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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.

The present work reports the biological assays between synthetic BF2-naphtyridine complexes and four proteins: human serum albumin (HSA), calf-thymus DNA (CT-DNA), tyrosinase and acetylcholinesterase enzymes via spectroscopic analysis at physiological conditions, combined with molecular docking simulations. The BF2-complexes presented spontaneous and moderate binding ability to HSA through the ground-state association (static fluorescence quenching mechanism). The main binding site is Sudlow's site I (subdomain IIA) and the binding does not perturb significantly both secondary and surface structure of HSA. Despite BF2-complexes showed good binding ability with HSA, these compounds presented weak intercalative ability with CT-DNA (the most conventional and simple model to preliminary studies), except in the case of 1 h, which suggested that the presence of electronic donor groups in both aromatic ring moieties of BF2-complex structure can increase the intercalative ability for DNA strands. Competitive binding displacement assays in the presence of methyl green and molecular docking calculations indicated that the studied compounds interact preferentially in the major groove of DNA. In addition, the assayed compounds presented the ability to activate or inhibit both tyrosinase (the decontrolled activity can induce melanoma carcinoma) or AChE (involved in reactions related to the function of neurotransmitters) enzymes.

The objectives of this study were to evaluate tetrahydropyridine derivatives as efflux inhibitors and to understand the mechanism of action of the compounds by in silico studies. Minimum inhibitory concentration (MIC) determination, fluorometric methods and docking simulations were performed. The compounds NUNL02, NUNL09 and NUNL10 inhibited efflux, and NUNL02 is very likely a substrate of the transporter protein AcrB. Docking studies suggested that the mechanism of action could be by competition with substrate for binding sites and protein residues. We showed for the first time the potential of tetrahydropyridines as efflux inhibitors and highlighted compound NUNL02 as an AcrB-specific inhibitor. Docking studies suggested that competition is the putative mechanism of action of these compounds.

Acute lymphoblastic leukemia (ALL) is a malignant disorder caused by the proliferation of lymphoid progenitor cells and is the most common cancer in children. Cytotoxic nucleoside analogues are important chemotherapeutic agents, which are used in many cancers, including leukemias. In this study, we investigated the effects of the synthetic nucleoside analogue 1-(5,5,5-trichloro-2-methoxy-4-oxopenten-2-yl)-4-trichloromethyl-pyrimidin-2(1H)-one, named compound 3 or C3, on leukemia cell lines. The compound stimulated cell death by apoptosis, evidenced by DNA fragmentation, phosphatidylserine externalization, and caspase-3 activation. Compound 3 seemed to trigger several cell death pathways. The mitochondrial pathway was evidenced through a disturbance of mitochondrial membrane potential, strong cytochrome c liberation, decrease of antiapoptotic Bcl-2 protein expression, and caspase-9 activation. The C3 also induced caspase-8 and -12 activation, an increase in the intracellular calcium level, and an overproduction of reactive oxygen species. Increased caspase 8 activity suggests that the extrinsic pathway was activated and that the ROS production and enzyme activity alteration (glutathione S-transferase, glutathione peroxidase, catalase, and glutathione reductase) might be related to oxidative stress. Finally, the increase in calcium release, CHOP expression, and caspase-12 activity might characterize endoplasmic reticulum stress. Compound 3 was likewise cytotoxic to leukemic and melanoma human cell lines. Taken together, the results contribute to further understanding the new pyrimidine analogue as a potential chemotherapeutic drug or lead molecule.

A simple procedure to obtain 4-acyl-1-substituted-1,2,3-triazoles, using a deep eutectic solvent (DES), ChCl and ethylene glycol at a 1 : 2 ratio, as the reaction medium is described. The products were obtained in high selectivity and good yields (70–84%). The advantages of the method include easy work-up, metal-free conditions, inexpensiveness, and the ability to be used four times without a loss in yield.

