Anti-asthmatic activity of azepino [2, 1-b] quinazolones, synthetic analogues of vasicine, an alkaloid from Adhatoda vasica

Asthma is characterized by persistent airway inflammation caused by over expression of pro-inflammatory immune response, predominantly by eosinophils and lymphocytes. Lymphocytes (CD4+ Th2) have been documented to be responsible for the pathogenesis of asthma by secreting Th2 cytokines and activating eosinophils, leading to airway hypersensitivity. Secretion of Th2 cytokines has been shown critical for the induction of the characteristic airway inflammation in humans and animal models of asthma. These cytokines influence the inflammatory response and lead to the pathological changes associated with asthma. In the present study, 10 azepino [2,1-b] quinazolone derivatives (R1 to R10) were synthesised and evaluated for their anti-asthmatic activity using a murine model of asthma. The compounds R2, R4, R6, R7 and R8 caused a notable decrease Th2 cytokine secretion and eosinophilia in asthma-induced animals. However, the decrease was highly significant in case of R8-treated animals. Crystal structure of R8 was made by X-ray crystallography. Molecular modelling studies were done for the compound R8 with transcription factors STAT6 and GATA3 which are the main transcription factors responsible for Th2 cell differentiation. Also the pharmacokinetics of R8 was carried out in mice after oral and intravenous administrations.