Identification of 1,3-(Dimethyl/Propyl)-8-Susbtituted (Cinnamic acid/Furan) Xanthine Derivatives with Anti-bronchospasmodic Activity Using in silico and in vivo Techniques

摘要

Asthma is a chronic obstructive pulmonary disease which affects the bronchi airways and results in the inflammation of bronchioles along with the hyper-responsiveness to some direct or indirect stimuli which leads to bronchoconstriction. Substituted xanthines have provided several lead compounds for the development of antiasthmatic agents over the decades. In this present paper, a series of 42 xanthine based derivatives (17 a-g; 18 a-g; 19 a-g; 20 a-g; 28 a-g and 29 a-g) were designed and synthesized. Chemical structures were elucidated by spectroscopic methods. All target compounds were evaluated for their in silico anti-bronchospasmodic potential using PASS software. Compounds with >95 potential (18 c-f; 28 a and 29 a-g) in comparison to the standard drug were selected for in vivo bronchospasmodic activity using histamine chamber model. In silico and in vivo activity revealed that the compounds substituted with furan spacer were more active than the cinnamic acid. Substitution with propyl functionality at 1-and 3-position of xanthine moiety is also accounted for the enhanced activity of furan derivatives (29 a-g). In conclusion, the synthesized new xanthine derivatives stands out as promising anti-bronchospasmodic agents for future development.