Novel NSAID 1-acyl-4-cycloalkyl/arylsemicarbazides and 1-acyl-5-benzyloxy/hydroxy carbamoylcarbazides as potential anticancer agents and antioxidants.

Abstract

The novel 1-acyl-4-cycloalkyl/arylsemicarbazides (5a-y) and 1-acyl-5-benzyloxy/hydroxycarbamoylcarbazides (8a-f) derived from the nonsteroidal anti-inflammatory drugs ibuprofen, fenoprofen and reduced ketoprofen were prepared, fully chemically characterized and evaluated for their cytostatic, antiviral and antioxidant activities. Compounds 5 and 8 consist of a region rich in electronegative atoms (five to nine nitrogen and oxygen atoms) framed by aryl or cycloalkyl residues on one or both terminal ends. The synthetic pathways applied for the preparation of the title compounds involved a benzotriazole as a synthetic auxiliary in several steps. Three of the tested compounds, namely 4-benzhydryl-1-[2-(3-phenoxyphenyl)propanoyl]semicarbazide (5l), 4-benzhydryl-1-[2-(3-benzylphenyl)propanoyl]semicarbazide (5s), and 4-benzhydryl-1-[2-(4-isobutylphenyl)propanoyl]semicarbazide (5f) showed pronounced antiproliferative activity in vitro against six cancer cell lines (IC(50)=3-23 μM). The same compounds highly inhibited soybean lipoxygenase (IC(50)=60 and 51.5 μM) and lipid peroxidation as well (99, 88 and 74%, respectively). 4-Benzyloxy-1-[2-(4-isobutylphenyl)propanoyl]semicarbazide (5t) and 5-benzyloxycarbamoyl-1-[2-(3-benzylphenyl)propanoyl]carbazide (8c) exerted complete lipid peroxidation inhibition. Semicarbazides 5w-y and carbazides 8d-f bearing a hydroxamic acid/hydroxyurea moiety showed a modest antiradical activity in DPPH test, while the best radical scavenger was 1-(1-benzotriazolecarbonyl)-4-benzyloxysemicarbazide (7). None of the compounds were inhibitory to a broad panel of DNA and RNA viruses in the cell culture at subtoxic concentrations.

• Authors: I Perković, I Butula, M Kralj, I Martin-Kleiner, J Balzarini, D Hadjipavlou-Litina, A-M Katsori, B Zorc
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 51 Pg. 227-38 (May 2012) ISSN: 1768-3254 [Electronic] France
• PMID: 22405290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents
• Antiviral Agents
• Free Radical Scavengers
• Semicarbazides
• carbamylhydrazine

Topics

• Anti-Inflammatory Agents, Non-Steroidal (chemistry, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Antiviral Agents (chemistry, pharmacology)
• Cell Proliferation (drug effects)
• Free Radical Scavengers (chemistry, pharmacology)
• Hydrophobic and Hydrophilic Interactions
• Inhibitory Concentration 50
• Semicarbazides (chemistry, pharmacology)
• Viruses (drug effects)