Synthesis, anti-bronchoconstrictive, and antibacterial activities of some new 8-substituted-1,3-dimethylxanthine derivatives

Methylxanthines especially theophylline have been recognized as potent bronchodilators for the relief of acute asthma for over 50 years. Recently, it was found that bacterial infection has a role in asthma pathogenesis. Accordingly, the present work involves the synthesis of different series of 8-substituted (aryl, aralkyl, cycloalkyl, and heteroaryl)-1,3-dimethylxanthines. The chemical structures of these compounds were elucidated by IR, 1H NMR, 13C NMR, elemental analyses, and high resolution EI-MS or FAB-MS for some compounds. The bronchodilator activity was evaluated using acetylcholine induced bronchospasm in guinea pigs, and most of the compounds showed significant anti-bronchoconstrictive activity in comparison with aminophylline as a standard. Also, the antibacterial activity of all the target compounds was investigated in-vitro against Gram-positive and Gram-negative bacteria using ampicillin as a reference drug. Results showed that some of the tested compounds have potent antibacterial activity. A pharmacophore model was computed to get useful insight on the essential structural features of bronchodilator activity.