Synthesis, biological evaluation, and in silico studies of novel chalcone- and pyrazoline-based 1,3,5-triazines as potential anticancer agents.

A novel series of triazin-chalcones (7,8)a-g and triazin-N-(3,5-dichlorophenyl)pyrazolines (9,10)a-g were synthesized and evaluated for their anticancer activity against nine different cancer strains. Triazine ketones 5 and 6 were synthesized from the cyanuric chloride 1 by using stepwise nucleophilic substitution of the chlorine atom. These ketones were subsequently subjected to a Claisen-Schmidt condensation reaction with aromatic aldehydes affording chalcones (7,8)a-g. Then, N-(3,5-dichlorophenyl)pyrazolines (9,10)a-g were obtained by cyclocondensation reactions of the respective chalcones (7,8)a-g with 3,5-dichlorophenylhydrazine. Among all the evaluated compounds, chalcones 7d,g and 8g exhibited more potent in vitro anticancer activity, with outstanding GI50 values ranging from 0.422 to 14.9 µM and LC50 values ranging from 5.08 µM to >100 µM. In silico studies, for both ligand- and structure-based, were executed to explore the inhibitory nature of chalcones and triazine derivatives. The results suggested that the evaluated compounds could act as modulators of the human thymidylate synthase enzyme.

2-Ethyl-1-[5-(4-methylphenyl)pyrazol-3-yl]-3-(thiophene-2-carbonyl)isothiourea: molecular ribbons containing three types of hydrogen-bonded ring.

The title compound, C18H18N4OS2, was prepared by reaction of S,S-diethyl 2-thenoylimidodithiocarbonate with 5-amino-3-(4-methylphenyl)-1H-pyrazole using microwave irradiation under solvent-free conditions. In the molecule, the thiophene unit is disordered over two sets of atomic sites, with occupancies of 0.814 (4) and 0.186 (4), and the bonded distances provide evidence for polarization in the acylthiourea fragment and for aromatic type delocalization in the pyrazole ring. An intramolecular N-H···O hydrogen bond is present, forming an S(6) motif, and molecules are linked by N-H···O and N-H···N hydrogen bonds to form a ribbon in which centrosymmetric R2(2)(4) rings, built from N-H···O hydrogen bonds and flanked by inversion-related pairs of S(6) rings, alternate with centrosymmetric R2(2)(6) rings built from N-H···N hydrogen bonds.

2-Ethylsulfanyl-7-(furan-2-yl)-4-(thiophen-2-yl)pyrazolo[1,5-a][1,3,5]triazine: π-stacked chains of hydrogen-bonded R2(2)(10) dimers.

In the title compound, C(15)H(12)N(4)OS(2), the bond distances in the fused heterocyclic system show evidence for aromatic-type delocalization in the pyrazole ring with some bond fixation in the triazine ring. The thiophenyl substituent is slightly disordered over two sets of atomic sites having occupancies of 0.934 (4) and 0.066 (4). The non-H atoms in the entire molecule are nearly coplanar, with the planes of the furanyl substituent and the major orientation of the thiophenyl substituent making dihedral angles of 5.72 (17) and 1.8 (3)°, respectively, with that of the fused ring system. Molecules are linked into centrosymmetric R2(2)(10) dimers by C-H...O hydrogen bonds and these dimers are further linked into chains by a single π-π stacking interaction. Comparisons are made with some related 4,7-diaryl-2-(ethylsulfanyl)pyrazolo[1,5-a][1,3,5]triazines which contain variously substituted aryl groups in place of the furanyl and thiophenyl substituents in the title compound.

Anticonvulsant profile of 2-ethylthio-7-methyl-4-(4-methylphenyl)pyrazolo[1, 5-a][1, 3, 5]triazine

This work evaluates the central nervous effects in ICR strain mice of 2-ethylthio-7-methyl-4-(4-methylphenyl)pyrazolo[1,5-a][1,3,5]triazine (MH4b1), a compound obtained by an efficient one-step reaction of S,S-diethyl 4-methylbenzoylimidodithiocarbonate with 5-amino-3-methyl-1H-pyrazole, in order to assess its neuro-pharmacological profile. The tests applied were: maximal electroshock seizure (MES), pentylenetetrazole (PTZ) seizures, forced swimming, plus maze, marble burying, sleeping time, rota-rod and catalepsy. In addition, MH4b1 binding to the benzodiazepine site of the GABA-A receptor and MH4b1 inhibition of monoamine oxidase (MAO) subtypes A and B were evaluated. MH4b1 showed anticonvulsant effects in a dose dependent manner (30-300 mg/kg, p.o.) against MES and inhibition of MAO-B (IC50: 24.5 µM) without activity at the benzodiazepine site. These data suggest that MH4b1 has anticonvulsant properties related to MAO-B inhibition.

