3-trifluoromethyl Phenyl Research Articles

Synthesis and fungicidal activity of 2-(methylthio)-4-methylpyrimidine carboxamides bearing a carbamate moiety

A series of 1-[2-(4-methyl-2-(methylthio)pyrimidine-5-carboxamido)phenyl]ethyl-substitutedphenyl carbamates (3a–3i) were designed and synthesized, using 4-methyl-2-(methylthio)pyrimidine-5-carboxylic acid, (2-aminophenyl)ethan-1-one, and substituted phenyl isocyanates as starting materials. Their structures were characterized by 1H NMR, 13C NMR, IR and HRMS. The in vitro fungicidal activities against Sclerotinia sclerotiorum were evaluated, and the result showed that some compounds displayed moderate antifungal activity with >60% inhibitory rates, among which 1-[2-(4-methyl-2-(methylthio)pyrimidine-5-carboxamido)phenyl] ethyl-(2- methyl phenyl)carbamate (3a) and 1-[2-(4-methyl-2-(methylthio)pyrimidine-5- carboxamido)phenyl] ethyl-(3-trifluoromethyl phenyl)carbamate (3g) held inhibitory rates of 69.5% and 70.3% at 100 mg/L, respectively. Molecular docking study showed that 3g can form two hydrogen bonds and a cation-π interaction with succinate dehydrogenase.

Synthesis and Critical View on the Structure-Activity Relationships of N-(Substituted phenyl)-/N-Diphenylmethyl-piperazine-Based Conjugates as Antimycobacterial Agents

This research focused on a three-step synthesis, analytical, physicochemical, and biological evaluation of hybrid molecules 6a–g, containing a lipophilic 3-trifluoromethylphenyl moiety, polar carbamoyloxy bridge, 2-hydroxypropan-1,3-diyl chain and 4-(substituted phenyl)-/4-diphenylmethylpiperazin-1-ium-1-yl fragment. The estimation of analytical and physicochemical descriptors (m/zmeasured via HPLC-UV/HR-MS, log ε2 (Ch–T) from UV/Vis spectrophotometry and log kw via RP-HPLC) as well as in vitro antimycobacterial and cytotoxic screening of given compounds were carried out (i.e., determination of MIC and IC50 values). These highly lipophilic molecules (log kw = 4.1170–5.2184) were tested against Mycobacterium tuberculosis H37Ra ATCC 25177 (Mtb H37Ra), M. kansasii DSM 44162 (MK), M. smegmatis ATCC 700084 (MS), and M. marinum CAMP 5644 (MM). The impact of the 6a–g set on the viability of human liver hepatocellular carcinoma (HepG2) cells was also investigated. 1-[2-Hydroxypropyl-{(3-trifluoromethyl)- phenyl}carbamoyloxy]-4-(3,4-dichlorophenyl)piperazin-1-ium chloride (6e) and 1-[2-hydroxy- propyl-{(3-trifluoromethyl)phenyl}carbamoyloxy]-4-(4-diphenylmethyl)piperazin-1-ium chloride (6g) most effectively inhibited the growth of Mtb H37Ra (MIC < 3.80 μM). The substance 6g also showed interesting activity against MM (MIC = 8.09 μM). All obtained data served as input values for structure-activity relationship evaluations using statistical principal component analysis. In fact, the toxicity of both 6e (IC50 = 29.39 μM) and 6g (IC50 = 22.18 μM) in HepG2 cells as well as selectivity index (SI) values (SI < 10.00) prevented to consider these promising antimycobacterials safe.

