Andrzej Fruziński

Novel 1,4‐Benzoxazin‐3(4H)‐one, 1,2‐Benzoxazolin‐3‐one and 1,3‐Benzoxazolin‐2,4‐dione Arylpiperazine Derivatives with Different 5‐HT1A and Antagonistic 5‐HT2A Activities

New 1‐arylpiperazine (series d—f) and 1,2,3,4‐tetrahydroisoquinoline (series g) derivatives of 1,4‐benzoxazin‐3(4H)‐one 1, 1,2‐benzoxazolin‐ 3‐one 2, and 1,3‐benzoxazolin‐2,4‐dione 3 with an n‐butyl chain were synthesized in order to explore the effect of spacer elongation on their binding affinity and in vivo functional activity at 5‐HT1A and 5‐HT2A receptors in comparison with trimethylene analogues (a, b c). 5‐HT1A receptor binding constants of derivatives 1d—g, 2d—f, and 3d—f were very high (Ki = 1.25—54 nM), and 5‐HT2A affinities were maintained at a similar, high level (Ki = 27—85 nM) for series d and e, and moderate (Ki = 246—495 nM) for series f. In respect of a spacer, the obtained results showed either no effect or a slight increase in the 5‐HT1A/5‐HT2A affinity in case of derivatives of 1 and 2, respectively. A striking effect was observed for derivatives 3d and 3f, whose 5‐HT1A affinity was reinforced by two orders of magnitude with a simultaneous decrease in 5‐HT2A binding constants in comparison with trimethylene analogues. As shown by X‐ray crystallography, this phenomenon may be attributed to the position of non‐carbonyl oxygen atom in the amide moiety. In vivo studies demonstrated that compounds 1e—g, 2d—f, and 3f behaved like typical postsynaptic 5‐HT1A receptor antagonists, whereas 3d and 3e might be qualified as their potential partial agonists. Moreover, 1e, 2e, and 3e demonstrated 5‐HT2A receptor antagonistic properties. Of the tested compounds, two derivatives showed some very outstanding properties: 3e may be regarded as a potential anxiolytic and/or antidepressant agent, while 3f as a new potent 5‐HT1A antagonist.

Structural studies, homology modeling and molecular docking of novel non-competitive antagonists of GluK1/GluK2 receptors.

Non-competitive ligands of kainate receptors have focused significant attention as medicinal compounds because they seem to be better tolerated than competitive antagonists and uncompetitive blocker of these receptors. Here we present structural studies (X-ray structure determination, NMR and MS spectra) of novel indole-derived non-competitive antagonists of GluK1/GluK2 receptors, homology models of GluK1 and GluK2 receptors based on novel AMPA receptor template as well as molecular docking of ligands to their molecular targets. We find that the allosteric site is in the receptor transduction domain, in one receptor subunit, not between the two subunits as it was indicated by our earlier studies.

Synthesis of novel isothiazolopyridines and their in vitro evaluation against Mycobacterium and Propionibacterium acnes

In this paper we describe synthesis, structures and some physicochemical properties of 20 isothiazolopyridines 8-13 substituted differently into an isothiazole ring as well as their in vitro antibacterial assays against Mycobacterium tuberculosis H37Rv, Mycobacterium fortuitum PCM 672 and Propionibacterium acnes PCM 2400. Compound 13a was found to be the most active derivative against M. tuberculosis H37Rv, demonstrating 100% growth inhibition of microorganisms in the primary screen (minimum inhibitory concentration [MIC] 6.25μg/mL). Nineteen of the prepared compounds were evaluated against M. fortuitum PCM 672 and P. acnes PCM 2400 and only compounds 9 and 12d exhibited excellent activity against individual strains of microorganisms with MIC90 <1μg/mL. The inhibitory action of the remaining isothiazolopyridines towards the tested strains of the microorganism was low, absent, or a non-linear correlation prohibited accurate determination of MIC values. Unexpectedly, seven of the remaining isothiazolopyridines tested against M. fortuitum and P. acnes stimulated growth of the microorganisms in the range 10-50% or even more (10b) under experimental conditions.

Similarities and differences in affinity and binding modes of tricyclic pyrimido- and pyrazinoxanthines at human and rat adenosine receptors.

A new series of 32 pyrimido- and 5 tetrahydropyrazino[2,1-f]purinediones was obtained and evaluated for their adenosine receptors (ARs) affinities. The 1,3-dibutyl derivative of 9-(4-(2-(dimethylamino)ethoxy)phenyl)-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione was found to be the most potent A1 AR antagonist of the present series, showing selectivity over the other AR subtypes. The structure-activity for the obtained purinediones was established. Docking experiments of the investigated library to homology models of the human and rat A1 and A2A ARs allowed to compare the expected binding modes for selected compounds. The detailed analysis of binding cavities within individual AR subtypes indicated small but significant structural variations that may underlie the observed differences in binding affinities of purinediones at particular subtypes and species.