Este trabalho avalia o efeito do 2-etiltio-7-metil-4-(4-metilfenil)pirazol[1,5-a][1,3,5]triazina (MH4b1) no sistema nervoso central de camundongos ICR. O MH4b1 foi obtido por a reação de 4-metilbenzoilimidoditiocarbonato de S,S-dietil e 5-amino-3-metil-1H-pirazol em uma única etapa. O perfil neurofarmacológico foi realizado por testes de convulsão induzida por eletrochoque (MES) e pentilenotetrazol (PTZ) e por testes de nado forçado, labirinto em cruz, esconder as esferas, sono barbitúrico, rota-rod e catalepsia. Também foi avaliada a união do MH4b1 ao o local de ligação de benzodiazepínicos do receptor GABA-A e a capacidade inibitória do MH4b1 sobre a monoaminoxidase (MAO) A e B. O MH4b1 mostrou efeito anticonvulsivante dependente da dose (30-300 mg) no teste do MES e apresentou atividade inibitória da MAO-B (CI50: 24.5 µM) sem interagir com o local de ligação de benzodiazepínicos do receptor. Os resultados sugerem que o MH4b1 tem atividade anticonvulsivante relacionada com a inibição da MAO-B.

Assessment of the anticonvulsant activity of pyrazolo[1,5-a][1,3,5]triazines obtained by synthesis / Evaluación de la actividad anticonvulsiva de pirazolo [1,5-a] [1,3,5] triazinas obtenidos por síntesis

Giving that the pyrazolo[1,5-a][1,3,5]triazine system is a potential source of pharmacological agents for treatment of central nervous system disorders this work was aimed to asses anticonvulsant and acute neurotoxic effects of six molecules obtained by synthesis, using experimental models in mice. A series of six pyrazolo[1,5-a][1,3,5]triazines (EAC-21, EAC-31, EAC-33, MH4a, MH4b1 and MH4c) obtained by one-step reaction from S,S-diethyl aroyl-/hetaroylimidodithiocarbonates and 5-aminopyrazoles were screened in vivo (300 mg/kg, v.o.) for their anticonvulsant activity in the maximal electroshock (MES) test in ICR mice and for acute toxicity in the rota-rod and wiring test. The structures of the obtained compounds were unambiguously established by IR, 1H and 13C-NMR spectroscopic techniques, COSY 1H-1H, HSQC and HMBC experiments, mass spectrometry and elemental analyses. Results shown that only MH4b1 showed protection against MES (p<0.05) and was devoid of gross neurotoxicity signs. Therefore, MH4b1 was chosen for additional anticonvulsant screening against MES, pentilenetetrazole, picrotoxin, strychnine and 6 Hz psychomotor seizure model, in a dose dependent manner (50, 150, 300 mg/kg, v.o.). MH4b1 also protected against 6 Hz seizure test (>150 mg/kg, v.o.). These data suggest that MH4b1 could be a source for anticonvulsant pyrazolo[1,5-a][1,3,5]triazine analogs potentially useful against tonic clonic and refractory seizures.

Dado el interés que el sistema pirazolo[1,5-a][1,3,5]triazina tiene como fuente potencial para la obtención de agentes farmacológicos para el tratamiento de trastornos del sistema nervioso central, en este trabajo se efectuó el cribado anticonvulsivante y el efecto neurotóxico agudo de seis moléculas derivadas de este sistema, en ratones ICR. La serie de compuestos denominados EAC-21, EAC-31, EAC-33, MH4a, MH4b1 y MH4c, obtenidas por la reacción de S,S-dietil aroil-/heteroilimidoditiocarbonatos y 5-aminopirazoles se evaluó in vivo (300 mg/kg, v.o.) en la prueba de convulsiones inducidas por electrochoque y en las pruebas de actividad neurotóxica aguda del eje rodante y del alambre. La estructura de estos compuestos se determinó por técnicas de infrarrojo, espectroscopia de 1H, 13C-NMR, COSY 1H-1H, experimentos de HSQC y HMBC, espectrometría de masas y análisis elemental. Los resultados mostraron que el compuesto MH4b1 confirió protección frente a las convulsiones inducidas por electrochoque (p<0.05) sin producir signos de neurotoxicidad aguda. Por consiguiente, MH4b1 se escogió para las siguientes pruebas de actividad anticonvulsivante, dosis - respuesta (50, 150, 300 mg/kg, v.o.): electrochoque, pentilenetetrazol, picrotoxin, estricnina y el modelo de convulsión psicomotora de 6 Hz. MH4b1 mostró efectos protectores en función de la dosis frente a las pruebas de convulsión por electrochoque (>150 mg/kg) y convulsión de 6 Hz (300 mg/kg, v.o.). Estos resultados sugieren que MH4b1 podría constituirse en fuente anticonvulsivante del sistema pirazolo[1,5-a][1,3,5]triazina eventualmente útil para el tratamiento de las crisis tónicas clónicas generalizadas y las crisis refractarias.

