ABSTRACT
Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acidic M17 leucyl-aminopeptidase (TcLAP) mediates the major parasite's leucyl-aminopeptidase activity and is expressed in all parasite stages. Here, we report the inhibition of TcLAP (IC50 = 66.0 ± 13.5 µM) by the bestatin-like peptidomimetic KBE009. This molecule also inhibited the proliferation of T. cruzi epimastigotes in vitro (EC50 = 28.1 ± 1.9 µM) and showed selectivity for the parasite over human dermal fibroblasts (selectivity index: 4.9). Further insight into the specific effect of KBE009 on T. cruzi was provided by docking simulation using the crystal structure of TcLAP and a modeled human orthologous, hLAP3. The TcLAP-KBE009 complex is more stable than its hLAP3 counterpart. KBE009 adopted a better geometrical shape to fit into the active site of TcLAP than that of hLAP3. The drug-likeness and lead-likeness in silico parameters of KBE009 are satisfactory. Altogether, our results provide an initial insight into KBE009 as a promising starting point compound for the rational design of drugs through further optimization.
ABSTRACT
A series of caracasine acid (1) derivatives were synthesized and evaluated for their in vitro cytotoxicity on human cancer-derived cell lines MCF-7 and PC-3, as well as for other activities such as antibacterial, antileishmanial and antitrypanosomal activity. Compound 1 was more effective than any of its derivatives against tested human cancer cell lines. PC-3 cells were more sensitive than MCF-7 to all compounds, particularly the methyl ester (2), the amide (9) and the epoxide (10). The evaluation of antiparasitic activity revealed that ester derivatives (2-8) and the amide derivative (9) were the most effective antileishmanial and antitrypanosomal compounds, even though their effect on Trypanosoma cruzi was modest. Finally, compound 1 and the derivatives evidenced a broad spectrum of antibacterial activity, as assayed against Gram-positive and Gram-negative bacteria.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antiprotozoal Agents/chemical synthesis , Carboxylic Acids/chemical synthesis , Phenanthrenes/chemical synthesis , Amides/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/pharmacology , Antiprotozoal Agents/pharmacology , Bacillus cereus/drug effects , Bacillus cereus/growth & development , Carboxylic Acids/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Epoxy Compounds/chemistry , Escherichia coli/drug effects , Escherichia coli/growth & development , Esters/chemistry , Humans , Inhibitory Concentration 50 , Leishmania mexicana/drug effects , Leishmania mexicana/growth & development , MCF-7 Cells , Phenanthrenes/pharmacology , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/growth & development , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , Structure-Activity Relationship , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/growth & developmentABSTRACT
13,14-Dihydroxy-8,11,13-podocarpatrien-7-one (1) and a series of ring C aromatic diterpene derivatives were synthesised from (+)-manool (4) and evaluated for their cytotoxic, leishmanicidal and trypanocidal activities. Our results indicated that compound 1 and other podocarpane-type intermediates are cytotoxic. Cleavage of C6-C7 bond of compound 7 improved cytotoxic activity, indicating that, in particular, the 6,7-seco-podocarpane-type compound 20 might serve as a lead compound for further development.
Subject(s)
Antiprotozoal Agents/pharmacology , Diterpenes/chemistry , Diterpenes/chemical synthesis , Trypanocidal Agents/pharmacology , Diterpenes/pharmacology , Fibroblasts/drug effects , Humans , Inhibitory Concentration 50 , Leishmania mexicana/drug effects , MCF-7 Cells , Molecular Structure , Trypanosoma cruzi/drug effectsABSTRACT
Se estudió la estabilidad de tabletas de liberación prolongada confeccionadas a partir de polimetacrilato de quinidina, mediante el control periódico de las características físicas químicas y los perfiles de liberación de la sustancia biológicamente activa en muestras envejecidas por diferentes métodos. Los resultados obtenidos demuestran que el producto analizado mantiene una estabilidad adecuada en condiciones normales de almacenamiento
Subject(s)
Drug Stability , Methylmethacrylates/pharmacokinetics , Chemistry, Pharmaceutical/methods , Quinidine/pharmacokinetics , Tablets , Arrhythmias, Cardiac/metabolismABSTRACT
Se estudió la estabilidad de tabletas de liberación prolongada confeccionadas a partir de polimetacrilato de quinidina, mediante el control periódico de las características físicas químicas y los perfiles de liberación de la sustancia biológicamente activa en muestras envejecidas por diferentes métodos. Los resultados obtenidos demuestran que el producto analizado mantiene una estabilidad adecuada en condiciones normales de almacenamiento
Subject(s)
Drug Stability , Chemistry, Pharmaceutical/methods , Quinidine/pharmacokinetics , Methylmethacrylates/pharmacokinetics , Tablets , Arrhythmias, Cardiac/metabolismABSTRACT
Se realizó un estudio de dosificación de radiaciones gamma en la descontaminación parcial de granulados de polimetacrilatos de quinidina y su influencia sobre la estabilidad química de dichos granulados, así como el efecto del envejecimiento de las muestras sobre los resultados microbiológicos obtenidos. Se concluyó que el tratamiento con radiaciones gamma y/o el almacenamiento a largo plazo de los granulados son métodos eficaces para lograr la descontaminación parcial de éstos sin riesgo de afectar su estabilidad química
Subject(s)
Drug Contamination/prevention & control , Gamma Rays , Methylmethacrylates/chemistry , Methylmethacrylates/radiation effects , Quinidine/chemistry , Quinidine/radiation effects , Time FactorsABSTRACT
Se realizó un estudio de dosificación de radiaciones gamma en la descontaminación parcial de granulados de polimetacrilatos de quinidina y su influencia sobre la estabilidad química de dichos granulados, así como el efecto del envejecimiento de las muestras sobre los resultados microbiológicos obtenidos. Se concluyó que el tratamiento con radiaciones gamma y/o el almacenamiento a largo plazo de los granulados son métodos eficaces para lograr la descontaminación parcial de éstos sin riesgo de afectar su estabilidad química (AU)
