Structure and molecular properties of (1)-Centbutindole. Comparison with Haloperidol

The structure and conformation of (1)-Centbutindole, a newly marketed neuroleptic compound, has been investigated by X-ray crystallography. It crystallizes in the monoclinic system and the non-centrosymmetric space group P2₁ (Z=2) with cell dimensionsa=8.434(6),b=6.620(3),c=18.419(9)Å, and =95.07(6)°. The chain conformation istrans extended. The embedded ³ piperidine ring exists in ahalf-chair conformation whereas the embedded piperazine ring exists in achair conformation. The propylene side chain is equatorial relative to the piperazine. A systematic conformational analysis of centbutindole and of a related molecule, Haloperidol, followed by a Monte Carlo search and a stochastic dynamics simulation, have been performed. Electronic and lipophilic properties have been computed and, molecular electrostatic potential (MEP) maps and molecular lipophilicity potential (MLP) maps, have been displayed for two selected conformers satisfying a reported pharmacophore. The two molecules exhibit very similar molecular properties.