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This paper describes the photophysical properties of a series of seven selected examples of 5-(alkyl/aryl/heteroaryl)-2-methyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidines (3), which contain alkyl, aryl, and heteroaryl substituents attached to the scaffolds of 3. Given the electron-donor groups and -withdrawing groups, the optical absorption and emission in the solid state and solution showed interesting results. Absorption UV–Vis and fluorescence properties in several solvents of a pyrazolo[1,5-a]pyrimidines series were investigated, and all derivatives were absorbed in the ultraviolet region despite presenting higher quantum emission fluorescence yields in solution and moderate emission in the solid state. Moreover, the solid-state thermal stability of compounds 3a–g was assessed using thermogravimetric analysis. The thermal decomposition profile showed a single step with almost 100% mass loss for all compounds 3. Additionally, the values of T0.05 are considerably low (72–187 °C), especially for compound 3a (72 °C), indicating low thermal stability for this series of pyrazolo[1,5-a]pyrimidines.

Graphical abstract, Highlights • Ultrasound is a powerful tool in the synthesis of pyrimidines. • Selectivity in the synthesis of pyrimidines under ultrasound is demonstrated. • Synergic effects of US combined with other methods are presented., The pyrimidine scaffold is present in many bioactive drugs; therefore, efficient synthetic routes that provide shorter reaction times, higher yields, and site-selective reactions are constantly being sought. Ultrasound (US) irradiation has emerged as an alternative energy source in the synthesis of these heterocyclic scaffolds, and over the last ten years there has been a significant increase in the number of publications mentioning US in either the construction or derivatization of the pyrimidine core. This review presents a detailed summary (with 140 references) of the effects of US (synergic or not) on the construction and derivatization of the pyrimidine core through classical reactions (e.g., multicomponent, cyclocondensation, cycloaddition, and alkylation reactions). The main points that were taken into consideration are as follows: chemo- and regioselectivity issues, and the results of conventional heating methods compared to US and mechanistic insights that are also presented and discussed for key reactions.

A systematic investigation to assess the degree of similarity between polymorphs was carried out. A similarity indices (IX) approach was applied in ten series of polymorphs with different characteristics and number of molecules in the asymmetric unit. Geometric (ID), contact area (IC), and stabilization energy (IG) parameters were used. It was possible to situate each comparison in different regions of similarity within the polymorphism phenomenon and determine the boundaries between quasi-isostructural polymorphs and polymorphs of low similarity. The multiparameter IDCG index was used as a robust tool to determine the total similarity within the polymorphism phenomenon. The highest contribution of the stabilization energy parameter (45%) toward the final value of similarity (IDCG) was observed, followed by the contact area index (32%). The geometric index contributed approximately 23% to the final value of IDCG. This information reinforces the importance of the contact area and stabilization energy in assessing the degree of similarity between crystalline structures. A new descriptor (IQ) based on the comparison of the energetic contribution of intermolecular interaction types present in each crystal structure is presented. IQ can be a versatile tool and applicable even for systems that do not share any similarity.

A series of seven N-phenylamides [R–C(O)NHPh, in which R: CH3, C(CH3)3, Ph, CF3, CCl3, CBr3, and H] were used as models in this study. Molecular packing and intermolecular interactions were evaluated by theoretical calculations, solution NMR, and quantum theory of atoms in molecules analyses. Crystallization mechanisms were proposed based on the energetic and topological parameters using the supramolecular cluster as demarcation. Concentration-dependent 1H NMR experiments corroborated the proposed interactions between molecules. For all compounds (except for R: H, which initially formed tetramers), layers (two-dimensional) or chains (one-dimensional) were formed in the first stage of the proposed crystallization mechanisms. The presence of strong intermolecular NH···O═C interactions promoted the first stages. The study in solution provided different values of association constant (Kass) governed by the hydrogen bond NH···O═C, showing that the stronger interactions are directly influenced by the substituen...