A simple and regioselectively controlled method for the preparation of both 1,4- and 1,6-regioisomers of 1-substituted 4(6)-trifluoromethyl-pyrimidin-2(1H)-ones is described. Both regioisomers were synthesized from the cyclocondensation reaction of 4-substituted 1,1,1-trifluoro-4-methoxybut-3-en-2-ones: with nonsymmetric ureas for the 1-substituted 4-(trifluoromethyl)pyrimidin-2(1H)-ones (1,4-isomer) and with nonsymmetric 1-substituted 2-methylisothiourea sulfates for the synthesis of 1-substituted 6-(trifluoromethyl)pyrimidin-2(1H)-ones (1,6-isomer). Each method furnished only the respective isomer in very good yields. The structure of the products was assigned based on the 1H and 13C NMR as well as 2D HMBC spectral analysis.

A mild and efficient protocol for the assembly of tetra-substituted 5-trifluoromethylpyrazoles is presented, involving halogenation at the 4-position of readily prepared tri-substituted 5-trifluoromethylpyrazoles to give 4-halo-1-phenyl-5-trifluoromethyl pyrazoles, and subsequent palladium-catalyzed Negishi or Buchwald–Hartwig cross-couplings to install carbon or nitrogen-based 4-substituents. Key to the success of these challenging cross-couplings is the use of XPhos and JosiPhos CyPF-tBu ligands, respectively.

The title pyrimidinones are highly regioselectively obtained by cyclocondensation of trichloro-alkenones with non-symmetric substituted isothiourea sulfates under mild basic conditions.

A concise method to synthesize 1-substituted 4-amino-2-(trifluoromethyl)-1H-pyrroles from the heterocyclization reaction of 5-bromo-4-methoxy-1,1,1-trifluoropent-3-en-2-ones with amines is described. This method has the following advantages: it uses a wide range of primary amines, starting materials are easily available, it is simple to perform, the reaction conditions are mild, it is environmentally friendly, and it furnishes yields of up to 98%.

This Letter reports the first series of seven examples of novel 7-amine-spiro[chromeno[4,3-b]quinoline- 6,1′-cycloalkanes], where cycloalkane is cyclopentane, cyclohexane, cycloheptane, 2-methyl-, 3-methyl-, 4-methyl-, and 4-t-butyl-cyclohexane. These new compounds were synthesized at yields of 30–65% by a one-pot cyclocondensation reaction of 2-aminobenzonitrile and seven examples of spiro[chroman-2,1′-cycloalkan]-4-ones, using AlCl3 as the catalyst, without solvent and under conventional thermal heating. Subsequently, these spirochromeno-quinolines were subjected to AChE and cytotoxicity activity, and molecular docking studies. Both results for these new tacrine analogues were correlated with the structural features and showed the best results for the tacrine hybrid that possesses the spirocyclopentane moiety.

Metal-free electrophilic fluorination, promoted by Selectfluor, of pyrazoles with methylene groups (CH2X), in which X = OH, OMe, F, N3, and NHMe at the C-4 position furnished the 4-fluoro-pyrazole products from unexpected C–C bond cleavage, at moderate to good yields. Otherwise, under the same reaction conditions, when X = NEt2 or SPr, the oxidation product 4-formyl-pyrazole was obtained.

A new one-pot method, for the synthesis of polysubstituted pyrrolo[3,4- d ]pyridazinones, is presented. The protocol consists in cascade reactions performed in the same media: (i) the thermal in situ pyrrole formation by the reaction of vinyl azides with 1,3-dicarbonyl compounds, via the 1,2-addition of 1,3-dicarbonyl compounds to 2 H -azirine intermediates; (ii) the nucleophilic addition of hydrazines to the ketone group present in the pyrroles previously formed, followed by intramolecular cyclization with the bordering ester, which furnishes the respective pyrrolo[3,4- d ]pyridazinones, substituted at the pyrrole and/or pyridazinone rings. All transformations occur in a two-step one-pot methodology, and a series of ten new compounds were obtained at yields of 42–87%.

