Aim: Synthesis of novel bronchodilatory active indole-pyridine conjugates. Results/methodology: Indole-pyridine conjugates (6a-n, 8a-i and 10a-c) were synthesized in a facile pathway through reaction of 2-[(1-alkyl-1H-indol-3-yl)methylene]malononitriles 4a,b with the corresponding ketone-containing compounds (5a-f, 7a-c and 9a,b) in the presence of sodium alkoxide. Single (6l, 8 g) and powder (6k, 8d) x-ray studies supported the structures.
Results: Histamine precontracted isolated tracheal rings of guinea pig exhibited the potent bronchodilation properties of 6c (about double-fold potency relative to the standard reference, theophylline). Some of the synthesized conjugates (8d, 6c, 6f and 6e) revealed promising reduction of IL-8 production during lipopolysaccharide-induced airway inflammatory bioassay. Computational studies (3D pharmacophore, 2D-QSAR 'quantitative structure-activity relationship') showed high approximations to the bronchodilation properties and explained the parameters controlling biological observations.
Keywords: QSAR; bronchodilator; conjugate; indole; molecular modeling; pharmacophore; pyridine.