The quest for concepts of isostructurality in organic crystals has been long and mostly based on geometric data, even with the development of modern software. This field of study is of great interest to the pharmaceutical industry and for the prediction of crystal structures. Despite this, there is still no methodology that provides broad quantitative and comparable similarity data between two complete crystalline structures. The present study demonstrated that the similarity between two crystalline structures could be estimated from the similarity between the two "supramolecular clusters". Quantitative indexes for similarity comparisons of crystal structures were shown using nine 5-aryl-1-(1,1-dimethylethyl)-1H-pyrazoles as a model. This proposal includes the quantitative data of a geometric parameter (ID), a contact area parameter (IC), and an energetic parameter (IG). The proposed indexes exhibited good perspective regarding the similarity data and distinct regions of similarity. The range of similarity was set at IX ≥ 0.80, 0.80 > IX > 0.60, and IX ≤ 0.60 (X = D, C, or G). Indexes with a value near 1.0 indicate systems with isostructural, isocontact, and isoenergetic behavior. The results indicated that supramolecular structures with high similarity must have high values for all three indexes (ID, IC, and IG).

An efficient synthesis methodology for a series of tetrazolo[1,5-a]pyrimidines substituted at the 5- and 7-positions from the cyclocondensation reaction [CCC + NCN] was developed. The NCN corresponds to 5-aminotetrazole and CCC to β-enaminone. Two distinct products were observed in accordance with the β-enaminone substituent. When observed in solution, the compounds can be divided into two groups: (a) precursor compounds with R = CF3 or CCl3, which leads to tetrazolo[1,5-a]pyrimidines in high regioselectivity with R at the 7-position of the heterocyclic ring; and (b) precursor compounds with R = aryl or methyl, which leads to a mixture of compounds, tetrazolo[1,5-a] pyrimidines (R in the 5-position of the ring) and 2-azidopyrimidines (R in the 4-position of the ring), which was attributed to an equilibrium of azide–tetrazole. In the solid state, all compounds were found as 2-azidopyrimidines. The regiochemistry of the reaction and the stability of the products are discussed on the basis of the data obtained by density functional theory (DFT) for energetic and molecular orbital (MO) calculations.

The present study investigates the antinociceptive effect of the pyrazolyl-thiazole derivative 2-(5-trichloromethyl-5-hydroxy-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-(4-bromophenyl)-5-methylthiazole (B50) in mice. Male albino Swiss mice (30-40 g) were used in the acetic acid-induced abdominal writhes and tail-immersion tests. B50 caused dose-dependent antinociception (8, 23 and 80 micromol/kg, s.c.) in the acetic acid writhing assay (number of writhes: vehicle: 27.69 +/- 6.15; B50 (8 micromol/kg): 16.92 +/- 3.84; B50 (23 micromol/kg): 13.85 +/- 3.84; B50 (80 micromol/kg): 9.54 +/- 3.08; data are reported as means +/- SEM for 9 animals per group). On the other hand, B50 did not cause antinociception in the tail immersion assay. Naloxone (2.75 micromol/kg, s.c.) prevented B50-induced antinociception (number of writhes: vehicle-saline: 31.11 +/- 3.15; vehicle-naloxone: 27.41 +/- 3.70; B50 (80 micromol/kg)-saline: 8.70 +/- 3.33; B50 (80 micromol/kg)-naloxone: 31.84 +/- 4.26; morphine-saline: 2.04 +/- 3.52; morphine-naloxone: 21.11 +/- 4.26; 8-9 animals per group). The removal of the methyl group of the thiazole ring of B50 or substitution of the bromo substituent with the methyl at position 4 of the phenyl group, which is attached to the thiazole ring of B50, resulted in loss of activity, suggesting that these substituents are important for antinociceptive activity. B50 had no effect on spontaneous locomotion or rotarod performance, indicating that the antinociceptive effect of B50 is not related to nonspecific motor effects. The antinociceptive profile of B50 seems to be closer to nonsteroidal anti-inflammatory drugs than to classic opioid agents, since it had no analgesic effect in a thermally motivated test.

