Design, synthesis, antimicrobial activity and molecular modeling studies of novel benzofuroxan derivatives against Staphylococcus aureus

Molecular modi. cation is a quite promising strategy in the design and development of drug analogs with better bioavailability, higher intrinsic activity and less toxicity. In the search of new leads with potential antimicrobial activity, a new series of 14 4-substituted [N`-(benzofuroxan-5-yl) methylene] benzohydrazides, nifuroxazide derivatives, were synthesized and tested against standard and multidrug-resistant Staphylococcus aureus strains. The selection of the substituent groups was based on physicochemical properties, such as hydrophobicity and electronic effect. These properties were also evaluated through the lipophilic and electrostatic potential maps, respectively, considering the compounds with better biological pro. le. Twelve compounds exhibited similar bacteriostatic activity against standard and multidrug-resistant strains. The most active compound was the 4-CF(3) substituted derivative, which presented a minimum inhibitory concentration (MIC) value of 14.6-13.1 mu g/mL, and a ClogP value of 1.87. The results highlight the benzofuroxan derivatives as potential leads for designing new future antimicrobial drug candidates. (C) 2009 Elsevier Ltd. All rights reserved.

Synthesis of potassium and tetra n-butylammonium 2-substituted-1,3-dithianotrifluoroborate salts and addition to chiral cyclic N-acyliminium ions

The synthesis of potassium 2-substituted-1,3-dithianotrifluoroborate salts and tetra-n-butyl ammonium derivatives is described. The reaction proceeds under mild reaction conditions and the corresponding products were obtained in moderate to good yields. The reactivity of these compounds in rections with chiral cyclic N-acyliminium ions was evaluated.

Ultrasound-assisted synthesis of functionalized 1,3-enynes by palladium-catalyzed cross-coupling reaction of alpha-styrylbutyltelluride with alkynyltrifluoroborate salts

An ultrasound-assisted synthesis of functionalized 1,3-enyne scaffolds is described and illustrated by palladium-catalyzed cross-coupling of potassium alkynyltrifluoroborate salts and alpha-styrylbutyltellurides. This procedure offers easy access to 1,3-enyne architecture that contains aliphatic and aromatic groups in good to excellent yields.

Synthesis of 2-Aryl- and 2,5-Diarylfurans and Thiophenes by Suzuki-Miyaura Reactions Using Potassium Trifluoroborate Salts and Heteroaryltellurides

The Suzuki-Miyaura cross-coupling reaction of 2-(butyltellanyl) or 2,5-bis-(butyltellanyl)furans and thiophenes with potassium aryltrifluoroborate salts catalyzed by palladium afforded 2-aryl- or 2,5-diaryl-furans and thiophenes in moderate to good yields.

Synthesis and characterization of the [Ru(3)O(CH(3)COO)(6)(py)(2)(BPE)Ru(bpy)(2)Cl](PF(6))(2) dimer

The polymetallic [Ru(3)O(CH(3)COO)(6)(py)(2)(BPE)Ru( bpy)(2)Cl](PF(6))(2) complex (bpy = 2,2`-bipyridine, BPE = trans- 1,2-bis(4-pyridil) ethylene and py = pyridine) was assembled by the combination of an electroactive [Ru(3)O] moiety with a [ Ru( bpy) 2( BPE) Cl] photoactive centre, and its structure was determined using positive ion electrospray (ESI-MS) and tandem mass (ESI-MS/MS) spectrometry. The [Ru(3)O(CH(3)COO)(6)(py)(2)(BPE)Ru(bpy)(2)Cl] (2+) doubly charged ion of m/z 732 was mass-selected and subject to 15 eV collision-induced dissociation, leading to a specific dissociation pattern, diagnostic of the complex structure. The electronic spectra display broad bands at 409, 491 and 692 nm ascribed to the [Ru(bpy)(2)(BPE)] charge-transfer bands and to the [Ru(3)O] internal cluster transitions. The cyclic voltammetry shows five reversible waves at - 1.07 V, 0.13 V, 1.17 V, 2.91 V and - 1.29 V (vs SHE) assigned to the [Ru(3)O](-1/0/+ 1/+ 2/+3) and to the bpy (0/-1) redox processes; also a wave is observed at 0.96 V, assigned to the Ru (+2/+ 3) pair. Despite the conjugated BPE bridge, the electrochemical and spectroelectrochemical results indicate only a weak coupling through the pi-system, and preliminary photophysical essays showed the compound decomposes under visible light irradiation.