The antioxidant capacity of a series of six novel synthetic pyrazoline derivatives (i) 5-hydroxy-3-methyl-5- trifluoromethyl-4,5-dihydro-1 H -carbaldehyde-pyrazole, (ii) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -1-acetyl-pyrazole, (iii) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -carboxyamide-pyrazole, (iv) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5- dihydro-1 H -1-benzoyl-pyrazole, (v) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -1-(2-hydroxybenzoyl)-pyrazole and (vi) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -1-(4-methoxybenzoyl)-pyrazole was evaluated as the capacity of compounds to transfer a hydrogen atom (protection against brain lipid peroxidation and glutathione oxidation) and their capacity to transfer a single electron (ferric-reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picrylhydrazyl radical scavenging (DPPH) assays). Compound 5 had the highest free radical scavenging capacity in the DPPH assay, while compound 2 had the highest FRAP value (P < 0.05). Only compounds 1, 4 and 5 protected against lipid peroxidation in rat brain homogenate. However, compound 5 was the most effective to prevent basal and iron-, sodium nitroprusside- and H 2 O 2 -stimulated lipid peroxidation (IC 50 < 15 μ M) and the only one effective to block glutathione oxidation-mediated by H 2 O 2 (at 150 μ M). Our results indicate that compound 5 has the greatest potential to prevent oxidative damage in brain homogenates.

Pain is the most common complaint in the medical field and the identification of compounds that can effectively treat painful states without induction of side-effects remains a major challenge in biomedical research. The aim of the present study was to investigate the antinociceptive effect of a novel compound, 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole (compound A) in several models of pain in mice and compare with those produced by the known trifluoromethyl-containing pyrazole compound celecoxib. Compound A or celecoxib were administrated by oral (78–780 µmol/kg), intrathecal (9–22.5 nmol/site) or intracerebroventricular (9–22.5 nmol/site) routes. Oral administration of either compound A or celecoxib abolished the mechanical allodynia, but not the oedema caused by intraplantar injection of carrageenan. Similarly, compound A reduced the overt nociception, but not the oedema, produced by bradykinin or capsaicin. However, compound A (500 µmol/kg, orally) did not alter nociception nor oedema caused by intraplantar injection of prostaglandin E2 or glutamate, whereas celecoxib reduced only the nociception induced by the former. Moreover, oral and intrathecal administration of compound A or celecoxib also reduced the nociception induced by acetic acid. However, only celecoxib reduced the acetic acid-induced nociception when it was injected by the intracerebroventricular route. Finally, neither compound A nor celecoxib was able to produce antinociceptive effect in the tail-flick test or to alter the motor performance and the body temperature. Besides, compound A or celecoxib did not induce gastric lesion. Thus, compound A seems to be an interesting prototype for the development of novel analgesic drugs.

In this work, we reported the synthesis and evaluation of the analgesic and anti-inflammatory properties of novel 3- or 4-substituted 5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-1-carboxyamidepyrazoles (where 3-/4-substituent = H/H, Me/H, Et/H, Pr/H, i-Pr/H, Bu/H, t-Bu/H, Ph/H, 4-Br-Ph/H and H/Me) designed in the exploration of the bioisosteric replacement of benzene present in salicylamide with a 5-trifluoromethyl-4,5-dihydro-1H-pyrazole scaffold. Target compounds were synthesized from the cyclocondensation of 4-alkoxy-1,1,1-trifluoromethyl-3-alken-2-ones with semicarbazide hydrochloride through a rapid one-pot reaction via microwave irradiation. In addition to spectroscopic data, the structure of the compounds was supported by X-ray diffraction. Subcutaneous administration of the 5-trifluoromethyl-4,5-dihydro-1H-pyrazoles decreased pain-related behavior during neurogenic and inflammatory phases of the formalin test in mice. Moreover, the more active analgesic compounds (3-/4- = Et/H and H/Me) significantly decreased carrageenan-induced paw edema in mice. The data obtained in this work suggest that the synthesized compounds could be promising candidates for the future development of novel analgesic and anti-inflammatory agents.

