Evaluation of the anti-inflammatory and analgesic activity of Me-UCH9, a dual cyclooxygenase-2/5-lipoxygenase inhibitor.

Recently, we reported the dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) activity by some phenylsulphonyl urenyl chalcone derivatives. 2,4-dichloro-4'N[N'(4''methylphenylsulphonyl)urenyl] chalcone (Me-UCH9), was selected in the present study to determine its potential anti-inflammatory and analgesic effect after oral administration in several animal models related to the activation of COX-2 and 5-LO pathways. In the zymosan stimulated mouse air pouch model, Me-UCH9, reduced in a dose-dependent manner leukotriene B(4) (LTB(4)) levels in pouch exudates obtained at 4 h, as well as prostaglandin E(2) (PGE(2)) generated through COX-2 activation at 24 h. Tumor necrosis factor alpha (TNF-alpha) and myeloperoxidase activity were also strongly inhibited in this model. Me-UCH9 significantly reduced granuloma size and vascular index determined in the murine air pouch granuloma model of angiogenesis. In the carrageenan-induced paw edema, this compound inhibited inflammatory response and pain, as well as PGE(2) and LTB(4) content in paw edematous fluid. Analgesic properties were corroborated in the murine phenyl-p-benzoquinone-induced writhing test. Finally, Me-UCH9 exerted anti-inflammatory effects in the chronic model of rat adjuvant-induced arthritis, both inhibiting paw swelling and reducing PGE(2) content. Our findings confirm that Me-UCH9 can modulate inflammatory and nociceptive responses in relation to the dual inhibition of COX-2 and 5-LO activities presented by this compound.

Phenylsulphonyl urenyl chalcone derivatives as dual inhibitors of cyclo-oxygenase-2 and 5-lipoxygenase.

Two series of phenylsulphonyl urenyl chalcone derivatives (UCH) with various patterns of substitution were tested for their effects on nitric oxide (NO) and prostaglandin E2 (PGE2) overproduction in RAW 264.7 macrophages. None of the tested compounds reduced NO production more than 50% at 10 microM but most of them inhibited the generation of PGE2 with IC50 values under the micromolar range. Me-UCH 1, Me-UCH 5, Me-UCH 9, Cl-UCH 1, and Cl-UCH 9 were selected to evaluate their influence on human leukocyte functions and eicosanoids generation. These derivatives selectively inhibited cyclo-oxygenase-2 (COX-2) activity in human monocytes being Me-UCH 5 the most potent (IC50 0.06 microM). Selected compounds also reduced leukotriene B4 synthesis in human neutrophils by a direct inhibition of 5-lipoxygenase (5-LO) activity, with IC50 values from 0.5 to 0.8 microM. In addition, lysosomal enzyme secretion, such as elastase or myeloperoxidase as well as superoxide generation in human neutrophils were also reduced in a similar range. Our findings indicate that UCH derivatives exert a dual inhibitory effect on COX-2/5-LO activity. The profile and potency of these compounds may have relevance for the modulation of the inflammatory and nociceptive responses with reduction of undesirable side-effects associated with NSAIDs.

A new chloroquinolinyl chalcone derivative as inhibitor of inflammatory and immune response in mice and rats.

The synthetic chalcone derivative 1-(2,4-dichlorophenyl)-3-(3-(6,7-dimethoxy-2-chloroquinolinyl))-2-propen-1-one (ClDQ) was evaluated for its anti-inflammatory, analgesic and immunomodulatory efficacy in-vitro and in-vivo. ClDQ concentration-dependently inhibited the production of nitric oxide (NO) (IC50 4.3 microM) and prostaglandin E(2) (PGE(2)) (IC50 1.8 microM) in RAW 264.7 macrophages stimulated with lipopolysaccharide. Human mononuclear cell proliferation was significantly inhibited by 10 microM ClDQ. Oral administration of ClDQ (10-30 mg kg(-1)) in the 24-h zymosan-stimulated mouse air-pouch model produced a dose-dependent reduction of cell migration as well as NO and PGE(2) levels in exudates. ClDQ (20 mg kg(-1), p.o.) inhibited ear swelling and leucocyte infiltration in the delayed-type hypersensitivity response to 2,4-dinitrofluorobenzene in mice. In the rat adjuvant-arthritis model, this compound reduced joint inflammation as well as PGE(2) and cytokine levels. In addition, ClDQ displayed analgesic effects in the phenylbenzoquinone-induced abdominal constriction model in mice and in the late phase of the nociceptive response to formalin. Our findings indicated the potential interest of ClDQ in the modulation of some immune and inflammatory conditions.

1-(2,3,4-trimethoxyphenyl)-3-(3-(2-chloroquinolinyl))-2-propen-1-one, a chalcone derivative with analgesic, anti-inflammatory and immunomodulatory properties.

