Multifunctional arylsulfonamide derivatives with 5-HT6/5-HT7 receptor antagonistic activity: a structural study

Abstract

Nowadays, a search for antagonists co-acting on serotonin receptor subtypes 6 and 7 (5-HT6R and 5-HT7R, respectively) is of great interest due to the increasing number of patients suffering from dementia and related behavioural and psychological symptoms. The X-ray crystal structures of four promising multifunctional ligands in the hydrochloride forms were determined, namely 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[3-(3-methylbenzenesulfonamido)propyl]piperidin-1-ium chloride, C22H27FN3O3S+·Cl−, (I), 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamido)butyl]piperidin-1-ium chloride, C25H28F2N3O3S2 +·Cl−, (II), 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[4-(6-fluorobenzo[b]thiophene-2-sulfonamido)butyl]piperidin-1-ium chloride, C24H26ClFN3O3S2 +·Cl−, (III), and 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[3-(3-chloro-4-fluorobenzenesulfonamido)propyl]piperidin-1-ium chloride, C21H22ClF2N3O3S2 +·Cl−, (IV). Two pharmacologically important functional groups, i.e. arylsulfonamide and piperidinyl–fluorobenzisoxazole, are linked by three- and four-membered aliphatic chains. These compounds crystallize as hydrochloride salts in monoclinic space groups, i.e. C2/c for (I), P21/c for (II) and (III), and P21/n for (IV). In the asymmetric unit, a charge-assisted hydrogen bond is observed between the cation located at the piperidine N atom and the chloride anion. The protonated piperidine N atom is critical to the pharmacological activity for the compounds, allowing for a strong interaction with monoaminergic receptors in the central nervous system. The sulfonyl group plays the role of a hydrogen-bond acceptor in the pharmacophore model and is involved in several C—H...O interactions. Two aromatic fragments of the presented structures are involved in C—H...π contacts, which were studied by Hirshfeld structure analysis. The distances between the mentioned functional groups are in agreement with pharmacophore models given in the literature. The studied interactions observed in the crystal structure indicate the main forces responsible for ligand–receptor recognition and binding.