The simple preparation of the title compounds succeeds in moderate to good yields via cyclocondensation of 4-substituted ethyl 4-alkoxy-2-oxobut-3-eneoates with 2-methyl or 2-benzylisothiourea.

The synthesis of a series of 14 new 1-(3-(aryl-4,5-dihydroisoxazol-5-yl)methyl)-4-trihalomethyl-1H-pyrimidin-2-ones from the 1,3-dipolar cycloaddition reaction of 1-allyl-4-(trihalomethyl)pyrimidin-2(1H)-ones with aryl nitrile oxides is described. Also, the antiproliferative activity of the title compounds was tested against five human tumoral cell lines: MCF-7 breast cancer cell line, ER+ (estrogen receptor positive); HepG-2 (hepatoma); T-24 (bladder cancer); HCT-116 cell (colorectal carcinoma); and CACO-2. The preliminary results are promising, since three compounds presented IC50 values below 2 μM, as well as moderate to high selectivity.

This study reports a facile and controllable synthetic method for the preparation of both 1,3- and 1,5-isomers of 4-(3(5)-aryl-3(5)-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamides, as well as a new series of 4-(3-aryl-5-hydroxy-5-(trifluoromethyl)-4,5-dihydropyrazol-1-yl)benzenesulfonamides, from the cyclocondensation reaction of 4-aryl-1,1,1-trifluoro-4-methoxybut-3-en-2-ones or 1-aryl-4,4,4-trifluoro-butane-1,3-diones or their enolic forms with 4-hydrazinylbenzenesulfonamide. All compounds of the new series of 3-substituted 1-(4-benzenesulfonamide)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydropyrazoles were tested for their effect on a pathological pain model in mice. The compounds 3a, 3b, 3c, 3e, and 3f presented anti-hyperalgesic action, while the compounds 3a, 3c, 3d, 3f, and 3g exhibited anti-edematogenic effects, without causing locomotive disorders in animals, thus making them comparable to Celecoxib in an arthritic pain model.

Reaction of trifluoroacetylated Kabbe adducts (IV) with phenylhydrazine or methylhydrazine proceeds with apposite regioselectivity furnishing chromenopyrazoles (VI) or (VIII), respectively.

The regiospecific synthesis of a novel series of nine 4-phenyl- and 3-alkyl(aryl)-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-tosylpyrazoles (pyrazolinyl p-tolyl sulfones), as well as their antimicrobial activity against yeast, such as fungi, bacteria, and alga are reported. The 1-p-tosyl-2-pyrazolines were obtained from the cyclocondensation reaction of 3-phenyl- and 4-alkyl(aryl)-1,1,1-trifluoro-4-alkoxy-3-alken-2-ones, [where alkyl = H, Me and aryl are -C6H5, 4-CH3C6H4, 4-OCH3C6H4, 4-FC6H4, 4-ClC6H4, 4-BrC6H4,] with p-tosylhydrazine in a yield of 58–92% when toluene was employed as solvent. The best activity was obtained when the structure possessed a 4-fluorophenyl substituent linked at the carbon-3 of the pyrazoline ring. Subsequently, the dehydration reaction of 3-(4-fluorophenyl) substituted 2-pyrazoline with thionyl chloride/pyridine in benzene as solvent furnished the corresponding 1H-pyrazole in only a moderate yield (49%).

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.