Hydrogen-bonding patterns in two aroylthiocarbamates and two aroylimidothiocarbonates.

In O-ethyl N-benzoylthiocarbamate, C(10)H(11)NO(2)S, the molecules are linked into sheets by a combination of two-centre N-H...O and C-H...S hydrogen bonds and a three-centre C-H...(O,S) hydrogen bond. A combination of two-centre N-H...O and C-H...O hydrogen bonds links the molecules of O-ethyl N-(4-methylbenzoyl)thiocarbamate, C(11)H(13)NO(2)S, into chains of rings, which are linked into sheets by an aromatic pi-pi stacking interaction. In O,S-diethyl N-(4-methylbenzoyl)imidothiocarbonate, C(13)H(17)NO(2)S, pairs of molecules are linked into centrosymmetric dimers by pairs of symmetry-related C-H...pi(arene) hydrogen bonds, while the molecules of O,S-diethyl N-(4-chlorobenzoyl)imidothiocarbonate, C(12)H(14)ClNO(2)S, are linked by a single C-H...O hydrogen bond into simple chains, pairs of which are linked by an aromatic pi-pi stacking interaction to form a ladder-type structure.

Three 4,7-diaryl-2-ethylsulfanylpyrazolo[1,5-a][1,3,5]triazines.

The molecular dimensions of 2-ethylsulfanyl-7-(4-methylphenyl)-4-phenylpyrazolo[1,5-a][1,3,5]triazine, C20H18N4S, (I), 7-(4-chlorophenyl)-2-ethylsulfanyl-4-phenylpyrazolo[1,5-a][1,3,5]triazine, C19H15ClN4S, (II), and 4,7-bis(4-chlorophenyl)-2-(ethylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine, C19H14Cl2N4S, (III), show evidence for some aromatic delocalization in the pyrazole rings. The conformations adopted by the ethylsulfanyl substituents are different in all three compounds. There are no hydrogen bonds in any of the crystal structures, but pairs of molecules in (II) and (III) are linked into centrosymmetric dimers by pi-stacking interactions.

Isolated molecules in 2-ethylsulfanyl-7-methyl-4-(4-methylphenyl)pyrazolo[1,5-a][1,3,5]triazine and hydrogen-bonded sheets of R2/2(10), R2/2(16), R4/4(22) and R4/4(24) rings in 2-ethylsulfanyl-7-methyl-4-(4-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazine.

In each of 2-ethylsulfanyl-7-methyl-4-(4-methylphenyl)pyrazolo[1,5-a][1,3,5]triazine, C15H16N4S, (I), and 2-ethylsulfanyl-7-methyl-4-(4-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazine, C14H13N5O2S, (II), there is significant bond fixation in the heterocyclic component. While there are no direction-specific intermolecular interactions in the structure of (I), the molecules of (II) are linked by a combination of C-H...O and C-H...S hydrogen bonds into sheets containing four types of ring, all centrosymmetric.

S-Ethyl N-(4-chlorobenzoyl)dithiocarbamate: sheets built from pi-stacked hydrogen-bonded chains.

Molecules of the title compound, C10H10ClNOS2, are linked into C4 chains by an N-H...O hydrogen bond [H...O = 2.16 A, N...O = 3.013 (3) A and N-H...O = 176 degrees ], and the chains are linked into sheets by a centrosymmetric pi-pi stacking interaction.

S-ethyl N-benzoyldithiocarbamate: two independent hydrogen-bonded R(2)2(8) dimers of different symmetry linked into chains by a C-H...pi(arene) interaction.

The title compound, C10H11NOS2, crystallizes with Z' = 2 in space group C2/c. The molecules are linked by two N-H...S hydrogen bonds [H...S = 2.60 and 2.62 A, N...S = 3.350 (2) and 3.490 (2) A, and N-H...S = 143 and 172 degrees] into two distinct types of R(2)2(8) dimer, viz. one generated by inversion and the other by a twofold rotation axis. A single C-H...pi(arene) hydrogen bond links the two types of dimer into chains.

Supramolecular hydrogen-bonded hexamers in two 5-aryl-3-methyl-1-phenyl-1,6,7,8-tetrahydropyrazolo[3,4-b][1,4]diazepines.

In both title compounds, i.e. 3-methyl-1,5-diphenyl-1,6,7,8-tetrahydropyrazolo[3,4-b][1,4]diazepine, C(19)H(18)N(4), (I), and 5-(4-chlorophenyl)-3-methyl-1-phenyl-1,6,7,8-tetrahydropyrazolo[3,4-b][1,4]diazepine, C(19)H(17)ClN(4), (II), an N-H...N hydrogen bond links six molecules to form an R(6)(6)(30) ring. Compound (I) crystallizes in the R3 space group and (II) crystallizes in P1 with three molecules in the asymmetric unit. The molecule of (I) contains a disordered seven-membered ring.