Synthesis of gallic acid based naphthophenone fatty acid amides as cathepsin D inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 17; pp. 4603 - 4608
• Main Authors: Srivastava, Vandana, Saxena, Hari Om, Shanker, Karuna, Kumar, J.K., Luqman, Suaib, Gupta, M.M., Khanuja, S.P.S., Negi, Arvind S.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2006; Elsevier
• Subjects: Amides; Amides - chemistry; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Cathepsin D - antagonists & inhibitors; Cathepsin D - metabolism; Cathepsin-D; Enzymes and enzyme inhibitors; Fatty Acids - chemistry; Fundamental and applied biological sciences. Psychology; Gallic acid; Gallic Acid - chemical synthesis; Gallic Acid - chemistry; Gallic Acid - pharmacology; Hydrolases; Ketones - chemistry; Medical sciences; Miscellaneous; Molecular Structure; Naphthalenes - chemistry; Pepstatins - antagonists & inhibitors; Pepstatins - metabolism; Pharmacology. Drug treatments; Protease inhibitors; Structure-Activity Relationship; Synthesis; Amides; Synthesis; Gallic acid; Protease inhibitors; Cathepsin-D; Short chain; Ether; Enzyme; Aliphatic compound; Benzene derivatives; Enzyme inhibitor; Ketone; In vitro; Naphthalene derivatives; Peptidases; Structure activity relation; Carboxylic acid; Vinylic compound; Hydrolases; Carboxamide; Aspartic endopeptidases; Cathepsin D; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.06.010

Gallic acid has been modified to naphthophenone fatty acid amide derivatives. The targeted amides had a conformationally restricted pharmacophore and a linear aliphatic chain based on structure and activity relationship of previous studies. Two of the derivatives have shown significant cathepsin D inhibition activity having IC 50 values 0.056 and 0.136 μM. Gallic acid, one of the most abundant plant phenolic acids, has been modified to cathepsin D protease inhibitors. The strategy of modification was proposed basing on some previously reported structure and activity relationship (SAR) studies. The synthesized naphthophenone fatty acid amide derivatives have been evaluated for in vitro cathepsin D inhibition activity. Two of them have shown significant inhibition activity with IC 50 values of 0.06 and 0.14 μM, respectively, as compared against pepstatin (0.0023 μM), the most potent inhibitor known so far. The study revealed that such attempts on gallic acid based pharmacophores might result in potent inhibitors of cathepsin D.