The pharmacological effects of 4-phenyl-2-trichloromethyl-3H-1, 5-benzodiazepine hydrogen sulfate (PTMB), a novel synthetic benzodiazepine, were examined in mice. In the elevated plus-maze test of anxiety, 0.3-1 mg/kg diazepam ip (F(3,53) = 3.78; P

This paper presents a study of solvent-free reaction conditions using microwave irradiation (MW) to obtain 4,5-dihydro-1H-pyrazoles and dehydrated pyrazoles by the cyclocondensation reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF3C(O)CH=C(R¹)OR, where R/R¹ = Et/H, Me/Me and Me/Ph] with hydrazines [NH2NH-R², where R² = CO2Me, Ph, CH2CH2OH]. Some reactions were performed under the same reaction conditions using methanol as solvent. The results obtained using MW equipment for synthesis under solvent-free conditions were also compared with those described in literature for conventional thermal heating and heating with a domestic MW oven. In general, the products furnished by reaction in MW equipment for synthesis presented better yields and shorter reaction times. In addition, it was demonstrated that the reaction temperature altered the formation of products for each hydrazine showing that MW equipment for synthesis is efficient for reacting hydrazines and 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones to procedure the products 4,5-dihydro-1H-pyrazoles and dehydrated pyrazoles. Este trabalho descreve a síntese de 4,5-diidro-1H-pirazóis pela reação de ciclocondensação de hidrazinas [NH2NH-R², onde R² = CO2Me, Ph, CH2CH2OH] com 4-alcóxi-1,1,1-trifluor-3-alquen-2-onas [CF3C(O)CH=C(R¹)OR, onde R/R¹ = Et/H, Me/Me and Me/Ph] sob irradiação de micro-ondas utilizando um equipamento de micro-ondas para síntese e em condição livre de solvente. Algumas reações foram realizadas na presença de metanol. Os resultados obtidos utilizando micro-ondas para síntese foram comparados com aqueles obtidos quando a reação foi feita pelo método convencional e no forno de micro-ondas doméstico. Os produtos foram obtidos com bons rendimentos em um intervalo de tempo pequeno. Além disso, foi demonstrado que a temperatura da reação alterou a formação dos produtos para cada hidrazina mostrando que o equipamento de micro-ondas para síntese é eficiente para as reações de hidrazinas com 4-alcóxi-1,1,1-trifluor-3-alquen-2-onas levando à formação dos produtos 4,5-diidro-1H-pirazóis e pirazóis.

Novel 1,4'-bipyrazoles were synthesized via highly regioselective cyclocondensation reactions of β-dimethylaminoenones with hydrazine monohydrate, tert-butylhydrazine hydrochloride, phenylhydrazine hydrochloride or carboxymethylhydrazine. X-ray diffraction technique was used in the elucidation of the regiochemistry of the β-dimethylaminoenaminones and of the 1,4'-bipyrazoles. 1,4'-Bipyrazolylisoxazoles were also reported. Este trabalho descreve a síntese de 1,4'-bipirazóis inéditos pela da reação de ciclocondensação de novas β-dimetilaminoenonas com as monoidrato de hidrazina, tert-butil hidrazina, fenil hidrazina, carboximetilhidrazina. Os produtos foram obtidos com alta regiosseletividade em rendimentos de bons a moderados (50-80%). A técnica de cristalografia de raios-X foi utilizada para a elucidação da regiosseletividade da formação dos produtos. 1,4'-Bipirazolilisoxazóis também foram descritos.

The reaction of 3-amino-5-methyl-1H-pyrazole with 1,1,1-trichloro-4-alkoxy-3-alken-2-ones [CCl3C(O)CH=C(R¹)OR, where R¹/R = H/Me, Me/Et, Et/Me, Pr/Et, Bu/Me, iso-Bu/Me] or β-dimethylaminovinyl ketones [R²C(O)CH=CHNMe2, where R² = Ph, Ph-4-Me, Ph-4-F, Ph-4-Cl, Ph-4-Br, Ph-4-NO2, fur-2-yl, thien-2-yl, pyrrol-2-yl, pyrid-2-yl], in acetic acid under reflux for 16 hours, furnished highly regioselective the halomethylated pyrazolo[1,5-a]pyrimidines and aryl[heteroaryl]pyrazolo[1,5-a]pyrimidines, respectively. A protocol for the bromination reaction at the 3-position pyrazolo[1,5-a]pyrimidines also was investigated. Este trabalho descreve a reação de ciclocondensação de 3-amino-5-metil-1H-pirazol com 1,1,1-tricloro-4-alcóxi-3-alquen-2-onas [CCl3C(O)CH=C(R¹)OR, onde R¹/R = H/Me, Me/Et, Et/Me, Pr/Et, Bu/Me, iso-Bu/Me] e β-dimetilaminovinil cetonas [R²C(O)CH=CHNMe2, onde R² = Ph, Ph-4-Me, Ph-4-F, Ph-4-Cl, Ph-4-Br, Ph-4-NO2, fur-2-il, tien-2-il, pirrol-2-il, pyrid-2-il], em refluxo de ácido acético para a obtenção de uma série de catorze pirazolo[1,5-a]pirimidinas. Os produtos foram obtidos em bons rendimentos (65-98%). Este trabalho apresenta ainda uma metodologia simples e seletiva para a obtenção de 3-bromo-pirazolo[1,5-a]pirimidinas, com rendimentos de 70-98%.

