Synthesis and antimalarial activity of urenyl Bis-chalcone in vitro and in vivo.

Some novel derivatives of Bis-chalcone were synthesized and characterized by their physical and spectral data. All the synthesized compounds were subsequently screened for in vitro globin hydrolysis, ß-hematin formation, and murine Plasmodium berghei, using chloroquine as the reference drug. Most of the synthesized compounds exhibited mild to moderate susceptibilities toward the parasite in comparison with the standard. The most active antimalarial compound was 1,1-Bis-[(3',4'-N-(urenylphenyl)-3-(3″,4″,5″-trimethoxyphenyl)]-2-propen-1-one 5, with a percentage of inhibition of heme polymerization of 87.05 ± 0.77, and this compound increased the survival time after infection, reduce the parasitemia and delay the progression of malaria.

Synthesis of chlorovinyl sulfones as structural analogs of chalcones and their antiplasmodial activities.

The synthesis of novel chlorovinyl sulfone-like chalcone derivatives and their antimalarial activity against cultured Plasmodium falciparum parasites, hemozoin formation, hemoglobin hydrolysis and murine malaria model are described. Compounds were prepared via Claisen-Schmidt condensation from available chloromethylphenyl sulfones with substituted aldehydes. Antiplasmodial IC(50) activity of these compounds ranged between 0.025 and 10 microM, those that blocked P. falciparum development at low micro molar concentrations were tested in a murine Plasmodium berghei model, and these compounds delayed the progression of malaria but did not eradicate infections. Much effort and attention are needed for discovery and development of new and less toxic antimalarial drugs.

Synthesis and evaluation of sulfonylurea derivatives as novel antimalarials.

We have synthesized a series of sulfonylureas and have tested their antimalarial activities, including inhibition of in vitro development of a chloroquine-resistant strain of Plasmodium falciparum, in vitro hemoglobin hydrolysis, hemozoin formation, and development of Plasmodium berghei in murine malaria. The most active antimalarial compound was (E)-1-[4'-(3-(2,4-difluorophenyl)acryloyl)phenyl]-3-tosylurea (22) with an IC(50) of 1.2microM against cultured P. falciparum parasites. Biological results suggest a fairly potent antimalarial activity for this derivative, but also imply that its activity may arise from an unknown mechanism. Indeed, these compounds may act against malaria parasites through multiple mechanisms.

Synthesis and antimalarial activity of E-2-quinolinylbenzocycloalcanones.

A series of E-2-quinolinylbenzocycloalcanones 5-21 were prepared and evaluated for their activity to inhibit beta-hematin formation and the hydrolysis of hemoglobin in vitro. Positive compounds for both assays were also tested for their efficacy in rodent Plasmodium berghei. Compounds 6, 16, 19, and 20, were the most promising. Inhibition of beta-hematin formation was minimal when a hydrogen or methoxy groups were present on the position 8 of the quinoline and position 4' of the indanone ring as it appeared for compounds 5, 7-15, 17, 18, and 21, and greatest with compounds (52%) and (90%) with a substitution of methoxy on position 6 and 7 or methyl on position 8 of the quinoline nucleus and methoxy or methyl groups on position 4' of the indanone. The most active compound to emerge from this study is 2-chloro-8-methyl-3-[(4'-methoxy-1'-indanoyl)-2'-methyliden]-quinoline 20 effective as antimalarial that target beta-hematin formation and the inhibition of the hydrolysis of hemoglobin in vitro together with a good survival in a murine malaria model, which should help delay the rapid onset of resistance to drugs acting at only a single site. Results with these assays suggest that quinolinylbenzocycloalcanones exert their antimalarial activity via multiple mechanisms.

Synthesis and evaluation of new antimalarial phenylurenyl chalcone derivatives.

Phenylurenyl chalcone derivatives have been synthesized and tested as inhibitors of in vitro development of a chloroquine-resistant strain of Plasmodium falciparum, activity of the cysteine protease falcipain-2, in vitro globin hydrolysis, beta-hematin formation, and murine Plasmodium berghei malaria. The most active antimalarial compound was 1-[3'-N-(N'-phenylurenyl)phenyl]-3(3,4,5-trimethoxyphenyl)-2-propen-1-one 49, with an IC(50) of 1.76 microM for inhibition of P. falciparum development. Results suggest that chalcones exert their antimalarial activity via multiple mechanisms.

