Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1787-1804 |
Number of pages | 18 |
Journal | Future Medicinal Chemistry |
Volume | 10 |
Issue number | 15 |
DOIs | |
State | Published - 2018 |
Keywords
- QSAR
- bronchodilator
- conjugate
- indole
- molecular modeling
- pharmacophore
- pyridine
ASJC Scopus subject areas
- Molecular Medicine
- Pharmacology
- Drug Discovery