This paper describes the synthesis of a new series of 2-[3-alkyl(aryl/heteroaryl)- 5-trifluoro(chloro)methyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl]-5-[3-alkyl(aryl/heteroaryl)-5-trifluoro(chloro)methyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl-1-carbonyl]pyridines by the cyclocondensation reaction of 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoro(chloro)-3-alken- 2-ones [CX3C(O)CH=CR¹OR, where R = Me, Et; R¹ = H, Me, Ph, 4-MeOPh, 4-NO2Ph, 4,4'-Biphenyl, 1-Naphthyl, Fur-2-yl, Thien-2-yl and X = F, Cl] with 6-hydrazinonicotinic hydrazide hydrate. Yields of 62 to 97% were obtained when the reactions were performed in ethanol as solvent at 78 ºC for 4 hours. In a subsequent step, the dehydration reactions of 2-(5-hydroxy-1H-pyrazol-1-yl)-5-(5-hydroxy-1H-pyrazol-1-yl-1-carbonyl)pyridines were carried out in pyridine/benzene in the presence of thionyl chloride and led to the isolation of a series of 2- [3-alkyl(aryl/heteroaryl)-5-trifluoro(chloro)methyl-1H-pyrazol-1-yl]-5-[3-alkyl(aryl/heteroaryl)-5-trifluoro(chloro)methyl-1H-pyrazol-1-yl-1-carbonyl]pyridines, in 64 to 86% yields. Este trabalho apresenta a síntese de uma nova série de 2-[3-alquil (aril/heteroaril)-5-trialometil-5-hidróxi-4,5-diidro-1H-pirazol-1-il]-5-[3-alquil(aril/heteroaril)-5-trialometil-5-hidróxi-4,5-diidro-1H-pirazol-1-il-1-carbonil]piridinas, obtida a partir de reações de ciclocondensação de 4-alcóxi-4-alquil(aril/heteroaril)-1,1,1-trialo-3-alquen-2-onas [CX3C(O)CH=CR¹OR, onde R = Me, Et; R¹ = H, Me, Ph, 4-MeOPh, 4-NO2Ph, 4,4'-Bifenil, 1-Naftil, Fur-2-il e Tien-2-il e X = F, Cl] com hidrato de hidrazida 6-hidrazino-nicotínica. Os melhores rendimentos foram obtidos quando as reações foram executadas em etanol como solvente a 78 ºC por 4 horas (67-97%). Em sequência, são descritas as reações de desidratação de 2-(1H-pirazol-1-il)-5-(1H-pirazol- 1-il-1-carbonil)piridinas. Estas reações foram realizadas em meio piridina / benzeno, na presença de cloreto de tionila e levaram ao isolamento de uma série de 2-[3-alquil(aril/heteroaril)-5-trifluormetil-1H-pirazol-1-il]-5-[3-alquil(aril/heteroaril)-5-trifluormetil-1H-pirazol-1-il-1-carbonil]piridinas, com rendimentos de 64 a 86%.