Ethyl 2-(3-methyl-5-sulfanyl­idene-4,5-dihydro-1H-1,2,4-triazol-4-yl)acetate

The title compound, C7H11N3O2S, exists in the 5-thioxo tautomeric form. The 1,2,4-triazoline ring is essentially planar, with a maximum deviation of 0.010 (2) Å for the substituted N atom. The ethyl acetate substituent is almost planar, with a maximum deviation of 0.061 (4) Å for the methylene C atom of the ethoxy group. The angle between the mean plane of this substituent and the mean plane of the 1,2,4-triazoline ring is 89.74 (8)°. In the crystal, molecules are linked by a combination of N—H⋯S, C—H⋯N and C—H⋯O hydrogen bonds into chains parallel to [100].

N-{2-[(4S)-4-tert-Butyl-4,5-dihydro-1,3-oxazol-2-yl]phen-yl}-5,6-diphenyl-1,2,4-triazin-3-amine.

The title compound, C28H27N5O, was synthesized using palladium cross-coupling amination of 3-bromo-5,6-diphenyl-1,2,4-triazine with 2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]aniline. The oxazoline ring is almost planar, with a maximum atomic deviation of 0.023 (5) Å. The phenyl rings make dihedral angles of 29.0 (1) and 54.6 (1)° with the triazine ring while the benzene ring makes a dihedral angle of 0.6 (1)° with the oxazoline ring. The conformation of the molecule is influenced by strong intramolecular N—H⋯N and weak C—H⋯N hydrogen bonds. In the crystal, screw-axis related molecules are linked into supramolecular chains by intermolecular C—H⋯O hydrogen bonds. π–π stacking is observed between the oxazoline and triazine rings of adjacent molecules, with a centroid–centroid distance of 3.749 (2) Å.

1-(3-Chloro-phen-yl)-3-(1-p-tolyl-imidazolidin-2-yl-idene)urea.

In the crystal structure of the title compound, C17H17ClN4O, the existence of only one 2-imino–oxo of the five possible N-amino–imino/O-keto–hydroxy tautomers is observed and the dihedral angle between the aromatic rings is 29.78 (11)°. The molecular conformation is stabilized by intramolecular C—H⋯N, N—H⋯O and C—H⋯O hydrogen bonds, in each case generating a six-membered ring. In the crystal structure, the glide-plane-related molecules are linked into C(4) amide chains by intermolecular N—H⋯O hydrogen bonds, and an intermolecular C—H⋯O link also occurs.

Crystal and Molecular Structure of 4-[ω-(Benzotriazolyl)alkyl]-1-(2-methoxyphenyl)piperazines with a Different Pharmacological Activity

The crystal structure of six 4‐[ω‐(benzotriazolyl)alkyl]‐1‐(2‐methoxyphenyl)piperazine hydrochlorides 1–6 with a similar in vitro but different in vivo activity has been solved. A conformational analysis of free bases by Random Search and AM1 methods has been performed. Molecular electrostatic potential distribution (MEP) and dipole moments for the optimized crystallographic structures and global energy minimum conformations were calculated. Crystallographic data, as well as the conformational analysis indicated that the investigated compounds can adopt a variety of conformations of small energy difference. The effect of conformational changes on MEP was discussed.

Discovery of nitroaryl urea derivatives with antiproliferative properties

Abstract A series of urea derivatives bearing nitroaryl moiety has been synthesized and assayed for their potential antiproliferative activities. Some of the tested compounds displayed activity in RK33 laryngeal cancer cells and TE671 rhabdomyosarcoma cells while being generally less toxic to healthy HSF human fibroblasts cells. One compound was demonstrated to be a moderate CDK2 inhibitor with IC50 = 14.3 µM. Its structure was solved by an X-ray crystallography and molecular modelling was performed to determine structure-activity relationship. Obtained compounds constitute novel structures and generally demonstrated greater cytotoxicity in comparison to cisplatin. This study offers new structural motifs with potential for further development.

Spacer conformation in biologically active molecules. Part 2. Structure and conformation of 4-[2-(diphenylmethylamino) ethyl]-1-(2-methoxyphenyl) piperazine and its diphenylmethoxy analog-potential 5-HT1A receptor ligands

Abstract As a part of studies on biologically active molecule structures with aliphatic linking chain, the structures of 4-[2-diphenylmethylamino)ethyl]-1-(2-methoxyphenyl)piperazine dihydrochloride (1) and 4-[2-diphenylmethoxy)ethyl]-1-(2-methoxyphenyl)piperazine fumarate (2) have been reported. In both compounds, four atomic non-all-carbons linking chains (N)C–C–X–C are present. The conformation of that linking spacer depends on the nature of the X-atom. The preferred conformation for chain with XNH has been found to be fully extended while for that with XO—the bend one. It was confirmed by conformational calculations (strain energy distribution and random search) and crystallographic data, including statistics from CCDC.