Synthesis, hydrolyses and dermal delivery of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) derivatives of phenol, imide and thiol containing drugs

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Abstract

Synthesis, characterization and hydrolysis in aqueous buffers of novel N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) derivatives of substituted phenols, theophylline (Th) and 6-mercaptopurine (6MP) were carried out. The mechanism of hydrolysis was further investigated by synthesis, characterization and hydrolysis of N-aryl-N-alkyloxycarbonylaminomethyl (NArNAOCAM) derivatives of phenols. The hydrolysis follows pseudounimolecular first order kinetics and operates by way of an SN1-type mechanism. Topical delivery of selected derivatives of acetaminophen (APAP), Th and 6MP was examined in in vitro diffusion cell experiments from IPM across hairless mice skins. The prodrug of APAP and 6MP increased permeation across the skin by about 2- and 4-fold, respectively, compared to the parent drug. NANAOCAM promoieties can act as novel prodrug derivatives of phenol, imide and thiol containing drugs for enhancing topical absorption.

Graphical abstract

The ability of N-alkyl-N-alkyloxycarbonylaminomethyl promoiety to act as soft alkylating agent and its influence in increasing membrane permeation for phenols, imides and thiols have been probed.

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