Two new trifluoroacetylketene O,N-acetals [CF3C(O)CH=C(OEt)(NS(O)R2), where R = CH3, Ph] derived from the reaction of 4,4-diethoxy-1,1,1-trifluorobut-3-en-2-one [CF3C(O)CH=C(OEt)2] with S,S-dimethyl- and S-methyl-S-phenyl-sulfoximide [HN=S(O)R2], in the presence of triethylamine, have been obtained, in 60-72% yields, and applied in the synthesis of S,S-dimethylsulfoximido-substituted pyrazoles, isoxazoles and pyrimidines, in 55-89% yields, from the reactions of 4-ethoxy-4-(S,S-dimethylsulfoximido)-1,1,1-trifluorobut-3-en-2-one with hydrazines, hydroxylamine hydrochloride and acetylguanidine. Este trabalho descreve a síntese de dois novos trifluoracetilceteno O,N-acetais [CF3C(O) CH=C(OEt)(NS(O)R2), onde R = CH3, Ph], obtidos da reação de 4,4-dietóxi-1,1,1-trifluorbut-3- en-2-ona [CF3C(O)CH=C(OEt)2] com S,S-dimetil- e S-metil-S-fenil-sulfoximida [HN=S(O)R2], na presença de trietilamina, com rendimentos de 60-72%, e suas aplicações na obtenção de pirazóis, isoxazóis e pirimidinas S,S-dimetilsulfoximido substituídos, em 55-89% de rendimento, a partir de reações de 4-etóxi-4-(S,S-dimetilsulfoximido)-1,1,1-trifluorbut-3-en-2-ona com hidrazinas, hidrazidas, cloridrato de hidroxilamina e acetilguanidina.

Reactions of methyl 4-methoxy-6-oxo-7,7,7-trihalo-4-heptenoates 1 and 2 with primary amines RNH2, where R = PhCH2, PhCH2CH2, Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, 2-pyridyl, 5-methyl-3-isoxazolyl, 4-NH2C6H4 affording methyl 4-[alkyl(aryl)amino]-6-oxo-7,7,7-trihalo-4-heptenoates 3, 4, in good yields (57-95%), which suffer quantitative intramolecular cyclocondensation to produce 1-alkyl(aryl)-5-(2-oxo-3,3,3-trihalopropylidene)pyrrolidin-2-ones 5, 6, are reported. The structures of the isolated new products were assigned by means of ¹H,13C NMR measurements and mass spectrometry. The Z and E configuration of compounds 3d and 5b respectively were established from X-ray crystallography. Este trabalho mostra a síntese, em bons rendimentos (57-95%), de duas séries de 1-alquil(aril)amino-2-oxo-5-(2-oxo-3,3,3-trialopropiliden)-pirrolidinas 5 e 6, a partir dos intermediários 4-[alquil(aril)amino]-6-oxo-7,7,7-trialo-4-hepteno-atos de metila 3 e 4 obtidos por substituição da metoxila-beta nos precursores 4-metoxi-6-oxo-7,7,7-trialo-4-heptenoatos de metila 1 e 2, pela série de aminas primárias RNH2, onde R = PhCH2, PhCH2CH2, Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, 2-piridnil, 5-metil-3-isoxazolil, 4-NH2C6H4. A estrutura molecular dos produtos inéditos foi atribuída a partir dos dados de RMN ¹H, 13C e espectrometria de massas. A configuração geométrica dos compostos 3d e 5b foi confirmada pelos dados de difração de raios-X em monocristal.

The synthesis of thirteen 1-cyanoacetyl-5-hydroxy-5-halomethyl-1H-4,5-dihydropyrazoles from the reaction of 4-alkoxy-3-alken-2-ones [R³C(O)C(R²)=C(R¹)(OR), where R³ = CF3, CCl3, CHCl2, CO2Et; R² = H, Me; R¹ = H, Me, Et, Pr, Pentyl, c-Hexyl, Ph, and R = Me, Et] with cyanoacetohydrazide is reported. In order to show the versatility of using the 1-cyanoacetyl-substituted pyrazoles as important building blocks in organic synthesis, some attempts to obtain pyrazole derivatives also are described. Este trabalho apresenta a síntese de uma série de treze 1-cianoacetil-5-hidroxi-5-halometil-1H-4,5-diidropirazóis a partir da reação de condensação entre cianoacetohidrazida e 4-alcoxi-3-alquen-2-onas [R³C(O)C(R²)=C(R¹)(OR), onde R³ = CF3, CCl3, CHCl2, CO2Et; R² = H, Me; R¹ = H, Me, Et, Pr, Pentil, c-Hexil, Ph, e R = Me, Et]. Reações de desidratação e derivatização destes compostos também são apresentadas com o objetivo de demonstrar a versatilidade de pirazóis 1-cianoacetil-substituídos como blocos precursores em síntese orgânica.