The anti-tumor activity of novel oxovanadium complexes derived from thiosemicarbazones and fluoro-phenanthroline derivatives

Three oxovanadium complexes incorporating thiosemicarbazones and fluoro-phenanthroline derivatives [VO(hntdtsc)(CF3PIP)] (1) (hntdtsc=2-hydroxyl-1-naphthaldehyde thiosemicarbazone, CF3PIP=2-(2-trifluoromethyl phenyl)imidazole[4,5-f][1,10]phenanthroline [VO(hntdtsc)(m-CF3PIP)] (2) (m-CF3PIP=2-(3-trifluoromethyl phenyl)imidazole[4,5-f][1,10]phenanthroline), [VO(hntdtsc)(p-CF3PIP)] (3) (p-CF3PIP=2-(4-trifluoromethyl phenyl)imidazole[4,5-f][1,10]phenanthroline) were newly synthesized and characterized by elemental analysis and spectroscopic techniques. Their interactions with calf-thymus DNA (CT-DNA) and photocleavage properties with plasmid pBR322 DNA were investigated by a host of analytical methods. The results suggest that these three complexes interact with CT-DNA through an non-classical intercalative mode and can efficiently cleavage plasmid pBR322 DNA upon exposure to ultraviolet light. In addition, they all exhibited considerable anti-proliferative activity in vitro against human Hela, CaSki, SiHa, ECa9706, ECa109, MDA-MB-231 and MCF-7 tumor cell lines, to have an IC50 values for cytotoxicity in the low micromole range 0.31–6.15μM, which is very close to that of cisplatin (0.52–2.49 μM). Furthermore, their antitumor mechanism has been analyzed by the cell cycle arrest, and apoptosis analysis. The results showed that complexes 2 and 3 caused G0/G1 phase arrest in ECa9706 cells, but differentiatedly induced G0/G1 and S phase arrest in ECa109 cells. And significant apoptosis were observed in both the two tumor cell lines, which indicate these oxovanadium complexes induce proliferative suppression of ECa9706 and ECa109 cells via the induction of apoptosis.

Development of a rapid LC‐MS/MS method for direct urinalysis of designer drugs

The current immunoassay screening methodologies used to detect sympathomimetic amines within the context of workplace drug testing may fail to detect a number of the emerging designer drugs, for example β-keto amphetamines and piperazine derivatives, commonly referred to as 'legal highs'. Therefore, a rapid multi-analyte qualitative screening method, using ultra-high-pressure liquid chromatography-tandem mass spectrometry (LC-MS/MS), was investigated for analysis of new designer drugs that have emerged from the former legal highs market. Eight analytes were targeted as model compounds: 4-methylmethcathinone (mephedrone), 3,4-methylenedioxymethcathinone (bk-MDMA, 'methylone'), 2-methylamino-1-(3,4-methylenedioxyphenyl)butan-1-one (bk-MBDB, 'butylone'), 4-methoxymethcathinone (bk-PMMA, 'methedrone'), 1-benzylpiperazine (BZP), 1-(3-trifluoromethyl phenyl)-piperazine (TFMPP), 1-(3-chloro phenyl)-piperazine (mCPP), and 3, 4-methylenedioxypyrovalerone (MDPV). The LC-MS/MS method developed encompassed direct analysis following a 1:4 dilution of urine with mobile phase to reduce matrix effects. Although not all compounds were completely resolved chromatographically, two product ions conferred sufficient specificity to allow target analyte identification. Although all target analytes were readily detected at 500 ng/ml, a cut-off of 1000 ng/ml was chosen to mirror the amphetamine screening cut-off commonly used for routine analysis of workplace drug testing samples. In conclusion, direct analysis using LC-MS/MS offers an attractive way forward for the development of a rapid routine screen for new psychoactive substances, particularly given the growing number of novel compounds.

A new family of salts for lithium Secondary batteries

ABSTRACTA novel family of salts suitable for lithium battery application was synthesized and characterized. These salts have a large delocalized anion whose charge is spread over a single SO2and a phenyl ring. Remarkable properties were obtained for the lithium N-(3-trifluoromethyl phenyl) trifluoromethanesulfonamide salt or LiTFPTS. The electrochemical stability window is around 4.0 V and its conductivity in solid poly(ethylene oxide) or PEO is close to the one of the lithium perchlorate salt. Calorimetric analysis also showed that LiTFPTS behaves as a plasticizer since it hinders, to a certain extent, the PEO crystallization when it is used in a solid polymer matrix. Above all, its synthesis is quite straightforward and leads to potentially inexpensive salts as the starting amines are made commercially on a large scale.

