Synthesis, characterization and pharmacological evaluation of certain enzymatically cleavable NSAIDs amide prodrugs

Tilal Elsaman; Omar A A Aldeeb; Tarek Aboul-Fadl; Elnazeer I Hamedelneil

doi:10.1016/j.bioorg.2016.12.005

Synthesis, characterization and pharmacological evaluation of certain enzymatically cleavable NSAIDs amide prodrugs

Bioorg Chem. 2017 Feb:70:144-152. doi: 10.1016/j.bioorg.2016.12.005. Epub 2016 Dec 23.

Authors

Tilal Elsaman¹, Omar A A Aldeeb², Tarek Aboul-Fadl³, Elnazeer I Hamedelneil⁴

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, Omdurman Islamic University, P.O. Box 2587, Khartoum, Sudan. Electronic address: Tilochem@yahoo.com.
² Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
³ Department of Medicinal Chemistry, College of Pharmacy, Assiut University, Assiut 71526, Egypt.
⁴ Department of Pharmaceutics, College of Pharmacy, Omdurman Islamic University, P.O. Box 2587, Khartoum, Sudan.

PMID: 28040207
DOI: 10.1016/j.bioorg.2016.12.005

Abstract

The presence of free carboxylic acid group in majority of non-steroidal anti-inflammatory drug (NSAIDs) is responsible from GI irritation. Coupling of the appropriate NSAIDs (diclofenac, naproxen, dexibuprofen and meclofenamic acid) 1-4, respectively with the appropriate amino acid ester 5 using dicyclohexylcarbodiimide afforded prodrugs 6-13. The structures of the prodrugs were verified based on spectral data. Chemical hydrolysis studies performed in three different non enzymatic buffer solutions at pH 1.2, 5.5 and 7.4, as well as in 80% human plasma and 10% rat liver homogenate using HPLC indicate no conversion of prodrugs to their respective NSAID in the studied buffers, while they underwent a reasonable plasma and rat liver homogenate hydrolysis. Furthermore, ulcerogenicity of prodrugs 9 and 12 were studied and results revealed no gastro-ulcerogenic effects.

Keywords: Amino acid ester; NSAIDs; Prodrugs; Ulcerogenicity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / metabolism*
Humans
Hydrolysis
Liver / metabolism*
Male
Plasma / metabolism
Prodrugs / adverse effects*
Prodrugs / chemical synthesis
Prodrugs / chemistry
Prodrugs / metabolism*
Rats
Rats, Wistar
Stomach Ulcer / chemically induced*

Substances

Anti-Inflammatory Agents, Non-Steroidal
Prodrugs