An efficient green procedure to prepare a series of twenty-six 4-amino-1,1,1-trihalo-3-alken-2-ones [CX3C(O)CH=C(R¹)NR² R³, where X = F, Cl, R¹ = H, Me, and R²/R³ = H/Ph, H/4-F-Ph, H/Bn, H/(CH2)2OH, Me/Ph, Me/Bu, Et/Et, -(CH2)4-] from the solvent-free reaction of 1,1,1-trihalo-4-alkoxy-3-alken-2-ones with primary and secondary amines at room temperature for five minutes is reported (yields of 73-99%). Este trabalho apresenta uma metodologia, ambientalmente adequada e mais econômica em relação àquelas descritas na literatura, para a obtenção de uma série de vinte e seis 4-amino-1,1,1-trialo-3-alquen-2-onas [CX3C(O)CH=C(R¹)NR² R³, com X = F, Cl, R¹ = H, Me, e R²/R³ = H/Ph, H/4-F-Ph, H/Bn, H/(CH2)2OH, Me/Ph, Me/Bu, Et/Et, -(CH2)4-], a partir da reação de 1,1,1-trialo-4-alcóxi-3-alquen-2-onas com aminas primárias e secundárias, na ausência de solvente, a temperatura ambiente e em cinco minutos (rendimentos de 73-99%).

This work reports the synthesis of two new series of N-substituted 6-trifluoromethyl-1,3-oxazinanes and N-substituted 6-trifluoromethyl-1,3-oxazinan-2-ones from the cyclization of 4-ylamino-1,1,1-trifluoro-butan-2-ols with formaldehyde and triphosgene, respectively. The 4-ylamino-1,1,1-trifluoro-butan-2-ols were obtained in good yields from the reduction of the parent 4-ylamino-1,1,1-trifluoro-but-3-en-2-ones with hydrogen and 10% Pd/C. Este trabalho apresenta a síntese de duas novas séries de 6-trifluormetil-1,3-oxazinanas N-substituídas e 6-trifluormetil-1,3-oxazinan-2-onas N-substituídas, a partir da ciclização de 4-ilamino-1,1,1-trifluor-butan-2-óis com formaldeído e trifosgênio, respectivamente. Os 4-ilamino-1,1,1-trifluor-butan-2-óis foram obtidos através da reação de redução dos precursores 4-ilamino-1,1,1-trifluor-but-3-en-2-onas, utilizando hidrogênio e 10% Pd/C, com bons rendimentos.

Neuropathic pain is a debilitating condition that is often resistant to common analgesics, such as opioids, but is sensitive to some antidepressants, an effect that seems to be mediated by spinal cord 5-HT3 receptors. Because the analgesic potential of monoamine oxidase-A (MAO-A) inhibitors is understudied, we evaluated the potential antinociceptive effect of the reversible MAO-A inhibitors moclobemide and 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in a mouse neuropathic pain model induced by chronic constriction injury (CCI) of the sciatic nerve. Neuropathic mice showed a decreased mechanical paw withdrawal threshold (PWT) 7days after lesion compared with the baseline PWT, characterizing the development of hyperalgesia. Moclobemide (100–300μmol/kg, s.c.) and 2-DMPI (30–300μmol/kg, s.c.) treatments were able to reverse the CCI-induced hyperalgesia, with 50% inhibitory dose (ID50) values of 39 (18–84) and 11 (4–33) μmol/kg, and maximum inhibition (Imax) values of 88±14 and 98±15%, respectively, at the 300μmol/kg dose. In addition, we observed a significant increase in the MAO-A activity in the lumbar spinal cord of CCI-submitted mice compared with sham-operated animals. Furthermore, the antihyperalgesic effects of both 2-DMPI and moclobemide were largely reversed by intrathecal injection of the 5-HT3 receptor antagonist ondansetron (10μg/site). These results suggest a possible involvement of MAO-A in the mechanisms of neuropathic pain and a potential utility of the reversible inhibitors of MAO-A in the development of new therapeutic approaches to treat it.