A convenient method to obtain 10 3-amino-5-trifluorom-ethyl-5-hydroxy-4,5-dihydroisoxazoles and 18 3-amino-5-trifluoromethyl-lH-pyrazoles by cyclocondensation reaction of 4-amino-4-ethoxy-1,1,1,-trifluorobut-3-en-2-ones [CF3COCH=C(OEt)NHR, where R=H, Me, Et, CH 2 CH 2 OH, CMe 2 Et, CH 2 Ph, Ph, 4-NH 2 C 6 H 4 , 4-ACC 6 H 4 , 4-NO 2 C 6 H 4 , 5-methylisoxazol-3-yl, thiazol-2-yl, CH 2 CO 2 Et, CH(Ph)CO 2 Me, CH(i-Bu)CO 2 Et] with hydroxylamine, hydrazine and phenylhydrazine is reported.

The antimalarial activity of chloroquine-pyrazole analogues, synthesized from the reaction of 1,1,1-trifluoro-4-methoxy-3-alken-2-ones with 4-hydrazino-7-chloroquinoline, has been evaluated in vitro against a chloroquine resistant Plasmodium falciparum clone. Parasite growth in the presence of the test drugs was measured by incorporation of [(3)H]hypoxanthine in comparison to controls with no drugs. All but one of the eight (4,5-dihydropyrazol-1-yl) chloroquine 2 derivatives tested showed a significant activity in vitro, thus, are a promising new class of antimalarials. The three most active ones were also tested in vivo against Plasmodium berghei in mice. However, the (pyrazol-1-yl) chloroquine 3 derivatives were mostly inactive, suggesting that the aromatic functionality of the pyrazole ring was critical.

This work reports a two-step synthetic strategy to obtain a series of 6-methylenesubstituted-4-trichloromethyl-2-methylsulfanylpyrimidines from the cyclization of 5-bromo-4-methoxy-1,1,1-trichloro-pent-3-en-2-ones with 2-methyl-2-pseudothiourea sulfate, followed by nucleophilic substitution of 6-bromomethyl-4-trichloromethyl-2-methylsulfanylpyrimidine with a series of nucleophiles. Alternative strategies to obtain 6-halomethyl-4-trichloro[fluoro]methyl-2-methylsulfanyl pyrimidines have been addressed.

A convenient method for the synthesis of a novel series of 7-trifluoromethyl-5,6-dihydrobenzo[c]acridines, in 44–82% yields, by intramolecular cyclization reactions of N-aryl-2-trifluoroacetyl-3,4-dihydronaphthylamines using poly-phosphoric acid (PPA), is described on this paper. Naphthylamine derivatives are obtained by an oxygen-nitrogen exchange reaction from 1-methoxy-2-trifluoroacetyl-3,4-dihydronaphthalene with substituted anilines.

Acetylcholinesterase (AChE) was studied in different rat brain regions (cerebellum, hypothalamus, striatum, hippocampus and cortex) in the presence of different organic solvents normally used in the in vitro assay. The organic solvents used were acetone (C3H6O), acetonitrile (C2H3N), ethyl alcohol (C2H6O), isopropyl alcohol (C3H8O), methyl alcohol (CH4O), tert-butyl alcohol (C4H10O) and dimethyl sulfoxide (DMSO, C2H6OS) ranging from 0.6 to 10%. Ethyl and methyl alcohol presented no effect on AChE activity at any of the concentrations and brain structures tested. In the hippocampus, isopropyl alcohol did not demonstrate a significant inhibitory effect, even at high concentrations. Tert-butyl alcohol presented an interesting result, increased AChE activity (P < .05) in the hypothalamus (1.8%), cortex (1.8 and 2.5) and striatum (1.2, 1.8 and 2.5%) and decreased activity at a concentration of 10% in the cortex (P < .05) and striatum (P < .01). Acetone and acetonitrile presented similar results, both significantly inhibiting AChE in all structures (5%, P < .05 and 10%, P < .01). DMSO exhibited a highly inhibitory effect at practically all concentrations tested (P < .01). In conclusion, for testing new compounds on AChE activity in vitro, methyl and ethyl alcohol may be the best organic solvent choice.

