Rational design, synthesis and QSAR study of vasorelaxant active 3-pyridinecarbonitriles incorporating 1H-benzimidazol-2-yl function

A variety of 2-alkoxy-4-aryl-6-(1H-benzimidazol-2-yl)-3-pyridinecarbonitriles 4a–r were prepared via either regioselective reaction of 3-aryl-1-(1H-benzimidazol-2-yl)-2-propen-1-ones 3 with malononitrile or ylidenemalononitriles 6 with 2-acetyl-1H-benzimidazoles 1 in the presence of sodium alkoxide in the corresponding alcohol. All the synthesized compounds showed significant vasodilation properties using isolated thoracic aortic rings of rats pre-contracted with norepinephrine hydrochloride standard technique. Compounds 4d, 4p, 4l, and 4f exhibited remarkable activity compared with prazosin hydrochloride, which was used as a reference standard in the present study. QSAR studies revealed a good predictive and statistically significant 3 descriptor model (r2 = 0.913, radjusted2=0.8808, rprediction2=0.7911).

Graphical abstractA variety of 3-pyridinecarbonitriles incorporating 1H-benzimidazol-2-yl function were synthesized exhibiting promising vasodilation properties.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 3-Pyridinecarbonitriles incorporating 1H-benzimidazol-2-yl function were synthesized. ► All the synthesized compounds showed significant vasodilation properties. ► Some prepared analogs exhibited remarkable activity compared with prazosin hydrochloride. ► QSAR studies revealed a good predictive 3 descriptor model.