Synthesis and antimalarial activity of sulfonamide chalcone derivatives.

A series of sulfonamide chalcone derivatives were synthesized and investigated for their abilities to inhibit beta-hematin formation in vitro and their activity against cultured Plasmodium falciparum parasites. Inhibition of beta-hematin formation was minimal in the aromatic ring of the chalcone moiety as it appeared for compounds 4b, 4d-f, and greatest with compounds 4g (IC50 0.48 microM) and 4k (IC50 0.50 microM) with a substitution of 3,4,5-trimethoxyl and 3-pyridinyl, respectively. In this study, the most active compound resulted 1[4'-N(2'',5''-dichlorophenyl) sulfonyl-amidephenyl]-3-(4-methylphenyl)-2-propen-1-one 4i, effective as antimalarial by the inhibition of cultured P. falciparum parasites (1 microM). These studies open up the novel possibility of development of sulfonamide derivatives as antimalarials that target beta-hematin formation and the inhibition of the development of cultured P. falciparum parasites, which should help delay the rapid onset of resistance to drugs acting at only a single site. Results with these assays suggest that chalcones exert their antimalarial activity via multiple mechanisms.

Role of nuclear factor-kappaB and heme oxygenase-1 in the mechanism of action of an anti-inflammatory chalcone derivative in RAW 264.7 cells.

The synthetic chalcone 3',4',5',3,4,5-hexamethoxy-chalcone (CH) is an anti-inflammatory compound able to reduce nitric oxide (NO) production by inhibition of inducible NO synthase protein synthesis. In this work, we have studied the mechanisms of action of this compound. CH (10-30 microm) prevents the overproduction of NO in RAW 264.7 macrophages stimulated with lipopolysaccharide (1 microg ml(-1)) due to the inhibition of nuclear factor kappaB (NF-kappaB) activation. We have shown that treatment of cells with CH results in diminished degradation of the NF-kappaB-IkappaB complex leading to inhibition of NF-kappaB translocation into the nucleus, DNA binding and transcriptional activity. We also demonstrate the ability of this compound to activate NfE2-related factor (Nrf2) and induce heme oxygenase-1 (HO-1). Our results indicate that CH determines a rapid but nontoxic increase of intracellular oxidative species, which could be responsible for Nrf2 activation and HO-1 induction by this chalcone derivative. This novel anti-inflammatory agent simultaneously induces a cytoprotective response (HO-1) and downregulates an inflammatory pathway (NF-kappaB) with a mechanism of action different from antioxidant chalcones.

Therapeutic administration of 3,4,5-trimethoxy-4'-fluorochalcone, a selective inhibitor of iNOS expression, attenuates the development of adjuvant-induced arthritis in rats.

We have previously investigated the effects of a series of dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, on nitric oxide production in LPS-stimulated murine RAW 264.7. The present study was designed to determine if 3,4,5-trimethoxy-4'-fluorochalcone (CH 17) could modulate the production of NO and/or prostaglandins in vivo. On the mouse macrophage cell line RAW 264.7 CH 17 inhibited dose-dependently NO production, with an IC(50) value in the nanomolar range, and reduced PGE(2) levels by a 58% at 10 microM. This compound had no direct inhibitory effect on iNOS and COX-2 activities. NO reduction was the consequence of inhibition of the expression of iNOS. In vitro experiments indicated that CH 17 is an inhibitor of the nuclear factor-kappaB (NF-kappaB) pathway of cellular activation in macrophages. This compound exhibited in vivo an inhibitory behaviour correlated with its in vitro results on nitrite and PGE(2) accumulation. In the rat adjuvant-induced arthritis, oral administration of CH 17 (25 mg/kg) on days 17-24 after adjuvant injection, significantly inhibited paw oedema, protected from weight loss and reduced the levels of inflammatory mediators (nitrites and PGE(2)) in paw homogenates, without affecting PGE(2) levels in stomach homogenates. The profile and potency of this compound, a selective inhibitor of iNOS expression that interferes with NF-kappaB activation, may have relevance for the inhibition of the inflammatory response, representing a new approach to the modulation of different inflammatory pathologies.

ttCH, a selective inhibitor of inducible nitric oxide synthase expression with antiarthritic properties.

