A highly regiospecific synthesis of a series of indenoindoles is reported, together with X-ray studies and their activity against human prostate cancer cells PC-3 and LNCaP in vitro. The most effective compound 7,7-dimethyl-5-[(3,4-dichlorophenyl)]-(4bRS,9bRS)-dihydroxy-4b,5,6,7,8,9bhexahydro-indeno[1,2-b]indole-9,10-dione 7q reduced the viability in both cell lines in a time and dose-dependent manner. Inhibitory effects were also observed on the adhesion, migration, and invasion of the prostate cancer cells as well as on clonogenic possibly by inhibition of MMP-9 activity. Molecular docking of 7q and 6k into MMP-9 human active site was also performed to determine the probable binding mode.
Antineoplastic Agents/pharmacology , Indenes/pharmacology , Indoles/pharmacology , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase Inhibitors/pharmacology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/enzymology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Indenes/chemical synthesis , Indenes/chemistry , Indoles/chemical synthesis , Indoles/chemistry , Male , Matrix Metalloproteinase Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors/chemistry , Molecular Docking Simulation , Molecular Structure , Prostatic Neoplasms/pathology , Structure-Activity Relationship
A series of phenylsubstituted pyrazolo and pyrimido benzothiazine dioxide derivatives were synthesized and investigated for their abilities to inhibit beta-hematin formation, hemoglobin hydrolysis and in vivo for their antimalarial efficacy in rodent Plasmodium berghei. Compounds 3-amino-7-chloro-9-(2'-methylphenyl)-1,9-dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2b and 2,4-diamino-8-chloro-10H-phenyl-pyrimido-[5,4-b]benzothiazine 5,5-dioxide 3a were the most promising as inhibitors of hemoglobin hydrolysis, however, their effect as inhibitors of beta-hematin formation was marginal, except for compound 3-amino-7-chloro-9-(3'-chlorophenyl)-1,9dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2g. The most active compound to emerge from the in vitro and in vivo murine studies was 2b, suggesting an antimalarial activity via inhibition of hemoglobin hydrolysis, however, not as efficient as chloroquine.
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Plasmodium berghei/drug effects , Thiazines/chemical synthesis , Thiazines/pharmacology , Animals , Antimalarials/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Spectrophotometry, Infrared , Thiazines/chemistry
An improved procedure for the synthesis of 3-amino-9-arylsubstituted-thieno[3,2-b]benzothiazine S,S-dioxide 2-decarboxylated is reported. Thieno-[3,2-b]benzothiazine S,S-dioxide derivatives were investigated for their abilities to inhibit beta-hematin formation, hemoglobin hydrolysis and in vivo for their efficacy in rodent Plasmodium berghei. Compounds 5j-o were the most promising as inhibitors of hemoglobin hydrolysis, however, the compounds are not as efficient as chloroquine. A structure-activity relationship (SAR) study was carried out in this series. Our results allow us to determine the minimal structural requirements to produce the biological response.
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Benzene/chemistry , Oxides/chemistry , Thiazines/chemical synthesis , Thiazines/pharmacology , Animals , Antimalarials/chemistry , Crystallography, X-Ray , Globins/metabolism , Hemeproteins/biosynthesis , Mice , Models, Molecular , Molecular Structure , Plasmodium berghei/drug effects , Static Electricity , Structure-Activity Relationship , Thiazines/chemistry
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.
Anti-Inflammatory Agents/chemical synthesis , Chalcone/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/pharmacology , Cell Line , Chalcone/administration & dosage , Chalcone/chemical synthesis , Dimethylamines/administration & dosage , Dimethylamines/chemical synthesis , Dimethylamines/pharmacology , Dinoprostone/antagonists & inhibitors , Dinoprostone/biosynthesis , Drug Evaluation, Preclinical , Edema/drug therapy , Edema/prevention & control , Enzyme Induction/drug effects , Macrophages/cytology , Macrophages/drug effects , Macrophages/metabolism , Mice , Nitric Oxide Synthase/biosynthesis , Nitric Oxide Synthase Type II , Structure-Activity Relationship
