Searching for new NO-donor aspirin-like molecules: Furoxanylacyl derivatives of salicylic acid and related furazans

Loretta Lazzarato; Clara Cena; Barbara Rolando; Elisabetta Marini; Marco Lucio Lolli; Stefano Guglielmo; Elena Guaita; Giuseppina Morini; Gabriella Coruzzi; Roberta Fruttero; Alberto Gasco

doi:10.1016/j.bmc.2011.08.018

Searching for new NO-donor aspirin-like molecules: Furoxanylacyl derivatives of salicylic acid and related furazans

Bioorg Med Chem. 2011 Oct 1;19(19):5852-60. doi: 10.1016/j.bmc.2011.08.018. Epub 2011 Aug 16.

Authors

Loretta Lazzarato¹, Clara Cena, Barbara Rolando, Elisabetta Marini, Marco Lucio Lolli, Stefano Guglielmo, Elena Guaita, Giuseppina Morini, Gabriella Coruzzi, Roberta Fruttero, Alberto Gasco

Affiliation

¹ Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.

PMID: 21906954
DOI: 10.1016/j.bmc.2011.08.018

Abstract

A new group of derivatives of salicylic acid containing NO-donor furoxans, and the related des-NO-furazans, were synthesized and evaluated as new aspirin-like molecules. Their stability was assessed in acid (pH 1) and physiological solutions (pH 7.4), and in human serum. No compound exhibited COX-inhibitory activity against COX-1 and COX-2 isoforms, when tested up to 100μM, respectively, on isolated platelets and on monocytes. Phenylsulfonyl- and cyano-substituted furoxans inhibited platelet aggregation induced by collagen in human platelet-rich plasma, through a cGMP dependent mechanism. Furoxan derivatives displayed cGMP-dependent vasodilator activities, tested on rat aorta strips precontracted with phenylephrine. All products showed anti-inflammatory activity similar to that of ASA, tested on rats by the carrageenan-induced paw edema assay. Unlike ASA, all products showed markedly reduced gastrotoxicity in a rat lesion model.

MeSH terms

Animals
Anti-Inflammatory Agents / chemistry*
Anti-Inflammatory Agents / pharmacology
Anti-Inflammatory Agents / therapeutic use
Aspirin / chemistry*
Collagen / chemistry
Collagen / metabolism
Cyclooxygenase 1 / chemistry
Cyclooxygenase 1 / metabolism
Cyclooxygenase 2 / chemistry
Cyclooxygenase 2 / metabolism
Disease Models, Animal
Drug Stability
Edema / chemically induced
Edema / drug therapy
Humans
Hydrogen-Ion Concentration
Nitric Oxide Donors / chemistry*
Nitric Oxide Donors / pharmacology
Nitric Oxide Donors / therapeutic use
Oxadiazoles / chemistry*
Oxadiazoles / pharmacology
Oxadiazoles / therapeutic use
Platelet Aggregation / drug effects
Platelet Aggregation Inhibitors / chemical synthesis
Platelet Aggregation Inhibitors / chemistry
Platelet Aggregation Inhibitors / pharmacology
Rats
Salicylic Acid / chemistry*
Vasodilator Agents / chemical synthesis
Vasodilator Agents / chemistry
Vasodilator Agents / pharmacology

Substances

Anti-Inflammatory Agents
Nitric Oxide Donors
Oxadiazoles
Platelet Aggregation Inhibitors
Vasodilator Agents
furoxans
Collagen
Cyclooxygenase 1
Cyclooxygenase 2
Salicylic Acid
Aspirin