Anna V. Dolzhenko

Pyrazolo[1,5-a][1,3,5]triazines(5-Aza-9-deazapurines): Synthesis and Biological Activity

The present review gives an account on the synthetic routes to pyrazolo(1,5-a)(1,3,5)triazine system, which is an isostere of purine, and polyfused systems bearing this heterocy clic core. Data concerning biological activity of compounds with pyrazolo(1,5-a)(1,3,5)triazine skeleton are also discussed.

1,2,4-Triazolo[1,5-a][1,3,5]triazines(5-Azapurines): Synthesis and Biological Activity

The present review gives an account of the various synthetic routes to the 5-aza-analogue of purine-1,2,4-triazolo[1,5-a][1,3,5]triazine nucleus and polyfused systems bearing this heterocyclic core. Data concerning biological activity of the compounds with l,2,4-triazolo[l,5-a][l,3,5]triazine skeleton are also discussed.

The significance of 2-furyl ring substitution with a 2-(para-substituted) aryl group in a new series of pyrazolo-triazolo-pyrimidines as potent and highly selective hA3 adenosine receptors antagonists: new insights into structure-affinity relationship and receptor-antagonist recognition

Among the heterocyclic structures identified as potent human A(3) (hA(3)) adenosine receptors antagonists, we have demonstrated that the new pyrazolo-triazolo-pyrimidines, bearing an aryl group in replacement of the C(2)-furyl ring, not only confer a good pharmacological profile (with significantly enhanced selectivity against other adenosine receptor subytpes) but also overcome the metabolic transformation of the furan ring into toxic intermediates. All the synthesized [2-(para-substituted) phenyl]-pyrazolo-triazolo-pyrimidines showed affinity at the hA(3) receptor in the low nanomolar range. The most potent derivative of the series presented better affinity and excellent selectivity (compound 31, K(i) hA(3) = 0.108 nM; hA(1)/hA(3) = 5200; hA(2A)/hA(3) = 7200), in comparison to the C(2)-furyl counterpart. A receptor-driven molecular modeling investigation, based on a recently proposed model of A(3) receptor derived from the crystallographic structure of human A(2A) receptor, has been carried out in order to support the experimental binding data and to justify the enhanced selectivity against the other receptor subtypes.

Synthesis of 5,7-Diamino[1,2,4]triazolo[1,2-a][1,3,5]triazines via Annulation of 1,3,5-Triazine Ring onto 3(5)-Amino-1,2,4-trizoles

The 5,7-diamino[1,2,4]triazolo[1,5-a][1,3,5]triazines were synthesized by cyclocondensation of 3(5)-amino-1,2,4-triazoles with cyanoguanidine. The substituted 3(5)-amino-1,2,4-triazoles were prepared from corresponding hydrazides and S-methylisothiourea via ring closure of the intermediate acylaminoguanidines. The 3,5-diamino-1,2,4-triazoles were prepared using partial aminolysis of dimethyl N-cyanodithiocarbonimidate followed by cyclization of the obtained N-substituted N’-cyano-S-methylisothioureas with hydrazine. The structures of the prepared compound were confirmed using NMR spectral data.

Synthesis and Heterocyclizations of 3,4-Dihydroquinazolin-2-yl Guanidine in the Search of New Anticancer Agents

The cyclocondensations of 3,4-dihydroquinazolin-2-yl guanidine with a variety of electrophilic reagents viz. aldehydes, ketones, triethyl orthoformate, diethyl ethoxymethylenemalonate, carbon disulfide and trichloroacetonitrile were found to afford 1,3,5-triazino[2,1-b]quinazolines. However, some unexpected reactions were also observed. The structural properties such as tautomerism and hinderance to conformational rotation were also investigated. The results of biological testing suggested that the 1,3,5-triazino[2,1-b]quinazoline nucleus could be a new promising scaffold for the development of potential anticancer agents.

Does the combination of optimal substitutions at the C2-, N5- and N8-positions of the pyrazolo-triazolo-pyrimidine scaffold guarantee selective modulation of the human A3 adenosine receptors?