OBJECTIVE AND DESIGN: The synthetic chalcone derivative 1-(2,3,4-trimethoxyphenyl)-3-(3-(2-chloroquinolinyl))-2-propen-1-one (TQ) was evaluated for its immunomodulatory and anti-inflammatory efficacy in vitro and in vivo. MATERIAL AND SUBJECTS: Human neutrophils and lymphocytes from healthy volunteers and RAW 264.7 murine macrophages. Swiss mice and Lewis rats were randomly divided into groups of six animals. TREATMENT: TQ was orally administered in all in vivo assays (10-30 mg/kg). METHODS: Elastase, superoxide and LTB(4) release were assayed in human neutrophils, NO/PGE(2) production and NF-kappaB activation in RAW 264.7, and (3)H thymidine incorporation in human lymphocytes. Zymosan-stimulated air pouches, DNFB-DTH, PBQ-induced writhings and formalin-induced pain were assayed in mice. Adjuvant-induced arthritis was tested in rats. Dunnett's t-test was employed for statistical analysis. RESULTS: Human T-cell proliferation, neutrophil functions and NO/PGE(2) production in murine macrophages were inhibited by TQ (IC(50) in the microM range), which showed anti-inflammatory, immunomodulatory and analgesic effects. CONCLUSIONS: Our findings indicate the potential interest of TQ in the modulation of some immune and inflammatory responses probably by NF-kappaB inhibition.

Divergent expression of delayed rectifier K(+) channel subunits during mouse heart development.

The repolarization phase of the cardiac action potential is dependent on transmembrane K(+) currents. The slow (I(Ks)) and fast (I(Kr)) components of the delayed-rectifier cardiac K(+) current are generated by pore-forming alpha subunits KCNQ1 and KCNH2, respectively, in association with regulatory beta-subunit KCNE1, KCNE2 and perphaps KCNE3. In the present study we have investigated the distribution of transcripts encoding these five potassium channel-forming subunits during mouse heart development as well as the protein distribution of KCNQ1 and KCNH2. KCNQ1 and KCNH2 mRNAs (and protein) are first expressed at embryonic day (E) 9.5, showing comparable levels of expression within the atrial and ventricular myocardium during the embryonic and fetal stages. In contrast, the beta-subunits display a more dynamic pattern of expression during development. KCNE1 expression is first observed at E9.5 throughout the entire myocardium and progressively is confined to the ventricular myocardium. With further development (E16.5), KCNE1 expression is mainly confined to the compact ventricular myocardium. KCNE2 is first expressed at E9.5 and it is restricted already to the atrial myocardium. KCNE3 is first expressed at E8.5 throughout the myocardium and with further development, it becomes restricted to the atrial myocardium. The fact that alpha subunits are homogeneously distributed within the myocardium, whereas the beta subunits display a regionalized expression profile during cardiac development, suggest that differences in the slow and fast component of the delayed-rectifier cardiac K(+) currents between the atrial and the ventricular cardiomyocytes are mainly determined by differential beta-subunit distribution.

In vitro antifungal evaluation and structure-activity relationships of a new series of chalcone derivatives and synthetic analogues, with inhibitory properties against polymers of the fungal cell wall.

Here we report the synthesis, in vitro antifungal evaluation and SAR study of 41 chalcones and analogues. In addition, all active structures were tested for their capacity of inhibiting Saccharomyces cerevisiae beta(1,3)-glucan synthase and chitin synthase, enzymes that catalyze the synthesis of the major polymers of the fungal cell wall.

Synthesis of quinolinyl chalcones and evaluation of their antimalarial activity.

Quinolinyl chalcones were synthesized and evaluated for their inhibition of the Plasmodium falciparum cystein protease falcipain and their activity against cultured P. falciparum parasites. They were also tested for in vivo efficacy in a rodent P. berghei model. Their activity against falcipain and as antimalarials was moderate, but antimalarial activity was probably not due to the inhibition of falcipain and may follow a different mechanism. 1-(2,4-Dichlorophenyl)-3-[3-(2-chloro-6,7-dimethoxiquinolinyl)]-2-propen-1-one 3j was the most promising compound among those here reported (IC50 19.0 microM).

4-dimethylamino-3',4'-dimethoxychalcone downregulates iNOS expression and exerts anti-inflammatory effects.

Reactive oxygen and nitrogen species contribute to the pathophysiology of inflammatory conditions. We have studied the effects of a novel superoxide scavenger, 4-dimethylamino-3', 4'-dimethoxychalcone (CH11) in macrophages and in vivo. CH11 has been shown to inhibit the chemiluminescence induced by zymosan in mouse peritoneal macrophages and the cytotoxic effects of superoxide. In the same cells, the modulation by superoxide of nitric oxide (NO) production in response to zymosan was investigated. CH11 was more effective than the membrane-permeable scavenger Tiron for inhibition of inducible nitric oxide synthase (iNOS) protein expression and nitrite production. We have shown that CH11 inhibited chemiluminescence in vivo, as well as cell migration, and eicosanoid and tumor necrosis factor-alpha (TNF-alpha) levels in the mouse air pouch injected with zymosan. This chalcone derivative also exerted anti-inflammatory effects in the carrageenan paw oedema.

Novel anti-inflammatory chalcone derivatives inhibit the induction of nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages.

