Experimental and computational structural studies of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles

Abstract

Four compounds (1–4) reported in our previous work as potential antipsychotics with affinity for dopamine D2 and serotonin 5-HT1A and 5-HT2A receptors, were now subjected to detailed structural characterization. The X-ray analysis conducted for studied compounds proved that interatomic distances and bond angles in their crystal structures lie within normal values. The indole group in all compounds is planar, whereas tetrahydropyridine moiety exhibits almost ideal or close to half-chair conformation and is slightly or significantly rotated in relation to the indole group plane by 9.49(1)°, 30.24(11)°, 7.43(6)° and 15.98(18)° in compounds 1–4, respectively. The R1 substituents of tetrahydropyridine group in all cases form a dihedral angle with the indole moiety with value ranging from 66.57(14)° (2) to 86.73(17)° (4). The crystal structure of 1 is stabilized by N–H···N hydrogen bonds and C–H···π interactions. The intermolecular C(12)−H(12B)···Cg(2) interactions form a supramolecular two-dimensional network. The molecules in the crystal of 2 are linked by N–H···N. The formed chains are additionally stabilized with C–H···S hydrogen bonds. In case of compound 3, molecule chains are formed by N–H···N hydrogen bonds and are further linked via C–H···O hydrogen bonds into layer. The crystal structure is also stabilized by intermolecular C–H···π interactions. The molecules of compound 4 are linked by N–H···N hydrogen bonds and further stabilized by intermolecular C–H···π interactions. Crystallographic analysis was complemented with computational studies, such as Frontier Molecular Orbital analysis, which indicated that all four compounds display similar chemical reactivity, regardless of different R1 and R2 substituents. In addition, the most reactive parts of the compounds appear to be the indole and double bond located in tetrahydropyridine moiety. Lastly, the calculations of electrostatic potential and non-covalent interactions have been performed.