A series of 10 heterocycles was obtained from the reaction of 1,1,1-trifluoro-4,4-diethoxy-3-buten-2-one and 1,1,1,2,2-pentafluoro-4,4-diethoxy-3-penten-2-one with different dinucleofiles (hydrazine, methyl hydrazine, hydroxylamine and sodium cyanide). The pyrazoles, 4,5-dihydroisoxazoles and pyrrolidinones polyfluoroalkyl substituted were obtained in moderate to good yields under mild conditions.

In this study, a new series of trihalomethyl-substituted pyrimidines and dihydropyrimidines were synthesized and tested as potential NTPDase inhibitors. For this purpose, synaptosomes from rat cerebral cortex were used as the enzyme source and ATP and ADP were used as the substrate. Among the new compounds, 4-methyl-2-methylsulfanyl-6-trichloromethylpyrimidine (2b) was found to be the most effective noncompetitive inhibitor, with an estimated K(i) value of 0.18 and 0.55 mM for ATP and ADP, respectively. Other pyrimidines inhibited NTPDase activity with the following rank order of inhibitory potency: 3,6-dimethyl-2-methylsulfanyl-4-trifluoromethyl-3,4-dihydro-pyrimidin-4-ol (3a) > 5-methyl-2-(4-methyl-6-trifluoromethyl-pyrimidin-2-yl)-3-trifluoromethyl-3,4-dihydro-2H-3-pyrazol-3-ol (6a) > 5-bromo-4,6-dimethoxy-4-trichloromethyl-1,2,3,4-tetrahydro-2-pyrimidin-2-one (9) for ATP and 6a > 9 > 3a for ADP. Our results demonstrate that a novel group of pyrimidines compounds can act as inhibitors of ATP and ADP hydrolysis in synaptosomes from rat cerebral cortex. These results can contribute for the understanding of the NTPDase activity and for further studies involving new compounds that can enlist as it inhibitors.

A simple and convenient synthesis of a series of 3-aminomethylenedihydrofuran-2-ones from the reaction of 3-trichloroacetyl-4,5-dihydrofuran with amines, is presented.

The synthesis of 1,1,1-trichloro-4,4-diethoxy-3-buten-2-one and three trichloroacetylacetate derivatives from the acylation reaction of respective trialkyl orthoacetates and orthopropionates with trichloroacetyl chloride in good yields, is reported. The title compounds were used for the regiospecific preparation of two isoxazoles and five pyrazoles in the cyclocondensation with hydroxylamine and hydrazines, respectively. The transformation of the trichloromethyl group under mild conditions into carboxylic groups is also described.

Using trichloromethyl substituent as convenient leaving group for the synthesis of interesting bi-heterocyclic compounds, a series of 6-methyl- and 7-alkyl(aryl)-5 H -thiazolo[3,2- a ]pyrimidin-5-ones, where alkyl=methyl, n -propyl, isopropyl, isobutyl, n -hexyl, isopentyl and aryl=phenyl, 4-toluyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl was obtained from a simple and regiospecific reaction of 4-alkoxy-1,1,1-trichloro-3-alken-2-ones with 2-aminothiazole in good yield (45–89%).

A convenient selective protection of the u-amino carboxyl group of amino acids bearing reactive side chain groups such as arginine, asparagine, glutamine, cysteine, histidine, serine and lysine, using 4-alkoxy-1,1,1-trifluoro[chloro]alk-3-en-2-ones is reported. The reactions were performed without esterification of the carboxyl group and N-deprotection was carried out using a six molar solution of hydrochloric acid.

The synthesis of a new series of 3-alkosy-5-hydmxy-5-trifluoromethyl pyrriolidin-2-ones 2a-h from the reaction of 1,1,1-trifluoro-4-alkoxyalk-3-en-2-ones la-h of the general formula F 3 CC(O)C(R 2 )=C(R 1 )OR. where: R=Me, Et, -(CH 2 ) 2 -, -(CH 2 ) 3 -; R 1 = H. Me, Ph, p-Me-Ph, p-F-Ph: and R 2 = H, Me, -(CH 2 ) 2 -, -(CH 2 ) 3 - with sodium cyanide in hydro-alcoholic medium is reported.