In an attempt to study the optimal combination of a phenyl ring at the C(2)-position and different substituents at the N(5)- and N(8)-positions towards the selective modulation of human A(3) adenosine receptors (hA(3)AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidines bearing either a methyl or phenylethyl at N(8) and chains of variable length at N(5). Through biological evaluation, it was found that the majority of the compounds had good affinities towards the hA(3)AR in the low nanomolar range. Compound 16 possessed the best hA(3)AR affinity and selectivity profile (K(i)hA(3)=1.33 nM; hA(1)/hA(3)=4880; hA(2A)/hA(3)=1100) in the present series of 2-(substituted)phenyl-pyrazolo-triazolo-pyrimidine derivatives. In addition to pharmacological characterization, a molecular modeling investigation on these compounds further elucidated the effect of different substituents at the pyrazolo-triazolo-pyrimidine scaffold on affinity and selectivity to hA(3)AR.

8-Methyl-2-[4-(trifluoro­meth­yl)phen­yl]-8H-pyrazolo­[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine methanol disolvate

In the title compound, C14H10F3N7·2CH4O, the heterocyclic ring system is essentially planar (r.m.s. deviation = 0.009 Å) and makes a dihedral angle of 6.91 (8)° with the attached benzene ring. In the crystal, the main molecules form centrosymmetric R 2 2(8) dimers via pairs of N—H⋯N hydrogen bonds between the amino groups and pyrimidine N atoms. One of the independent methanol molecules and its inversion equivalent are linked to the dimers via O—H⋯N and N—H⋯O hydrogen bonds, forming R 4 4(16) graph-set motifs. The dimers along with the hydrogen-bonded methanol molecules are stacked along the a axis, with π–π interactions between the pyrazole and triazole rings [centroid–centroid distance = 3.4953 (10) Å].

3-Pyridin-2-yl-1H-1,2,4-triazol-5-amine.

In the title compound, C7H7N5, the non-H atoms are almost coplanar (r.m.s. deviation = 0.050 Å), with the N atom of pyridine ring oriented to the N—N(H) side of the 1,2,4-triazole ring. The mean planes of the pyridine and 1,2,4-triazole rings form a dihedral angle of 5.58 (7)°. The N atom of the amino group adopts a pyramidal configuration. The molecules are linked into a two-dimensional network parallel to (10) by N—H⋯N hydrogen bonds.

N-Carbethoxy-N-(3-(4-methylphenyl)-1H-1,2,4-triazol-5- yl)thiourea

The title compound, [systematic name: ethyl ({[3-(4-methylphenyl)-1H-1,2,4-triazol-5-yl]amino}carbonothioyl)carbamate], C13H16N5O2S, exists in the 3-aryl-5-thioureido-1H-1,2,4-triazole tautomeric form. The molecular structure is stabilized by intramolecular hydrogen bonding (N—H⋯S=C between the endocyclic N-bound H atom and the thioureido S atom, and N—H⋯O=C within the ethoxycarbonylthiourea unit), both arranged in an S(6) graph-set motif. The mean planes of the phenyl and 1,2,4-triazole rings make a dihedral angle of 6.59 (10)°. In the crystal structure, the molecules form two types of centrosymmetric dimers connected by intermolecular hydrogen bonds; in the first, the N—NH triazole sides of two molecules are connected [R 2 2(6) graph-set motif] and the second is an N—H⋯S=C interaction between the imide H atoms and the thiocarbonyl S atoms [R 2 2(8) graph-set motif]. Together, they form a network parallel to the (111) plane.

N-Carbethoxy-N'-(3-phenyl-1H-1,2,4-triazol-5-yl)thiourea.

The title compound {systematic name: ethyl N-[N-(3-phenyl-1H-1,2,4-triazol-5-yl)carbamothioyl]carbamate}, C12H13N5O2S, exists in the 3-phenyl-5-thioureido-1H-1,2,4-triazole tautomeric form stabilized by intramolecular hydrogen bonding between the endocyclic NH H atom and the thioureido S atom. The molecular structure is also stabilized by intramolecular N—H⋯O=C hydrogen bonds arranged in an S(6) graph-set motif within the carbethoxythiourea moiety. The mean planes of the phenyl and 1,2,4-triazole rings make a dihedral angle of 7.61 (11)°. In the crystal, the molecules form two types of inversion dimers. Intermolecular hydrogen bonds are arranged in R 2 2(6) and R 2 2(8) graph-set motifs, together forming a network parallel to (111).