Synthesis, Characterisation, Computational ADME studies, Pharmacological screening and In-vitro Hydrolysis studies of potential novel mutual prodrugs of N-(2,3-xylyl anthranillic acid)

Abstract

In the present work we report Synthesis, Computational ADME study, Pharmacological evaluation and In-vitro hydrolysis study of new mutual prodrugs of N-(2,3-xylyl anthranillic acid) prepared with and without spacer using Dicyclohexylcarbodiimide (DCC) as coupling agent. The structures of mutual prodrugs formed were confirmed by advanced spectroscopic techniques. The title compounds were tested for analgesic activity by Eddy’s hot plate and tail-flick method; for anti-inflammatory activity by carrageenan induced rat paw edema method and for ulcerogenicity and acute oral toxicity. Title compounds exhibited promising analgesic and anti-inflammatory activity. The compounds were found to be devoid of ulcerogenicity at the test dose level and presented significant values of the ADME properties studied, obeying Lipinski Rule of five violations, good oral absorption and lipophilicity. Hydrolysis studies revealed that the compounds were sufficiently stable at pH 1.2, indicating that no appreciable hydrolysis to the free acids might occur in the stomach. The amount of free drug released on hydrolysis in 80% human plasma (pH 7.4) was greater than that released in aqueous buffers, suggesting that the rate of hydrolysis of compounds in 80% human plasma was markedly accelerated compared with that in aqueous buffers.