The antipyretic effect of dipyrone is unrelated to inhibition of PGE(2) synthesis in the hypothalamus

BACKGROUND AND PURPOSE Bacterial lipopolysaccharide (LPS) induces fever through two parallel pathways; one, prostaglandin (PG)-dependent and the other, PG-independent and involving endothelin-1 (ET-1). For a better understanding of the mechanisms by which dipyrone exerts antipyresis, we have investigated its effects on fever and changes in PGE(2) content in plasma, CSF and hypothalamus induced by either LPS or ET-1. EXPERIMENTAL APPROACH Rats were given (i.p.) dipyrone (120 mg center dot kg-1) or indomethacin (2 mg center dot kg-1) 30 min before injection of LPS (5 mu g center dot kg-1, i.v.) or ET-1 (1 pmol, i.c.v.). Rectal temperature was measured by tele-thermometry. PGE(2) levels were determined in the plasma, CSF and hypothalamus by elisa. KEY RESULTS LPS or ET-1 induced fever and increased CSF and hypothalamic PGE(2) levels. Two hours after LPS, indomethacin reduced CSF and hypothalamic PGE(2) but did not inhibit fever, while at 3 h it reduced all three parameters. Three hours after ET-1, indomethacin inhibited the increase in CSF and hypothalamic PGE(2) levels but did not affect fever. Dipyrone abolished both the fever and the increased CSF PGE(2) levels induced by LPS or ET-1 but did not affect the increased hypothalamic PGE(2) levels. Dipyrone also reduced the increase in the venous plasma PGE(2) concentration induced by LPS. CONCLUSIONS AND IMPLICATIONS These findings confirm that PGE(2) does not play a relevant role in ET-1-induced fever. They also demonstrate for the first time that the antipyretic effect of dipyrone was not mechanistically linked to the inhibition of hypothalamic PGE(2) synthesis.

Increase of core temperature induced by corticotropin-releasing factor and urocortin: A comparative study

This study compared the ability of CRF and UCN1 to induce a thermoregulatory response when centrally injected into rats. The effects of antipyretic drugs and CRF receptor antagonists (CRF(1) and CRF(2)) on the temperature (T) changes induced by these peptides were also investigated. Rectal (rT) and tail skin (T(sk)) temperatures were measured with a thermistor probe while body (bT) temperature was measured with a battery-operated biotelemetry transmitter in male Wistar rats (200 g) every 30 min over a period of 6 h, after intracerebroventricular (i.c.v.) injection of 1 nmol of either CRF or UCN1. Rats were pre-treated with indomethacin (2 mg kg(-1), i.p.) or celecoxib (5 mg kg(-1), p.o.), dexamethasone (0.5 mg kg(-1), s.c.), astressin (a CRF(1)/CRF(2) antagonist, 7 nmol, icy.) or antalarmin (a CRF(1) antagonist, 20 mg kg 1, i.p.). The increase in body temperature induced by CRF was accompanied by a reduction in T(sk) while the response induced by UCN1 was accompanied by an elevation in T(sk). Indomethacin or celecoxib did not change the increases in rT caused by either CRF or UCN1. Although dexamethasone attenuated the increase in rectal temperature in response to CRF, dexamethasone did not modify the response induced by UCN1. Astressin blocked the UCN1-induced hyperthermia and reduced CRF-induced fever. Antalarmin did not modify the hyperthermia in response to UCN1, but reduced the fever evoked by CRF. This study demonstrated that CRF by acting on the CRF(1) receptor induces a prostaglandin-independent fever which seems to depend, at least in part, on the synthesis of other mediators while UCN1 acts on the CRF(2) receptor, promoting a hyperthermic response which seems to be independent on synthesis/release of any mediator. (C) 2010 Elsevier B.V. All rights reserved.

Dehydromonocrotaline induces cyclosporine A-insensitive mitochondrial permeability transition/cytochrome c release

Monocrotaline (MCT) is a pyrrolizidine alkaloid present in plants of the genus Crotalaria that causes cytotoxicity and genotoxicity in animals and humans. It is well established that the toxicity of MCT results from its hepatic bioactivation to dehydromonocrotaline (DHM), an alkylating agent, but the exact mechanism of action remains unknown. In a previous study, we demonstrated DHM`s inhibition of mitochondrial NADH-dehydrogenase activity at micromolar concentrations, which is an effect associated with a significant reduction in ATP synthesis. As a follow-up study, we have evaluated the ability of DHM to induce mitochondrial permeability transition (MPT) and its associated processes in isolated rat liver mitochondria. In the presence of 10 mu M Ca(2+), DHM (50-250 mu M) elicited MPT in a concentration-dependent, but cyclosporine A-independent manner, as assessed by mitochondrial swelling, which is associated with mitochondrial Ca(2+) efflux and cytochrome c release. DHM (50-250 mu M) did not cause hydrogen peroxide accumulation but did deplete endogenous glutathione and NAD(P)H, while oxidizing protein thiol groups. These results potentially indicate the involvement of mitochondria, via apoptosis, in the well-documented cytotoxicity of monocrotaline. (C) 2009 Elsevier Ltd. All rights reserved.

