Synthesis, characterization, and molecular docking studies of novel hippuric acid anhydrides as potential antiurolithic, analgesic and free radical scavenging agents

Abstract

Hippuric acid is a biotransformation product in humans which is excreted through urine. Dietary intake of phenolic compounds increases its concentration in urine. Hippuric acid is experimentally proved to be a regulator of calcium oxalate super saturation in human urine and has a solvent effect on oxalate salts. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used analgesics employed in associated renal colic of urolithiasis. The objective of the present study was to chemically link hippuric acid through anhydride linkage to various NSAIDs to synthesize potential mutual prodrugs for urolithiasis and associated renal colic. Hippuric acid was linked to eleven NSAIDs through anhydride linkage by first synthesizing hippuryl chloride using oxalyl chloride as chlorinating agent, followed by its reaction with sodium salts of NSAIDs. Structures of obtained compounds were elucidated using UV spectrophotometry, FTIR spectrometry, 1H NMR and C-13 NMR spectrometry. Synthesized compounds were evaluated for in vitro antioxidant, in vivo acute toxicity, in vivo antiurolithic, in vivo analgesic and in vitro hydrolysis studies. Molecular docking analysis on TNF-α and COX-2 was carried out to determine target protein binding. Synthesized compounds showed stability at acidic pH which indicate potential gastro protective effect of synthesized conjugates. Compounds P9 an P6 showed maximum in vivo antiurolithic activity while P9 and P8 showed maximum in vitro antioxidant activity. All the conjugates except P2 showed significant analgesic activity which show that conjugation of hippuric acid to NSAIDs did not result in loss of analgesic potential. Docking studies showed better affinity with TNF-α as compared to COX-2.