In a previous work, we investigated the effects of a series of dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, on nitric oxide production in lipopolysaccharide-stimulated murine RAW 264.7 cells. The present study was designed to determine if 2,4,6-trimethoxy-2'-trifluoromethylchalcone (ttCH) could modulate the production of nitric oxide (NO) and/or prostaglandins in vitro and in vivo. On the mouse macrophage cell line RAW 264.7, ttCH inhibited dose-dependently NO and prostaglandin E(2) production, with IC(50) in the micromolar range. This compound had no direct inhibitory effect on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 activities. NO reduction was the consequence of inhibition of the expression of iNOS. This compound also exhibited in vivo an inhibitory behaviour on nitrite and prostaglandin E(2) levels. We have assessed the effect of ttCH in the treatment of acute and chronic inflammatory processes such as the mouse carrageenan paw oedema and the rat adjuvant-induced arthritis. The present study demonstrated that ttCH exerts acute and chronic anti-inflammatory effects that may be related with the inhibition of iNOS expression.

Chemotherapeutic agents against malaria: what next after chloroquine?

This is a general review of currently available antimalarial drugs, these compounds are gathered according with its chemical structure and the biological targets. A great number of these new antimalarial agents are now moving actively in the pipeline from basic science to clinical studies.

Synthesis and inhibitory activity of dimethylamino-chalcone derivatives on the induction of nitric oxide synthase.

A series of nine dimethylamino-chalcone derivatives (1,3-diaryl-propenones) was synthesized and screened as potential inhibitors of NO and PGE(2) production in the RAW 264.7 macrophage cell line. 4-Dimethylamino-2',5'-dimethoxychalcone (6) was found to be the most potent and dual inhibitor (IC(50s) in the submicromolar range) of NO and PGE(2) production. 2',6'-Dimethoxylation appeared to be an effective requirement for selective and potent inhibition of nitric oxide synthase induction as it was confirmed by Western blot analysis. Chalcone (6) at 25 mg kg(-1) by oral route, inhibited significantly the formation of oedema in the carrageenan-induced model of inflammation in mice.

The synthesis and effect of fluorinated chalcone derivatives on nitric oxide production.

Dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, were synthesized and evaluated for their influence on nitric oxide production. Some of them, chalcones 1, 5, 7, 10, 11 and 17, inhibited NO production with an IC(50) in the submicromolar range; 17 is especially noteworthy because of its potency (IC(50) 30nM). These effects were not the consequence of a direct inhibitory action on enzyme activity but the inhibition of enzyme expression.

Synthesis and antimalarial activity of substituted pyrazole derivatives.

The development of new antimalarial drugs is an urgent priority considering the increasing prevalence of drug-resistant Plasmodium falciparum parasites. A series of pyrazoles are described as part of efforts directed toward the synthesis of some potent antimalarial agents. The replacement of the ester group as a substituent in the pyrazole ring by nitrile group caused a precipitous loss of activity as antimalarial due to the lack of hydrogen-bond formation. Further modification of the heterocyclic ring to give substituted aryl derivatives afforded potent antimalarial derivatives: methyl 5-amino-3-anisidinepyrazole-4-carboxylic acid 3a (IC50: 0.149 mumol/l) and methyl 5-amino-3-(m anisidin)pyrazole-4-carboxylic acid 3c (IC50: 0.15 mumol/l). The synthesis, structure-activity relationships (SAR), X-ray crystallography and pharmacological activity associated with these series of compounds are discussed.

Prostaglandinas obtenidas a partir del coral blando Plexaura homomalla y algunas modificaciones quimicas / Prostaglandins obtained from soft coral Plexaura homomalla and some chemical modifications

El presente estudio, es parte de un programa de investigación de la vida marina en la costa de Venezuela, donde fueron identificados varios derivados prostanoicos extraídos del coral blando Plexaura homomalla y se hicieron algunas modificaciones quimicas a la estructura del intermediario PGA. 2.

Síntesis de éteres cíclicos prostanoides con actividad hematológica o inmunológica / Synthesis of prostandid cyclic ethers with hematological or inmunological activity

En este trabajo se presenta la síntesis de algunos éteres cíclicos prostanoides, análogos de la prostaciclina obtenidos partiendo del intermediario PGA2 (extraído del coral blando Plexura homomalla, recolectado en la costa note de Venezuela); conjuntamente con algunas pruebas farmacológicas preminares en el área de inmunología o hematología