Title compounds are synthesized in high yields from butenones (I) and urea in short reaction times compared to other known methods.

The reaction proceeds via in situ prepared (Me-CH=CH-CH2)Al2Br3 and (H2C=CH-CH2)Al2Br3, respectively.

Rufinamide analogues of type (III)/(IV) are prepared by 1,3-dipolar cycloaddition and/or electrocyclization reactions of trifluoroalkenones of type (I) with 2,6-difluorobenzyl azide (II).

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 study examines the effect of new 1,5 benzodiazepines on acetylcholinesterase (AChE) and ATPDase (apyrase) activities from cerebral cortex of adult rats. Simultaneously, the effects of the classical 1,4-benzodiazepine on these enzymes were also studied for comparative purpose. The compounds 2-trichloromethyl-4-phenyl-3H-1,5-benzodiazepin and 2-trichloromethyl-4-(p-methyl-phenyl)-3H-1,5-benzodiazepin significantly inhibited acetylcholinesterase activity (p < 0.01) when tested in the range of 0.18–0.35 mM. The inhibition caused by these two new benzodiazepines was noncompetitive in nature. Similarly, at concentrations ranging from 0.063 to 0.25 mM, the 1,5 benzodiazepines inhibited ATP and ADP hydrolysis by synaptosomes from cerebral cortex (p < 0.01). However, the inhibition of nucleotide hydrolysis was uncompetitive in nature. Our results suggest that, although diazepam and the new benzodiazepines have chemical differences, they both presented an inhibitory effect on acetylcholinesterase and ATPDase activities.

A simple and regiospecific synthesis of 4-alkoxy(amino)-2-trifluoromethyl pyrroles from 5-azido-4-alkoxy(amino)-1,1,1-trifluoro-pent-3-en-2-ones by an aza-Wittig cyclization of aminophosphoranes is described. The structures of the pyrroles and their synthetic intermediates were supported by NMR and HRMS analysis.

Cycloaddition reactions between the nitrile group of β-cyanocarboxylic acids with sodium azide in the presence of zinc chloride afford tetrazolic acids, structural analogues of succinic acid.

Title compounds (IV) are obtained in a two-step procedure that involves the reaction of enones (I) with hydrazones (II), followed by deprotective hydrolysis and intramolecular nucleophilic heterocyclization.

This paper describes firstly the synthesis of a new series of 3-hydroxy-2-[(3(5)-(methyl/phenyl)-5(3)-(trifluoromethyl)-1 H -pyrazol-4-yl)arylmethyl]-cyclohex-2-en-1-ones (2), where aryl = C 6 H 5 , 4-NO 2 C 6 H 4 , 4-OCH 3 C 6 H 4 , from an ANRORC ring transformation reaction of 3-acyl-4-aryl-2-(trifluoromethyl)-2-hydroxy-3,4,7,8-tetrahydro-2 H -chromen-5(6 H )-ones (1), where acyl = acetyl and benzoyl, in the presence of hydrazine hydrate, at 63–90% yields. In subsequent steps, an oxidative aromatization reaction from 2 was done in an iodine/methanol medium for the preparation of 3(5)-trifluoromethyl-5(3)-methyl-4-[(2,6-dimethoxyphenyl)-(4-methoxyphenylmethyl)]-1 H -pyrazole (3) at 72% yields. Also, the alkylation reaction using benzyl chloride easily converted a pyrazole like 2 to its N -benzyl derivative (4), at 69% yield. Finally, the structural assignment of compounds 2–4 was deduced by mass spectrometry, X-ray crystal diffraction and density functional theory (DFT) calculations, which clearly and unambiguously furnished values very close to those determined from 1 H, 13 C and 19 F NMR data.

