Synthesis, 3D-pharmacophore modelling and 2D-QSAR study of new pyridine-3-carbonitriles as vasorelaxant active agents

• Published in: New journal of chemistry Vol. 45; no. 17; pp. 7731 - 774
• Main Authors: Srour, Aladdin M, Dawood, Dina H, Saleh, Dalia O
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 07.05.2021; Royal Society of Chemistry
• Subjects: Chemistry; Chemistry, Multidisciplinary; Pharmacology; Physical Sciences; Receptors (physiology); Science & Technology; Three dimensional models; Two dimensional models; Vasodilation; DRUG; ALPHA-ADRENORECEPTOR ANTAGONISTS; QSAR; URINARY-TRACT SYMPTOMS; DERIVATIVES; DISCOVERY; RATIONAL DESIGN
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/d0nj06319c

A new set of pyridine-3-carbonitriles ( 3a-v ) conjugated with various five-membered ring systems at pyridinyl C-6 were designed and synthesized as vasorelaxant active agents. The majority of the new target derivatives exhibited noteworthy vasodilation efficacy and compounds 3b , 3k , 3l , 3m , 3o , 3p , 3s , 3u and 3v were the most potent analogues with IC 50 values = 220.7, 256.7, 164.1, 252.2, 229.8, 265.2, 247.9, 239.1 and 159.8 μM, respectively, which were superior to that of prazosin hydrochloride (IC 50 = 272.8 μM). Moreover, 3b , 3l , 3o and 3v displayed significant α 1 -adrenergic receptor (α 1 -AR) blocking efficiency ranging from 65.38 to 87.86% compared with 89.34% for prazosin hydrochloride. Furthermore, a 2D-QSAR study and 3D-pharmacophore model were introduced to carry out compare-fit study for the designed molecules with the generated hypothesis and creating a statistically significant model. A new set of pyridine-3-carbonitriles ( 3a-v ) conjugated with various five-membered ring systems at pyridinyl C-6 were designed and synthesized as vasorelaxant active agents.