SR57746A: a survival factor for motor neurons in vivo.

SR57746A(1-[2-(naphth-2-yl)ethy]]-4-(3-trifluoromethyl phenyl)-1,2,5,6-tetrahydropyridine, hydrochloride) is a non-peptide compound which has been shown to exhibit a wide range of neurotrophic effects both in vitro and in vivo. Here we examine the ability of SR57746A on axotomized spinal motor neuron death in the developing rat spinal cord. After postnatal unilateral section of rat sciatic nerve, there was approximately a 50% survival of motor neurons in the fourth lumbar segment (L4). Intraperitoneal injection of SR57746A for consecutive 14 days rescued motor neuron death but did not preserve the motor neuron diameter both on axotomy and non-axotomy side. These results suggest that SR57746A is a survival factor for motor neurons in vivo and may serve as therapeutic agent for damaged motor neurons.

Evaluation of phenylpiperazines as targeting agents for neuroblastoma.

The potential of radiolabelled phenylpiperazines as agents for the detection and therapy of tumours of neural crest origin was evaluated by in vitro pharmacological studies with human neuroblastoma cell lines [SK-N-SH and SK-N-BE(2C)], and in vivo by biodistribution measurements. The ability of phenylpiperazines: 4-phenyl-piperazine (PP), 1-carboxamidino-4-phenyl-piperazine (CAPP), [4-(3-chlorophenyl)-piperazine (mCPP), 4-(3-trifluoro methyl phenyl)-piperazine (TFMPP), and (1,1-dimethyl-4-phenyl)-piperazinium hydrochloride (DMPP) and chlorophenyl hydroxypiperidine [CP(OH)P], to inhibit MIBG uptake by neuroblastoma cells was determined by incubation with [125I]MIBG (0.1 microM) for 2 h in the presence of varying concentrations (10(-8)-10(-3) M) of ligand. For measuring uptake, cells were incubated with [125I]IPP (0.1 microM) and cell-associated radioactivity was measured at various times. Retention was studied by incubating cells in the presence of [125I]IPP (0.1 microM) for 2 h, followed by replacement with drug-free medium and determination of cell-bound radioactivity. Selectivity of [125I]IPP uptake was studied by inhibition studies with MIBG, DMI, 5HT and phenylpiperazines. The biodistribution of [125I]IPP was measured in normal rats at 0.083, 0.5, 1, 2 and 24 h (six animals per group). The IC50S (microM) for inhibition of [125I]MIBG uptake were: PP, 1.5; CPP, 2.5; CAPP, 2.5; DMPP, 5; CP(OH)P, 30 and TFMPP, 65. The rate of cellular uptake of [125I]IPP was greatest between 0 and 60 min and decreased after 60 min, similar to MIBG. After an initial rapid washout of approximately 50% of the radioactivity, retention remained constant for 3 h. The IC50S (microM) for inhibition of [125I]IPP uptake were: MIBG, 18-25; DMI, 0.6-1.5; 5HT, > 100; IPP, 1.8-2.5; CPP, 7.0-9.0 and TFMPP, > or = 20. The in vivo studies demonstrated a pattern of distribution similar to MIBG. The results demonstrate that phenylpiperazines display significant affinity for neuroblastoma with uptake and retention characteristics similar to MIBG.

