Discovery of a new pyrido[2,3-d]pyridazine-2,8-dione derivative as a potential anti-inflammatory agent through COX-1/COX-2 dual inhibition.

In this paper, we present the design and synthesis of a novel series of pyrido[2,3-d]pyridazine-2,8-dione derivatives via the annulation of the 2-pyridone pattern. The synthesized derivatives were evaluated for in vivo anti-inflammatory activity using an ear edema model. Compound 7c, which showed a greater inhibition of ear edema (82%), was further tested for its in vitro COX-1/COX-2 inhibitory activity. Compound 7c showed similar inhibitory activities against COX-1 and COX-2 isoenzymes. The structural features that ensure the dual inhibition of COX-1 and COX-2 were elucidated using molecular docking studies. Overall, the ring closing of 2-pyridone pattern I transformed this highly selective COX-2 inhibitor into a dual COX inhibitor (7c), which could serve as a model for determining selectivity for COX-2.

Regiodivergent Synthesis of 3,4- and 4,5-Disubstituted N-Methylpyrazoles from 4-Acyl-1H-pyrrole-2,3-dione and Methylhydrazine.

A simple, efficient and highly regioselective method for the preparation of 3,4- and 4,5-disubstituted N-methylpyrazoles in a one-pot procedure is reported. The methodology developed was based on the regiochemical control of the reaction of 4-acyl-1H-pyrrole-2,3-diones and methylhydrazine with an influence of the addition or absence of acid and the substrate structure.

Synthesis of novel 3,5,6-trisubstituted 2-pyridone derivatives and evaluation for their anti-inflammatory activity.

The inflammatory response is the reaction of living tissue to an injury of a foreign nature, such as infection and irritants, and occurs as part of the body's natural defence response. Compounds capable of inhibiting cyclooxygenase (COX) enzymes, especially COX-2, have great potential as anti-inflammatory agents. Herein we present the regioselective synthesis of 49 novel compounds based on the 2-pyridone nucleus. The topical anti-inflammatory activity of seventeen compounds was evaluated in mice by croton oil (CO) induced ear edema assay. Most of the compounds exhibited a high level of in vivo anti-inflammatory activity, reducing ear edema and myeloperoxidase (MPO) activity. The most active compounds (2a and 7a) were inhibitors of COX enzymes. Compound 2a selectively inhibited the COX-2, while 7a was nonselective. Further, the compound 2a showed effective binding at the active site of COX-2 co-crystal by docking molecular study.

Unconventional Method for Synthesis of 3-Carboxyethyl-4-formyl(hydroxy)-5-aryl-N-arylpyrazoles.

An alternative highly regioselective synthetic method for the preparation of 3,5-disubstituted 4-formyl-N-arylpyrazoles in a one-pot procedure is reported. The methodology developed was based on the regiochemical control of the cyclocondensation reaction of ß-enamino diketones with arylhydrazines. Structural modifications in the ß-enamino diketone system allied to the Lewis acid carbonyl activator BF3 were strategically employed for this control. Also a one-pot method for the preparation of 3,5-disubstituted 4-hydroxymethyl-N-arylpyrazole derivatives from the ß-enamino diketone and arylhydrazine substrates is described.