Synthesis of indole derivatives by domino hydroformylation/indolization of 2-nitrocinnamaldehydes

The present work furnishes an innovative preparation of substituted indoles based on tandem hydroformylation, where the chemo- and the regio-selectivities are good, so the yield of the reaction. The novelty has been established in the four-step transformation of substituted alpha nitrocinnamaldehydes into desired indoles in a one-pot reaction. Under hydroformylation reaction conditions we have been able to trigger off a cascade of reactions, which gave substituted indoles in high yields. Useful intermediates are prepared by using this technique for the synthesis of well-known biologically active molecules. (C) 2008 Elsevier B.V. All rights reserved.

Use of virtual screening, flexible docking, and molecular interaction fields to design novel HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia

Dietary changes associated with drug therapy can reduce high serum cholesterol levels and dramatically decrease the risk of coronary artery disease, stroke, and overall mortality. Statins are hypolipemic drugs that are effective in the reduction of cholesterol serum levels, attenuating cholesterol synthesis in liver by competitive inhibition regarding the substrate or molecular target HMG-CoA reductase. We have herewith used computer-aided molecular design tools, i.e., flexible docking, virtual screening in large data bases, molecular interaction fields to propose novel potential HMG-CoA reductase inhibitors that are promising for the treatment of hypercholesterolemia.

Reduction of parasitism tissue by treatment of mice chronically infected with Trypanosoma cruzi with lignano lactones

The reduction of parasitism tissue upon treatment with two lignano lactones, namely (-)- cubebin (CUB) and (-)-hinokinin (HNK), was evaluated in the chronic phase of Chagas` disease by quantifying the enzyme beta-galactosidase expressed by the CL B5 clone strain of Trypanosoma cruzi. Tissue karyometry was also performed. Treatment with the assessed lignans led to a larger reduction in parasitism tissue in all evaluated organs, compared with benznidazole (BZN). Oral treatment with CUB or HNK was more effective. Karyometry results demonstrated that the infected control animals had increased nuclear area compared with uninfected controls, indicating cellular hypertrophy. Results also revealed that use of CUB or HNK was able to significantly prevent this increase, and a slight decrease in the nuclear area was observed, compared with mice treated with BZN. Taken together, these data demonstrate that CUB and HNK could be considered as potential compounds for the development of new drugs for treatment of Chagas` disease.

Novel and facile solution-phase synthesis of 2,5-diketopiperazines and O-glycosylated analogs

This work describes the synthesis in Solution of a series of related diketopiperazines with potential biological activities: cyclo(L-Pro-L-Ser), cyclo(L-Phe-L-Ser), cyclo(D-Phe-L-Ser) and the corresponding glycosylated analogs of the latter, cyclo[D-Phe-L-Ser(alpha GlcNAc)] and cyclo[D-Phe-L-Ser(beta GlcNAc)]. The synthetic approach involved coupling reactions of -OH or O-glycosylated serine benzyl esters with NFmoc-protected amino acids (Pro or Phe), followed by one-pot deprotection-cyclization reaction in the presence of 20% piperidine in DMF. (C) 2009 Elsevier Ltd. All rights reserved.

Synthesis of (-)-hinokinin by oxidation of (-)-cubebin catalyzed by biomimetic metalloporphyrin catalytic systems

A catalytic system consisting of iron tetraphenylporphyrin supported on an alumina matrix for oxidation of (-)-cubebin with iodosylbenzene or hydrogen peroxide is reported. Conversion of (-)-cubebin is very efficient (100%) with 100% selectivity producing only (-)-hinokinin when iodosylbenzene is used as the oxidant and 70% conversion with 100% selectivity when hydrogen peroxide is the oxidant at room temperature under atmospheric pressure. (c) 2008 Elsevier B.V. All rights reserved.

Synthesis, antichagasic in vitro evaluation, cytotoxicity assays, molecular modeling and SAR/QSAR studies of a 2-phenyl-3-(1-phenyl-1H-pyrazol-4-yl)-acrylic acid benzylidene-carbohydrazide series

Chagas disease (American trypanosomiasis) is one of the most important parasitic diseases with serious social and economic impacts mainly on Latin America. This work reports the synthesis, in vitro trypanocidal evaluation, cytotoxicity assays, and molecular modeling and SAR/QSAR studies of a new series of N-phenylpyrazole benzylidene-carbohydrazides. The results pointed 6k (X = H, Y = p-NO(2), pIC(50) = 4.55 M) and 6l (X = F, Y = p-CN, pIC(50) = 4.27 M) as the most potent derivatives compared to crystal violet (pIC(50) = 3.77 M). The halogen-benzylidene-carbohydrazide presented the lowest potency whereas 6l showed the most promising pro. le with low toxicity (0% of cell death). The best equation from the 4D-QSAR analysis (Model 1) was able to explain 85% of the activity variability. The QSAR graphical representation revealed that bulky X-substituents decreased the potency whereas hydrophobic and hydrogen bond acceptor Y-substituents increased it. (C) 2008 Elsevier Ltd. All rights reserved.