Monoamine oxidase (MAO) inhibitors were the first antidepressant drugs to be prescribed and are still used today with great success, especially in patients resistant to other antidepressants. In this study, we evaluated the MAO inhibitory properties and the potential antidepressant action of 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in mice. We found that 2-DMPI inhibited both MAO isoforms (K(i) values were 1.53 (1.3-1.8) μM and 46.67 (31.8-68.4) μM for MAO-A and MAO-B, respectively) with 30-fold higher selectivity toward MAO-A. In relation to the nature of MAO-A inhibition, 2-DMPI showed to be a mixed and reversible inhibitor. The treatment with 2-DMPI (100-1000 μmol/kg, s.c.) caused a significant decrease in immobility time in the tail suspension test (TST) without affecting locomotor activity, motor coordination or anxiety-related activities. Conversely, moclobemide (1000 μmol/kg, s.c.) caused a significant increase in immobility time in the TST, which appeared to be mediated by a nonspecific effect on motor coordination function. 2-DMPI (300 μmol/kg, s.c.) decreased serotonin turnover in the cerebral cortex, hippocampus and striatum, whereas dopamine turnover was diminished only in the striatum, and norepinephrine turnover was not changed. The antidepressant-like effect of 2-DMPI was inhibited by the pretreatment of mice with methysergide (2 mg/kg, s.c., a non-selective serotonin receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) or haloperidol (0.05 mg/kg, i.p., a non-selective dopamine receptor antagonist). These results suggest that 2-DMPI is a prototype reversible and preferential MAO-A inhibitor with potential antidepressant activity, due to its modulatory effect on serotonergic and dopaminergic systems.

The one-pot, simple and efficient three-component condensation protocol for the preparation of a series of twenty-five new 3-acyl-4-aryl-2-(trifluoromethyl)-2-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-ones, where aryl = Ph, 4-tolyl, 4-ClPh, 4-NO2Ph and 4-CHOPh, and acyl = Ac, Bz, 4-FBz, furan-2-oyl, thien-2-oyl and naphth-1-oyl, employing 1,3-cyclohexanedione, five aryl aldehydes and for the first time, six 4-alkyl(aryl/heteroaryl)-4-methoxy-1,1,1-trifluoroalk-3-en-2-ones, is described. Yields in 15–75% were obtained when the MCRs were performed in the presence of a catalytic amount of triethylamine (25 mol%) and in ethanol as solvent under reflux for 16 h. A representative X-ray diffraction data for 3-acetyl-4-phenyl-2-(trifluoromethyl)-2-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one is also showed.

An efficient and regioselective procedure for the synthesis of a series of alkyl(aryl/heteroaryl) substituted 3-trifluoromethyl-1 H -1-phenylpyrazoles and alkyl 3-carboxylate analogs, from the cyclocondensation reactions of 4-alkoxy-1,1,1-trihaloalk-3-en-2-ones [CX 3 C(O)CR 2 =CR 1 (OMe/OEt), where R 1 = H, Me, Ph, 2-Furyl; R 2 = H; R 1 -R 2 = -C 4 H 8 - and X = F, Cl] and 1-phenylsemicarbazide in an acidified alcoholic medium (R 3 OH/H 2 SO 4 ), where R 3 = Me, Et, Pr i was successfully applied and is described here in detail.

A regioselective synthesis of 3-trifluoromethyl-1-phenyl-1H-pyrazoles (1,3-isomers) as well as their 1,5-isomers (5-trifluoromethyl-1-phenyl-1H-pyrazoles), is described. The 1,3-isomers were obtained from the reaction of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones with arylhydrazones followed by deprotective hydrolysis while the 1,5-isomer was obtained by direct cyclocondensation of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones with phenylhydrazine. An unequivocal assignment of the 1,3- and 1,5-isomers of the pyrazole products is given.