Evaluation and in vivo efficacy study of pyrano[3,2‐c]quinoline analogues as TNF‐α inhibitors

Abstract

A series of pyrano[3,2 c]quinoline was evaluated for its in vivo efficacy as TNF‐α inhibitor using LPS, phosphodiesterase (PDE)‐4, and CIA assays in different mice/rat models. The synthesis was performed using one‐pot multicomponent condensation between 2,4‐dihydroxy‐1‐methylquinoline, malononitrile, and diverse un(substituted) aromatic aldehydes. In vivo efficacy of the title compounds was evaluated using LPS assay in BALB/c mice, PDE4 inhibition in ketamine–xylazine‐induced anesthetize SD rats, and CIA assay was performed in DBA/1J mice as per the standard literature protocols. The outcome of the study revealed that compound 4v was found to be most promising candidate of the series. It was efficacious with 48.8 ± 13.0% inhibition of TNF‐α release at 100 mg/kg p.o., in the LPS assay in Balb/c mice model. It was effective in PDE4 assay in ketamine–xylazine‐induced anesthetize SD rats with duration of 38.3 ± 4.5 min for reversal of anesthetic effect and also showed significant inhibition of PDE4 in salbutamol treated U937 cell assay. It was also abolished TNF‐α induced phosphorylation and degradation of IκBα. Ultimately, its effect on CIA‐related bone and cartilage damage was found statistically similar to Enbrel.

Synthesis of pyrano[3,2-c]quinolones and furo[3,2-c]quinolonesviaacid-catalyzed tandem reaction of 4-hydroxy-1-methylquinolin-2(1H)-one and propargylic alcohols

“…Pyrano[3,2- c ]quinolone is a structural motif occurring in a number of natural products 1 with a wide range of important biological activities such as anticancer, 2 antibacterial, 2 antimalarial, 3 antiinflammatory 4 and antifungal 5 properties and inhibition of calcium signaling, 6 TNF-α, 7 platelet aggregation, 8 and nitric oxide production. 9 For example, alkaloids zanthosimuline and huajiaosimuline 10 exhibit cytotoxicity against cancer cells, which is considered as potential anticancer agents (Scheme 1a).…”