti-oxidant, anti-lipid peroxidation, and secretory phospholipase A₂ (sPLA₂) inhibition in vitro, and sPLA₂ induced mouse paw edema. All the derivatives retained their anti-oxidant property compared to ascorbic acid at 6 × 10^-4M and are good inhibitors of lipid peroxidation at 1 mg ml^-1 as evaluated by 2, 2-Diphenyl-1-picrylhydrazyl radical and thio-barbituric acid methods, respectively. Compounds 5e and 5f significantly inhibited purified group I sPLA₂ from Naja naja and group II sPLA₂ from Vipera russelli, human synovial fluid and human pleural fluid with IC ₅₀ value ranging from 64 ± 1.95 to 82 ± 1.3 and 48 ± 2.27 to 61 ± 2.23 μM, respectively. The compounds 5e and 5f also showed varying degree of potency in neutralizing indirect hemolytic activity of sPLA₂ at 50 μM concentration, and sPLA₂ induced mouse paw edema at the dose 3 mg/kg. Further docking studies also confirmed that compounds 5e and 5f have maximum interaction with increasing negative energy value. Single molecule possessing both anti-oxidant and anti-inflammatory activities is of great therapeutic significance in inflammatory disorders.