Andrzej Maślankiewicz

Quinoline- and isoquinoline-sulfonamide derivatives of LCAP as potent CNS multi-receptor-5-HT1A/5-HT2A/5-HT7 and D2/D3/D4-agents: the synthesis and pharmacological evaluation.

Two series of arylpiperazinyl-alkyl quinoline-, isoquinoline-, naphthalene-sulfonamides with flexible (13-26) and semi-rigid (33-36) alkylene spacer were synthesized and evaluated for 5-HT(1A), 5-HT(2A), 5-HT(6), 5-HT(7) and selected compounds for D(2), D(3), D(4) receptors. The compounds with a mixed 5-HT and D receptors profile 16 (N-{4-[4-(3-chlorophenyl)-piperazin-1-yl]-butyl}-3-quinolinesulfonamide) and 36 (4-(4-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethyl}-piperidine-1-sulfonyl)-isoquinoline), displaying antagonistic activity at 5-HT(7), 5-HT(2A), D(2) postsynaptic sites, produced antidepressant-like effects in the forced swim test in mice and showed significant anxiolytic activity in the plus-maze test in rats. The lead compound 36, a multi-receptor 5-HT(2A)/5-HT(7)/D(2)/D(3)/D(4) agent, also displayed significant antipsychotic properties in the MK-801-induced hyperlocomotor activity in mice.

Antidepressant and antipsychotic activity of new quinoline- and isoquinoline- sulfonamide analogs of aripiprazole targeting serotonin 5-HT1A/5-HT2A/5-HT7 and dopamine D2/D3 receptors

A series of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole was synthesized to explore the influence of two structural features - replacement of ether/amide moiety with sulfonamide one, and localization of a sulfonamide group in the azine moiety. In contrast to aripiprazole, compound 33 (N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)quinoline-7-sulfonamide) and 39 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)isoquinoline-3-sulfonamide) displaying multireceptor 5-HT(1A)/5-HT(2A)/5-HT(7)/D(2)/D(3) profile, and behaving as 5-HT(1A) agonists, D(2) partial agonists, and 5-HT(2A)/5-HT(7) antagonists, produced significant antidepressant activity in FST in mice. On the other hand, their 4-isoquinolinyl analog 40 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)isoquinoline-4-sulfonamide), with similar receptor binding and functional profile, additionally displayed remarkable antipsychotic properties in the MK-801-induced hyperlocomotor activity in mice.

Arene- and quinoline-sulfonamides as novel 5-HT7 receptor ligands

Novel arene- and quinolinesulfonamides were synthesized using different solutions and a solid-support methodology, and were evaluated for their affinity for 5-HT(1A), 5-HT(2A), 5-HT(6), and 5-HT(7) receptors. Compound 54 (N-Ethyl-N-[4-(1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-2-yl)butyl]-8-quinolinesulfonamide) was identified as potent 5-HT(7) antagonist (K(i)=13 nM, K(B)=140 nM) with good selectivity over 5-HT(1A), 5-HT(2A), 5-HT(6) receptors. In the FST in mice, it reduced immobility in a manner similar to the selective 5-HT(7) antagonist SB-269970.

N,N-DIALKYLAMINOALKYL SUBSTITUTED QUINOBENZO[1,4]THIAZINES AND DIQUINO[1,4]THIAZINES#

Abstract 12-(N,N-Dialkylaminoalkyl)quino[1,4]benzothiazines 2c-2g were obtained by alkylation of 12H-quino[1,4]benzothiazines 2a and 2b with N,N-dialkylaminoalkyl chlorides in dioxane. 14H-Diquino [1,4]thiazine 4a was unreactive in the same conditions. 14-(N,N-Dialkylaminoalkyl)diquino[1,4]thiazines 4b-4d were synthesized in the annulation of 4,4′-dichloro-3,3′-diquinolinyl sulfide 3 with alkanediamines in hot phenol.

X-ray structure and NMR assignment of 3,3′-dimethylthio-4,4′-diquinolinyl sulfide

The title compound (C20H16N2S3) is triclinic, witha=9.494(3)b=9.890(3),c=19.456(5)Å,a=90.26(3)°,°=100.47(3)°, γ=99.18(3)°,Z=4 and space groupP¯1. The structure was solved by direct methods and refined toR=0.045 for 6076 reflections. There are two nonequivalent molecules in the unit cell. Two pairs of sulfur atoms in ortho-positions remain in very close contact. The S-methyl groups are nearly coplanar to the quinoline moieties and turned to the orthoposition, 2. CP MAS spectrum shows two conformers in the solid state but1H and13C NMR spectra in CDCl3 solution show rapid equilibrium of the conformers giving rise to average NMR data.

X-ray structure of 3,3′-bis(4-methylthioquinolinyl) sulfide

The structure of the title compound has been solved by direct methods, and refined to anR value of 0.035 for 1613 reflections. Both methyl carbon atoms deviate from the plane of the pyridine ring by 1.505(3) Å in opposite directions. Both sulfur atoms S(1) and S(2) remain in short contact, at 3.247(1) Å. The two pyridine rings are inclined at 61.4(2)° to each other.

X-ray structure of thioquinanthrenediinium dichloride

The title compound (C18H12N2S2)2+ 2Cl− is monoclinic:a=8.632(2),b=13.292(3),c=14.345(3) Å,Z=4,P212121. The structure was solved by direct methods, and refined by weighted full-matrix least squares. The refinement, based on 1918 reflections withI≥3.0σ(I), converged to a finalR of 0.036 (Rw=0.042). The conformation of 1,4-dithiino ring is a boat. The linear hydrogen bond distance N-H⋯Cl is 2.980(3) Å.

Quinoline-2-sulfonamide

In the title compound, C9H8N2O2S, the sulfamoyl –NH2 group is involved in intermolecular hydrogen bonding with the sulfonamide O and quinoline N atoms. In the crystal, molecules are linked into dimers via pairs of N—H⋯N hydrogen bonds, forming an R 2 2(10) motif. The dimers are further assembled into chains parallel to the b axis through N—H⋯O hydrogen bonds, generating a C(4) motif. The crystal packing is additionally stabilized by intermolecular C—H⋯O interactions. The crystal studied was a non-merohedral twin with a domain ratio of 0.938 (2):0.062 (2). Density functional theory (DFT) calculations, at the B3LYP/6–31 G(d,p) level of theory, were used to optimize the molecular structure and to determine interaction energies for the title compound. The resulting interaction energy is ∼4.4 kcal mol−1 per bridge for the C(4) chain and ∼5.9 kcal mol−1 per bridge for the R 2 2(10) motif.

Quinoline-8-sulfonamide

In the title compound, C9H8N2O2S, the sulfamoyl NH2 group is involved in intramolecular N—H⋯N and intermolecular N—H⋯O hydrogen bonding. In the crystal, molecules are linked via pairs of N—H⋯O hydrogen bonds, forming inversion dimers, which are further associated through π–π stacking interactions between the quinoline benzene rings [centroid–centroid distance = 3.649 (1) Å] into a one-dimensional polymeric structure extending along the a axis.

COMPLETE ASSIGNMENT OF THE 1H AND 13C NMR SPECTRA OF THIOQUINANTHRENE AND ISOTHIOQUINANTHRENE

The proton and carbon chemical shifts and the coupling constants nJ(H,H) and nJ(C,H) of thioquinanthrene and isothioquinanthrene were completely assigned from COSY, HETCOR and INEPT studies.