ABSTRACT
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).
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Chalcone/analogs & derivatives , Chalcone/pharmacology , Quinolones/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/therapeutic use , Chalcone/chemical synthesis , Chalcone/therapeutic use , Drug Design , Drug Evaluation, Preclinical , Endopeptidases/metabolism , Gas Chromatography-Mass Spectrometry , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Malaria/drug therapy , Male , Mice , Mice, Inbred BALB C , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Quinolones/chemical synthesis , Quinolones/chemistry , Quinolones/therapeutic use , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Chalcone/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Inflammation/drug therapy , Nitric Oxide Synthase/genetics , 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology , Animals , Anti-Inflammatory Agents/therapeutic use , Carrageenan , Chalcone/analogs & derivatives , Chalcone/therapeutic use , Chalcones , Edema/chemically induced , Edema/drug therapy , Enzyme Inhibitors/pharmacology , Female , Free Radical Scavengers , Luminescent Measurements , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/physiology , Mice , Nitric Oxide/biosynthesis , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase Type II , Oxidative Stress , Respiratory Burst/drug effects , Superoxides/pharmacology , Zymosan/pharmacologyABSTRACT
Compound 2 considered as a rigid non-hydroxylated 2-amino tetralin was synthesized and biologically evaluated. Central administration of compound 2 (50 microg or 100 microg/10 microl) induced a reduction in urinary sodium and potassium excretion at 3 and 6 h of urine collection. We speculate that compound 2 may be acting as a dopamine receptor antagonist.
Subject(s)
Amines/pharmacology , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Heterocyclic Compounds/pharmacology , Phenalenes , Polycyclic Compounds/pharmacology , Receptors, Dopamine D1/antagonists & inhibitors , Amines/chemical synthesis , Amines/chemistry , Animals , Diuresis/drug effects , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/chemistry , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Male , Molecular Structure , Natriuresis/drug effects , Polycyclic Compounds/chemical synthesis , Polycyclic Compounds/chemistry , Potassium/urine , Rats , Rats, Sprague-Dawley , Sodium/urineABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Chalcone/analogs & derivatives , Isoenzymes/biosynthesis , Macrophages, Peritoneal/enzymology , Nitric Oxide Synthase/biosynthesis , Prostaglandin-Endoperoxide Synthases/biosynthesis , Animals , Cyclooxygenase 2 , Dinoprostone/biosynthesis , Dose-Response Relationship, Drug , Enzyme Induction/drug effects , Female , Lipopolysaccharides/pharmacology , Mice , Nitric Oxide Synthase Type II , Nitrites/metabolism , Zymosan/pharmacologyABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Chalcone/analogs & derivatives , Chalcone/chemical synthesis , Propiophenones/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arachidonate 5-Lipoxygenase/blood , Chalcone/chemistry , Chalcone/pharmacology , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/pharmacology , Drug Design , Humans , Isoenzymes/blood , Leukotriene B4/blood , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemistry , Lipoxygenase Inhibitors/pharmacology , Membrane Proteins , Mice , Molecular Structure , Neutrophils/drug effects , Neutrophils/physiology , Propiophenones/chemistry , Propiophenones/pharmacology , Prostaglandin-Endoperoxide Synthases/blood , Structure-Activity RelationshipABSTRACT
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.