BIMT 17, a 5-HT1A receptor agonist/5-HT2A receptor antagonist, directly activates postsynaptic 5-HT inhibitory responses in the rat cerebral cortex

BIMT 17 (1-[2-[4-(3-trifluoromethyl phenyl) piperazin-1-yl] ethyl] benzimidazol- [1H]-2-one), a 5-HT1A receptor agonist/5-HT2A receptor antagonist (see Borsini et al., accompanying paper), in a dose range of 1-10 mg/kg i.v., dose-dependently inhibited the electrical activity of rat medial prefronto-cortical neurons, whereas buspirone, in a dose range of 0.1-1000 micrograms/kg, increased it. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and 1-[2-(2-thenoylamino)ethyl]-4-[1-(7-methoxynaphthyl)] piperazine (S 14671) presented biphasic patterns of response; they increased electrical activity at doses in the range of 0.1-10 micrograms/kg and 0.1-3 micrograms/kg i.v. respectively, and reduced it at high doses, 30-300 micrograms/kg and 10-30 micrograms/kg i.v., respectively. The inhibitory effect of BIMT 17 on the firing rate of neurons in the frontal cortex was antagonized by the 5-HT1A antagonists tertatolol and WAY 100135, and was still present after destruction of serotonin (5-HT) containing neuronal endings by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 150 micrograms/rat, given intraventricularly), which reduced the cortical 5-HT content by 85%. This destruction of 5-HT neurons, while suppressing the ability of 8-OH-DPAT to inhibit the firing rate at high doses, did not change the excitatory action of this compound at low doses. The addition of ritanserin, a 5-HT2A receptor antagonist, potentiated both the excitatory and inhibitory effects of 8-OH-DPAT on neuronal electrical activity. Direct microiontophoretic application (100 nA/20 s) of 5-HT and BIMT 17, but not that of 8-OH-DPAT, onto medial prefronto-cortical neurons, decreased the firing rate of these neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of action of gonadotropin releasing hormone: Role of lipoxygenase products of arachidonic acid in luteinizing hormone release

The mechanism of action of gonadotropin-releasing hormone (GnRH) upon pituitary luteinizing hormone (LH) secretion has not yet been elucidated, but recent evidence has suggested that arachidonic acid or its metabolites are involved in GnRH action. In cultured rat pituitary cells, arachidonic acid and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) elicited concentration-dependent release of LH with EC50 of about 12 microM. Other lipoxygenase derivatives including 11-, 12- and 15-HETE, had no consistent effect on LH release, and leukotrienes (B4 and C4) exerted only minor stimulatory actions on LH release. The lipoxygenase inhibitors nordihydroguaiaretic acid (NDGA), 5,8,11,14-eicosatetraynoic acid (ETYA), and 3-amino-1-(3-trifluoromethyl phenyl)-2-pyrazoline hydrochloride (BW 755C) caused dose-dependent inhibition of GnRH-induced LH release, with IC50 values of 5, 8.5, and 175 microM, respectively. In contrast, the cyclooxygenase inhibitor, indomethacin, had a biphasic action on GnRH-stimulated LH release, with potentiation of GnRH action at low doses (up to 25 microM) and no effect at higher concentrations. These findings are consistent with the potential role of a 5-lipoxygenase product of arachidonic acid in the mechanism of action of GnRH on pituitary gonadotropin release.

Inhibition of leukotriene C 4 and B 4 generation by human eosinophils and neutrophils with the lipoxygenase pathway inhibitors U60257 and BW755C

Human eosinophils and neutrophils have the capacity to generate leukotriene C 4 (LTC 4) and leukotriene B 4 (LTB 4) respectively when stimulated by calcium ionophore A23187. Leukotriene production by mixtures of these cell types was measured by radioimmunoassay for LTC 4 and LTB 4, and the specificities of the assays determined by assessing cross-reactivities with a number of other arachidonic acid metabolites. The IC 50s for LTC 4 and LTB 4 in their respective assays were 1.76 ± 0.04 nmol and 3.00 ± 0.08 nmol. Cross-reactivity for anti-LTC 4 was shown by leukotriene D 4 (LTD 4) (70%) and leukotriene E 4 (LTE 4) (8%), when compared to LTC 4, whereas in the radioimmunoassay for LTB 4, only the 5(S), 12(R) 6-trans isomer of LTB 4 showed appreciable interaction (12%). LTC 4 production by eosinophil enriched cell fractions obtained from metrizamide gradients was inhibited in a dose-dependent fashion by the prostacyclin analogue, 6,9-deepoxy-6,9-phenylimino-Δ 6,8-prostaglandin I, (U60257) and by 3-amino-1-(3-trifluoromethyl phenyl)-2-pyrazole (BW755C). The ID 50 values for U60257 and BW755C were 2 × 10 −6 and 5 × 10 −6 M respectively. This demonstration of LTC 4 production by human eosinophils, which are known to be important cells in clinical asthma, provides an in vitro model to assess 5-lipoxygenase inhibitors in human tissue.