In a previous work, we tested a series of chalcone derivatives as possible anti-inflammatory compounds. We now investigate the effects of three of those compounds, CHI, CH8 and CH12, on nitric oxide and prostanoid generation in mouse peritoneal macrophages stimulated with lipopolysaccharide and in the mouse air pouch injected with zymosan, where they showed a dose-dependent inhibition with inhibitory concentration 50% values in the microM range. This effect was not the consequence of a direct inhibitory action on enzyme activities. Our results demonstrated that chalcone derivatives inhibited de novo inducible nitric oxide synthase and cyclooxygenase-2 synthesis, being a novel therapeutic approach for inflammatory diseases.

Synthesis and anti-inflammatory activity of chalcone derivatives.

Chalcones and their derivatives were synthesized and evaluated for their anti-inflammatory activity. In vitro, chalcones 2, 4, 8, 10 and 13 inhibited degranulation and 5-lipoxygenase in human neutrophils, whereas 11 behaved as scavenger of superoxide. Only four compounds (4-7) inhibited cyclo-oxygenase-2 activity. The majority of these samples showed anti-inflammatory effects in the mouse air pouch model.

Synthesis and antimalarial effects of phenothiazine inhibitors of a Plasmodium falciparum cysteine protease.

Acridinediones have previously been shown to have potent antimalarial activity. A series of sulfur isosteres of acridinediones have been synthesized and evaluated for their inhibition of the Plasmodium falciparum cysteine protease falcipain and for their antimalarial activity. A number of these phenothiazines inhibited falcipain and demonstrated activity against cultured P. falciparum parasites at low micromolar concentrations. We propose that the compounds exerted their antimalarial effects by two mechanisms, one of which involves the inhibition of falcipain and a consequent block in parasite degradation of hemoglobin. These compounds and related phenothiazines are worthy of further study as potential antimalarial agents.

N-aralkyl substitution of 2-aminoindans. Synthesis and their inotropic and chronotropic activity in isolated guinea pig atria.

Amino substitution of rigid forms of dopamine 4,5-dihydroxy-2-aminoindan and 5,6-dihydroxy-2-aminoindan with aralkyl functionalities were carried out to investigate the role of such structural modifications upon cardiac inotropic-chronotropic activity. Compounds synthesized demonstrated a modest inotropic selectivity, while one of them, described as 5,6-dihydroxy-N-[2-(4-hydroxyphenyl)-1-methylethyl]-2-aminoindan hydrobromide 17, showed a marked inotropic action on isolated heart tissue.

In vitro antimalarial activity of chalcones and their derivatives.

A series of chalcones and their derivatives have been synthesized and identified as novel potential antimalarials using both molecular modeling and in vitro testing against the intact parasite. A large number of chalcones and their derivatives were prepared using one-step Claisen-Schmidt condensations of aldehydes with methyl ketones. These condensates were screened in vitro against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and shown to be active at concentrations in the nanomolar range. The most active chalcone derivative, 1-(2,5-dichlorophenyl)-3-(4-quinolinyl)-2-propen-1-one (7), had an IC50 value of 200 nM against both a chloroquine-resistant strain (W2) and a chloroquine-sensitive strain (D6). The resistance indexes for all compounds were substantially lower than for chloroquine, suggesting that this series will be active against chloroquine-resistant malaria. Structure-activity relationships (SAR) of the chalcones in the context of a homology-based model structure of the malaria trophozoite cysteine protease, the most likely target enzyme, are presented.

Synthesis of bicyclic ketones in prostaglandins and their antimitotic activity.

The synthesis of a second ring in the prostaglandin structure, located at positions C-11 and C-13, has been accomplished starting from prostaglandin A2. Also an efficient enantioselectivity was obtained through the conjugate addition of carbanions at position C-11, together with the stereospecificity of a Claisen rearrangement at position C-13. Evaluation of the inhibitory effects on the proliferation of the K-562 cell line, in vitro, is presented. A structure-activity relationship indicated that alterations of the functional groups incorporated in the second ring of the prostaglandin structure affected their hydrophobicity. The antimitotic activity for prostanoids 7b, 7c and 7e have shown substantial improvements in their activities according to their ID50 values (12.5, 9.0 and 1.12 micrograms/ml), respectively). Attention is called to the importance of derivative 7a in terms of its high potency, determined by its ID50 values (0.35 micrograms/ml).

Synthesis of C(10)-halogenated prostaglandins.

The synthesis of halogenated prostaglandins at position C(10), starting from prostaglandin A2, has been accomplished, as well as an efficient regioselective hydroxylation of the upper chain of the prostanoid structure. Evaluation of the inhibitory effects on the proliferation of the K-562 cell line in vitro is presented. When the prostaglandin was modified in the upper chain, the antimitotic activity for bromo derivatives 4b, c and iodo derivative 5b had shown substantial improvements in their activities according to their ID50 values (28, 25, and 22 micrograms/mL, respectively). Attention is called to the significance of chloro derivative 3a in terms of its high potency, determined by its ID50 value (0.06 micrograms/mL).

The prostaglandins: an introduction.

Se presenta una introduccion en el campo de las prostaglandinas, incluye historia, nomenclatura, procedencia y una breve descripcion de las propiedades biologicas.Asi como tambien se reporta la sintesis de algunas de ellas