ABSTRACT
N-substituted-(indol-3-yl)carboxamides 10-15 and alkanamides 16-18 were prepared starting from the corresponding acids and submitted to screening for evaluation of their anti-inflammatory activity. None of the considered carboxamides exhibited significant inhibitory effect in the carrageenin-induced rat paw oedema after oral administration of 0.1 mM x kg(-1); nevertheless introduction of an alkyl chain, leading to alkanamides 16-18, induced moderate to high activity: 46-95% inhibition. The efficacy of these compounds in the inhibition of topical inflammation was confirmed by measuring reduction of ear thickness in the acute tetradecanoyl phorbol acetate (TPA)-induced mouse ear swelling assay. Preliminary pharmacomodulation brought to the fore that toxic effects induced, at 0.4 mM x kg(-1), by N-(pyridin-4-yl)(indol-3-yl)propanamide (17) could be attenuated or suppressed by 5-fluorination or introduction of a methoxycarbonylborane moiety, leading to 18 and 21.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Inflammation/drug therapy , Pyridines/chemical synthesis , Pyridines/pharmacology , Administration, Topical , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Carrageenan/pharmacology , Drug Design , Drug Evaluation, Preclinical , Ear, External/drug effects , Ear, External/pathology , Edema/chemically induced , Edema/drug therapy , Edema/pathology , Indoles/administration & dosage , Indoles/therapeutic use , Inflammation/chemically induced , Inflammation/pathology , Magnetic Resonance Spectroscopy , Male , Mice , Pyridines/administration & dosage , Pyridines/therapeutic use , Rats , Spectrophotometry, Infrared , Structure-Activity Relationship , Tetradecanoylphorbol Acetate/pharmacologyABSTRACT
Our on going work in the series of enamido-diketones issued from 2-azaarylindane-1,3-diones led us to synthesize and experiment N and C2-substituted derivatives of 2-(2 and 4-pyridinyl)indane-1,3-diones as well as of structurally related compounds resulting from the replacement of pyridine by quinoline and benzimidazole. Pharmacological evaluation of their anti-inflammatory activity (by inhibition of carrageenan foot edema) and their anticoagulant activity (by prothombin assay) led to the conclusion of the possibility of achieving a selective anti-inflammatory effect. It has been previously established that anticoagulants are liable to exert a protective effect in the development of cancer metastasis. Nevertheless none of the six experimented 2-(pyridin-2-yl)indane-1,3-diones extended survival time of mice treated by P388 lymphocytic leukemia.
