ABSTRACT
A novel series of thalidomide derivatives (4a-f) designed by molecular hybridization were synthesized and evaluated in vitro and in vivo for their potential use in the oral treatment of sickle cell disease symptoms. Compounds 4a-f demonstrated analgesic, anti-inflammatory, and NO-donor properties. Compounds 4c and 4d were considered promising candidate drugs and were further evaluated in transgenic sickle cell mice to determine their capacity to reduce the levels of the proinflammatory cytokine tumor necrosis factor α (TNFα). Unlike hydroxyurea, the compounds reduced the concentrations of TNFα to levels similar to those induced with the control dexamethasone (300 µmol/kg). These compounds are novel lead drug candidates with multiple beneficial actions in the treatment of sickle cell disease symptoms and offer an alternative to hydroxyurea treatment.
Subject(s)
Anemia, Sickle Cell/drug therapy , Antisickling Agents/chemical synthesis , Antisickling Agents/pharmacology , Drug Design , Acetic Acid , Analgesics/chemical synthesis , Analgesics/chemistry , Analgesics/pharmacology , Anemia, Sickle Cell/genetics , Anemia, Sickle Cell/metabolism , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antisickling Agents/chemistry , Capsaicin , Colic/chemically induced , Colic/metabolism , Colic/prevention & control , Ear/pathology , Edema/chemically induced , Edema/metabolism , Edema/prevention & control , Female , Male , Mice , Mice, Transgenic , Models, Chemical , Molecular Structure , Peritonitis/chemically induced , Peritonitis/metabolism , Peritonitis/prevention & control , Thalidomide/chemical synthesis , Thalidomide/chemistry , Thalidomide/pharmacology , Thioglycolates , Tumor Necrosis Factor-alpha/metabolismABSTRACT
We report the synthesis and total NMR characterization of 5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid-3-[[[(4''-nitrophenoxy)carbonyl]oxy]-methyl]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (5), a new cephalosporin derivative. This compound can be used as the carrier of a wide range of drugs containing an amino group. The preparation of the intermediate product, 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (6), as well as the synthesis of the antimalarial primaquine prodrug 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]- 5-dioxide (7) are also described, together with their total (1)H- and (13)C-NMR assignments.
Subject(s)
Cephalosporins/chemical synthesis , Cephalosporins/therapeutic use , Cephalosporins/chemistry , Isomerism , Magnetic Resonance Spectroscopy , Primaquine/chemical synthesis , Primaquine/chemistry , Prodrugs/chemical synthesis , Prodrugs/chemistryABSTRACT
O processo de modificação molecular denominado latenciação é revisto, apresentando formas avançadas no transporte de fármacos, utilizando macromoléculas como transportadores e sistemas de liberação sítio-específica como: CDS (Chemical Delivery Systm), ADEPT (Antibody-Directed Enzyme Prodrug Therapy), GDEPT/ VDEPT (Gene-Directed Enzyme Produg Therapy/Vrus-Directed Enzyme Prodrug Therapy), ODDS (Osteotropic Drug Delivery System), PDEPT (Polymer-Directed Enzyme Prodrug Therapy), PELT (Polymer - Enzyme Liposome Therapy) e LEAPT (Lectin-Directed Enzyme-Activated Prodrug Therapy)
Subject(s)
Pharmaceutical Preparations , Pharmacokinetics , Macromolecular Substances , PolymersABSTRACT
The synthesis of mutual prodrugs of nitrofurazone with primaquine, using specific and nonspecific spacer groups, has been previously attempted seeking selective antichagasic agents. The intermediate reaction product, hydroxymethylnitrofurazone (NFOH-121), was isolated and tested in LLC-MK(2) culture cells infected with trypomastigotes forms of Trypanosoma cruzi showing higher trypanocidal activity than nitrofurazone and benznidazol in all stages. The mutagenicity tests showed that the prodrug was less toxic than the parent drug. Degradation assays were carried out in pH 1.2 and 7.4.
