Synthesis and biological activity of novel tert-amylphenoxyalkyl (homo)piperidine derivatives as histamine HR ligands.

As a continuation of our search for novel histamine H receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2-21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H receptor (hHR). The highest affinities were observed for pentyl derivatives 6-8 (K=8.

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.

Chlorophenoxy aminoalkyl derivatives as histamine H(3)R ligands and antiseizure agents.

A series of twenty new chlorophenoxyalkylamine derivatives (9-28) was synthesized and evaluated on their binding properties at the human histamine H3 receptor (hH3R). The spacer alkyl chain contained five to seven carbon atoms. The highest affinities have shown the 4-chloro substituted derivatives 10 and 25 (Ki=133 and 128 nM, respectively) classified as antagonists in cAMP accumulation assay (EC50=72 and 75 nM, respectively).

(2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.

Within the constantly growing number of histamine H4 (H4R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties.

Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.

A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM.

Efficient synthesis of 2'-deoxyzebularine and its α-anomer by the silyl method of N-glycosylation. Crystal structures and conformational study in solution.

2'-Deoxyzebularine and its α-anomer have been efficiently synthesized with relatively high stereoselectivity by a modified procedure of the silyl method of the N-glycosidic bond formation. An SnCl4-catalyzed condensation of silylated pyrimidin-2-one with 1-α-chloro-3,5-di-O-p-toluoyl-2-deoxy-d-ribofuranose under kinetic control condition (-33°C, 1,2-dichloroethane) led to the mixture of β- and α-anomeric nucleosides in 3:1 ratio. Analogous condensation at +35°C (thermodynamic control conditions) provided mainly p-toluoyl protected α-2'-deoxyzebularine (α:β=4:1), easily separated by crystallization from the anomeric mixture.

Synthesis, biological activity and molecular modelling studies of tricyclic alkylimidazo-, pyrimido- and diazepinopurinediones.

Syntheses and biological activities of imidazo-, pyrimido- and diazepino[2,1-f]purinediones containing N-alkyl substituents (with straight, branched or unsaturated chains) are described. Tricyclic derivatives were synthesized by the cyclization of 8-bromo-substituted 7-(2-bromoethyl)-, 7-(3-chloropropyl)- or 7-(4-bromobutyl)-theophylline with primary amines under various conditions. Compound 22 with an ethenyl substituent was synthesized by dehydrohalogenation of 9-(2-bromoethyl)-1,3-dimethyltetrahydropyrimido[2,1-f]purinedione.

Synthesis and anticonvulsant properties of new N-Mannich bases derived from 3,3-diphenyl- and 3-ethyl-3-methyl-pyrrolidine-2,5-diones. Part III.

Twenty-four new N-[(4-phenylpiperazin-1-yl)-methyl] derivatives of 3,3-diphenyl- (7-18) and 3-ethyl-3-methyl-pyrrolidine-2,5-dione (19-30) were synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurological toxicity was determined using the rotorod screen. Eleven compounds were active and revealed protection only in electrically induced seizures (MES).

Synthesis and SAR-study for novel arylpiperazine derivatives of 5-arylidenehydantoin with α₁-adrenoceptor antagonistic properties.

The study is focused on a series of 5-arylidenehydantoin derivatives with a phenylpiperazine-hydroxypropyl fragment at N3 of the hydantoin ring. The compounds were assessed on their affinity for α(1)-adrenoceptors and evaluated in functional bioassays for their antagonistic properties. Crystal structures of (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)imidazolidine-2,4-dione (7) and hydrochloride of (Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione (10a) were solved using the X-ray diffraction method.

Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones.

Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by cyclization of 7-halogenoalkyl-8-bromo-1,3-dimethylxanthine derivatives with aminocycloalkanes. The obtained compounds (1-33) were evaluated for their affinity to rat adenosine A(1) and A(2A) receptors.

Desulfurization of 2-thiouracil nucleosides: conformational studies of 4-pyrimidinone nucleosides.

4-Pyrimidinone ribofuranoside (H(2)o(4)U) and 4-pyrimidinone 2'-deoxyribofuranoside (dH(2)o(4)U) were synthesized by the oxidative desulfurization of parent 2-thiouracil nucleosides with m-chloroperbenzoic acid. The crystal structures of H(2)o(4)U and dH(2)o(4)U and their conformations in solution were determined and compared with corresponding 2-thiouracil and uracil nucleosides. The absence of a large 2-thiocarbonyl/2-carbonyl group in the nucleobase moiety results in C2'-endo puckering of the ribofuranose ring (S conformer) in the crystal structure of H(2)o(4)U, which is not typical of RNA nucleosides.

Design, synthesis, and anticonvulsant activity of new N-Mannich bases derived from spirosuccinimides and spirohydantoins.

The synthesis and anticonvulsant properties of new N-Mannich bases of [7,8-f]benzo-2-aza-spiro[4.5]decane-1,3-diones (5a-h) and [7,8-f]benzo-1,3-diaza-spiro[4.5]decane-2,4-diones (7a-h) were described.

Four- and five-coordinate copper(II) complexes with N-(4,4-diphenyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl)glycine.

The two title mononuclear compounds are four-coordinate bis[N-(5-oxo-4,4-diphenyl-4,5-dihydro-1H-imidazolidin-2-ylidene)glycinato]copper(II) dimethylformamide disolvate, [Cu(C(17)H(14)N(3)O(3))(2)].2C(3)H(7)NO, (I), and five-coordinate aquabis[N-(5-oxo-4,4-diphenyl-4,5-dihydro-1H-imidazolidin-2-ylidene)glycinato]copper(II) dimethylformamide disolvate, [Cu(C(17)H(14)N(3)O(3))(2)(H(2)O)].2C(3)H(7)NO, (II).

tert-Butyl N-[(S)-3-isopropyl-2-oxo-oxetan-3-yl]carbamate.

