Molecular Modeling Design, Synthesis and Biological Evaluation of New Imidazoline Derivatives Linked as α1-AR Antagonists and Ang II Receptor Antagonists

Two new series of 5-spiroalkyl-4-substituted-imidazoline derivatives connected to various 4-arylpiperazinyl-oxoethyl (XIa-g) and tetrazolyl (or cyano)biphenylyl-methylthio moieties (XIIa-e) were designed, synthesized, and biologically evaluated for their in vivo hypotensive activities. The design of compounds XIa-g was based upon the molecular modeling simulation fitting to the previously generated 3D α1-adrenoceptor (α1-AR) antagonists hypothesis using CATALYST (HipHop) modules. The simulation study revealed the high fitting affinities of these compounds to the α1-AR antagonists hypothesis and compound XIg showed the highest fitting affinity. The in vivo hypotensive activity of these compounds on normotensive cats was consistent with the results of molecular modeling study, where compound XIg exhibited the highest hypotensive activity at different doses. Meanwhile, the design of compounds XIIa-e was based upon the molecular modeling simulation fitting to the previously generated Ang II receptor antagonists hypothesis using catalyst (HipHop) modules. The simulation study revealed that the tetrazolyl analogues of the cyano precursors XIIa-e could be considered as promising hits, while the cyano precursors have low fitting affinities. As expected, the in vivo hypotensive evaluation of the cyano analogues indicated their low activity.