Synthesis, molecular modeling studies and bronchodilation properties of nicotinonitrile containing-compounds.
Soliman EA, Panda SS, Aziz MN, Shalaby EM, Mishriky N, Asaad FM, Girgis AS.
Facile synthetic pathway for nicotinonitriles 5a‒o, 7a‒i was demonstrated through reaction of ketones 4a‒k, 6a‒f with ylidenemalononitrile 3 in the presence of sodium alkoxide. Meanwhile, nucleophilic attack of amines on 2-bromonicotinonitrile 9 (obtained through reaction of propenone 8 with malononitrile, followed by bromination with bromine in acetic acid) afforded 3-pyridinecarbonitriles 11a‒d. Single crystal X-ray of compound 7i reveals the monoclinic space group C2/c with 8 molecules per unit cell. Optimized structure of 7i [DFT/B3LYP, 6-31G(d,p)] shows close correlations to that of X-ray study. Compound 5l seems superior among all the synthesized analogues exhibiting bronchodilation properties about three folds potency compared to theophylline (standard reference) through pre-contracted tracheal rings with histamine standard method. Also compound 5a reveals promising observations (about two folds potency of the standard reference). Molecular modeling studies (3D-pharmacophore and 2D-QSAR) supported the observed biological properties.