5-Bromo[5,5-dibromo]-1,1,1-trihalo-4-methoxy-3-penten[hexen]-2-ones are explored as precursors to the synthesis of 3-ethoxymethyl-5-trifluoromethyl-1H-pyrazoles from a cyclocondensation reaction with hydrazine monohydrate in ethanol. 3-Ethoxymethyl-carboxyethyl ester pyrazoles were formed as a result of a substitution reaction of bromine and chlorine by ethanol. The dibrominated precursor furnished 3-acetal-pyrazole that was easily hydrolyzed to formyl group. In addition, brominated precursors were used in a nucleophilic substitution reaction with sodium azide to synthesize the 3-azidomethyl-5-ethoxycarbonyl-1H-pyrazole from the reaction with hydrazine monohydrate. These products were submitted to a cycloaddition reaction with phenyl acetylene furnishing the 3-[4(5)-phenyl-1,2,3-triazolyl]5- ethoxycarbonyl-1H-pyrazoles and to reduction conditions resulting in 3-aminomethyl-1H-pyrazole-5-carboxyethyl ester. The products were obtained by a simple methodology and in moderate to good yields.

A highly regioselective and inexpensive method is developed for the synthesis of 1,2-dihydropyridines.

A study is presented for the synthesis of a series of 1-tert-butyl-3(5)-(trifluoromethyl)-1H-pyrazoles from the reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF3C(O)CH=C(R1)(OR), where R = Et and R1 = H or R = Me and R1 = Me, Ph, 4-Me-C6H4, 4-MeO-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-I-C6H4, fur-2-yl, thien-2-yl, or naphth-2-yl] with tert-butylhydrazine hydrochloride. When [BMIM][BF4] (1-butyl-3-methylimidazolium tetrafluoroborate) and pyridine were used as the reaction media, we obtained a mixture of 1-tert-butyl-3(5)-trifluoromethylpyrazoles. The formation of 5-trifluoromethyl-1-tert-butyl-1H-pyrazoles with high regioselectivity occurred when the reaction was carried out with NaOH in EtOH. The formation of 1-tert-butyl-3-trifluoromethyl-1H-pyrazoles occurred, after hydrolysis of the 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones in H2O and H2SO4, followed by cyclization in [BMIM][BF4] and pyridine.

This study describes an improved one-pot, four-step synthesis­ of a new series of 1-aryl-3-trifluoroacetyl pyrroles from the reaction of 3-trifluoroacetyl-4,5-dihydrofuran with arylamines, giving 1,1,1-trifluoro-3-(2-hydroxyethyl)-4-arylamino-3-buten-2-ones, which were directly submitted to Swern oxidation to furnish 1,1,1-trifluoro-3-(2-ethanal)-4-arylamino-3-buten-2-ones. Subsequent intramolecular cyclization of the corresponding enaminoaldehydes followed by aromatization rendered the title compounds in a 30 to 56% overall yield.

This paper describes the one-pot simple and efficient oxidative aromatization reaction employing an iodine/alcohol medium for the preparation of a series of 11 new 3-acyl-2-hydroxy-5-alkoxy-4-aryl-2-(trifluoromethyl)chromanes, where acyl = Ac, Bz, furan-2-oyl; aryl = Ph, 4-NO 2 C 6 H 4 , 4-OCH 3 C 6 H 4 and alkoxy = OMe, O-Pr n , EtO and OBn from the respective 3-acyl-4-aryl-2-(trifluoromethyl)-2-hydroxy-3,4,7,8-tetrahydro-2 H -chromen-5(6 H )-ones. Yields in the range of 50–89% were obtained when the oxidative reactions were performed using both conventional thermal heating (CTH) and microwave (MW) procedures. In general, the MW method produced similar yields with shorter reaction times and easier reaction workups. As an example, a representative X-ray diffraction ORTEP for 3-benzoyl-2-hydroxy-5-methoxy-4-methoxyphenyl-2-(trifluoromethyl)chromane is also shown.