Synthesis and biological evaluation of fluorinated 1,5-diarylpyrrole-3-alkoxyethyl ether derivatives as selective COX-2 inhibitors endowed with anti-inflammatory activity.

Abstract

A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers were previously synthesized and the potential anti-inflammatory and antinociceptive activities of these compounds were evaluated in vivo. The compounds displayed a very good activity against both carrageenan-induced hyperalgesia and oedema in the rat paw test. Therefore, in a very preliminary test, compounds (8a,b) showed antiproliferative activity in the HaCaT (aneuploid immortal keratinocyte from adult human skin) cell models. On these basis, our research continued with the synthesis of fluorinated derivatives (8c,d, 9b-d, and 10b-d) with the aim of improving the pharmacokinetic profile of the previous active compounds. Substitution of a hydrogen atom by a fluorine atom may change the conformational preferences of the molecules due to stereoelectronic effects and also fluorine atom may be able to exert the metabolic obstruction reducing the "first-pass effect". Compound 10b exhibited a prominent in vivo anti-inflammatory and antinociceptive activities, in addition its antiproliferative power in an in vitro model of human skin cancer is herein described.

• Authors: Angela Di Capua, Claudia Sticozzi, Simone Brogi, Margherita Brindisi, Andrea Cappelli, Lidia Sautebin, Antonietta Rossi, Simona Pace, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Giuseppe Valacchi, Gianluca Giorgi, Antonio Giordani, Giovanna Poce, Mariangela Biava, Maurizio Anzini
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 109 Pg. 99-106 (Feb 15 2016) ISSN: 1768-3254 [Electronic] France
• PMID: 26774035 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• Analgesics
• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents
• Cyclooxygenase 2 Inhibitors
• Pyrroles
• Cyclooxygenase 2

Topics

• Adult
• Analgesics (chemical synthesis, chemistry, therapeutic use)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, therapeutic use)
• Antineoplastic Agents (chemical synthesis, chemistry, therapeutic use)
• Cell Line
• Cell Proliferation (drug effects)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (chemical synthesis, chemistry, therapeutic use)
• Edema (drug therapy)
• Halogenation
• Humans
• Hyperalgesia (drug therapy)
• Models, Molecular
• Pyrroles (chemical synthesis, chemistry, therapeutic use)
• Rats
• Skin (drug effects, pathology)
• Skin Neoplasms (drug therapy, pathology)