24 Modulation by combined pretreatment with GnRH and estradiol benzoate anp/or clomiphene citrate of the secretion of LH and FSH by the pituitary gland of the long-term ovariectomized rat. An in-vitro study

The mechanism of action of gonadotropin-releasing hormone (GnRH) upon pituitary luteinizing hormone (LH) secretion has not yet been elucidated, but recent evidence has suggested that arachidonic acid or its metabolites are involved in GnRH action. In cultured rat pituitary cells, arachidonic acid and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) elicited concentration-dependent release of LH with EC50 of about 12μM. Other lipoxygenase derivatives including 11-, 12- and 15-HETE, had no consistent effect on LH release, and leukotrienes (B4 and C4) exerted only minor stimulatory actions on LH release. The lipoxygenase inhibitors nordihydroguaiaretic acid (NDGA), 5,8,11,14-eicosatetraynoic acid (ETYA), and 3-amino-1-(3-trifluoromethyl phenyl)-2-pyrazoline hydrochloride (BW 755C) caused dose-dependent inhibition of GnRH-induced LH release, with IC50 values of 5, 8.5, and 175μM, respectively. In contrast, the cyclooxygenase inhibitor, indomethacin, had a biphasic action on GnRH-stimulated LH release, with potentiation of GnRH action at low doses (up to 25 μM) and no effect at higher concentrations. These findings are consistent with the potential role of a 5-lipoxygenase product of arachidonic acid in the mechanism of action of GnRH on pituitary gonadotropin release.

Comparison of the uptake and bioconcentration of fluridone and terbutryn by rainbow trout andChironomus tentans in sediment and water systems

The rates of uptake and clearance of the aquatic herbicides terbutryn (14C) (2-t-butylamino4-ethylamino-6-methylthio-s-triazine) and (14C) fluridone (1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-4-(1H)-pyridinone) from water by rainbow trout andChironomus tentans (4th Instar) larvae were determined in static systems. Uptake rates for both herbicides were much lower than those for more hydrophobic compounds tested under similar conditions. Bioconcentration factors (BCFs) for fish of 91 and 312 were estimated for fluridone and terbutryn, respectively, by use of a pharmacokinetic model. Uptake and clearance of fluridone and terbutryn by chironomid larvae were more rapid than for rainbow trout. BCFs for chironomid larvae were estimated to be 128 for fluridone and 48 for terbutryn. Liver, intestine, and pyloric caeca of adult rainbow trout accumulated the highest residues of (14C)-fluridone and -terbutryn. Most of the radioactivity was found to be in the form of fluridone or 4-hydroxyfluridone (1-methyl-3-(4-hydroxyphenyl)-5-(3-trifluoromethyl phenyl)-4(1H)-pyridinone) while terbutryn and de-ethylated terbutryn (2-amino-4-(t-butylamino)-6-(methylthio)-s-triazine) were the major products in tissues of fish exposed to terbutryn. Accumulation of (14C)-fluridone and -terbutryn by chironomid larvae was studied in sediment spiked with 0.5 and 0.05 μg/g of each herbicide. Larvae in contact with sediment accumulated levels of radioactivity of both herbicides that were similar to the levels in larvae held in a screened cup above the sediment.