The structure of the title compound, C(11)H(19)NO(4), contains two crystallographically independent mol-ecules in the asymmetric unit. Both adopt the same conformation and they form pseudosymmetric R(2) (2)(8) dimers via two N-H⋯O hydrogen bonds. The dimers are linked by weak C-H⋯O inter-actions and are stacked in columns along the a axis.

Phenylethyl-substituted pyrimido[2,1-f]purinediones and related compounds: structure-activity relationships as adenosine A(1) and A(2A) receptor ligands.

The synthesis of N-(un)substituted-phenylalkylpyrimido[2,1-f]purinediones was performed starting with 7-(3-chloropropyl)-8-bromotheophylline and 7-(3-chloropropyl)-8-bromo-1,3-dipropylxanthine. Compounds with unsubstituted or substituted ethylene spacer to an aromatic ring were synthesized. Additionally variations in the spacer-elongation of the linker containing more than two atoms, introduction of a double bond or heteroatoms were performed.

N9-benzyl-substituted 1,3-dimethyl- and 1,3-dipropyl-pyrimido[2,1-f]purinediones: synthesis and structure-activity relationships at adenosine A1 and A2A receptors.

Synthesis and physicochemical properties of N-benzyl pyrimido[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-chloropropylo-8-bromo-1,3-dimethyl- or 1,3-dipropyl xanthine derivatives with corresponding (un)substituted benzylamines. Dipropyl derivatives were obtained under microwave irradiation conditions either.

tert-Butyl N-[(S)-3-isobutyl-2-oxooxetan-3-yl]carbamate.

The structure of the title compound, C(12)H(21)NO(4), contains two crystallographically independent mol-ecules in the asymmetric unit. Mol-ecules are linked into pseudosymmetric R(2) (2)(8) dimers through two N-H⋯O hydrogen bonds. The dimers are connected by weak C-H⋯O inter-actions, resulting in a three-dimensional network.

Synthesis and biological activity of tricyclic aryloimidazo-, pyrimido-, and diazepinopurinediones.

Syntheses and physicochemical properties of N-aryl-substituted imidazo-, pyrimido-, and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-haloalkyl-8-bromo-1,3-dimethyl- or 1,3-dipropyl-xanthine derivatives with corresponding arylamines. The obtained compounds (1-40), which can be envisaged as sterically fixed and configurationally stable analogs of 8-styrylxanthines, were evaluated for their affinity to adenosine A(1) and A(2A) receptors, the receptor subtypes that are predominant in the brain.

Synthesis, physicochemical and anticonvulsant properties of N-benzyl and N-aminophenyl derivatives of 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione. Part I.

To continue our systematic SAR studies, two series of N-benzyl- (X=CH2) and N-aminophenyl- (X=NH) derivatives of 2-azaspiro[4.4]nonane (1a-1j) and 2-azaspiro[4.5]decane-1,3-dione (2a-2j) were synthesized, and evaluated in maximum electroshock seizure (MES), subcutaneous pentylenetetrazole (sc.

Tricyclic oxazolo[2,3-f]purinediones: potency as adenosine receptor ligands and anticonvulsants.

Synthesis and physicochemical properties of 7-mono- and 6,7-disubstituted dihydrooxazolo-[3,2-f]purinediones are described. Oxazolo[2,3-f]purinediones were synthesized by cyclization of 8-bromotheophylline with oxiranes. The obtained compounds (1-22) were evaluated for their affinity at adenosine A(1) and A(2A) receptors.

Imidazo[2,1-b]thiazepines: synthesis, structure and evaluation of benzodiazepine receptor binding.

As a continuation of our search for new ligands acting on benzodiazepine receptors among the fused 2-thiohydantoin derivatives, a series of 5-substituted imidazo[2,1-b]thiazepines was synthesized and investigated in radioligand binding studies at the benzodiazepine binding site of GABA(A) receptors in rat brain cortical membranes. Among ortho-substituted 5-arylidene-imidazo[2,1-b]thiazepines compounds could be identified which exhibit affinity for the benzodiazepine binding site at low micromolar concentrations. X-ray structure analyses for two compounds (6ae and 6ag) have been performed.

Impact of the aryl substituent kind and distance from pyrimido[2,1-f]purindiones on the adenosine receptor selectivity and antagonistic properties.

Adenosine receptor (AR) antagonists belong to two major groups of compounds: xanthines and non-xanthines. Recently several annelated xanthine derivatives have been described as selective A(1), A(2A), A(2B) and A(3) ARs antagonists. Contrary to dipropyl derivatives, in the group of dimethyl (un)substituted arylalkyl pyrimido[2,1-f]purindiones selective mainly adenosine A(2A) receptor antagonists were identified.

Synthesis and effects on chloroquine susceptibility in Plasmodium falciparum of a series of new dihydroanthracene derivatives.

To suggest a mechanism of action for drugs capable to reverse the chloroquine resistance, a new set of 9,10-dihydro-9,10-ethano and ethenoanthracene derivatives was synthesized and compounds were tested with the aim to assess their effect on chloroquine susceptibility in Plasmodium falciparum resistant strains. With respect to this, reversal of resistance and change in drug accumulation were compared. Structure-activity relationship and molecular modeling studies made it possible to define a pharmacophoric moiety for reversal agents and to propose a putative model of interaction with some selected amino acids.