ABSTRACT
To identify a new safe antiplasmodial molecular scaffold, an original series of 2-trichloromethylquinazolines, functionalized in position 4 by an alkyl- or arylamino substituent, was synthesized from 4-chloro-2-trichloromethylquinazoline 1, via a cheap, fast and efficient solvent-free operating procedure. Among the 40 molecules prepared, several exhibit a good profile with both a significant antiplasmodial activity on the W2 Plasmodium falciparum strain (IC(50) values: 0.4-2.2 microM) and a promising toxicological behavior regarding human cells (HepG2/W2 selectivity indexes: 40-83), compared to the antimalarial drug compounds chloroquine and doxycycline. The in vitro antitoxoplasmic and antileishmanial evaluations were conducted in parallel on the most active molecules, showing that these ones specifically display antiplasmodial properties.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Leishmania donovani/drug effects , Plasmodium falciparum/drug effects , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Toxoplasma/drug effects , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Aniline Compounds/toxicity , Animals , Antimalarials/chemistry , Antimalarials/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Leishmania donovani/growth & development , Plasmodium falciparum/growth & development , Quinazolines/chemistry , Quinazolines/toxicity , Structure-Activity Relationship , Toxoplasma/growth & developmentABSTRACT
The discovery of the potent anticancer properties of natural alkaloids in the pyrido-thiazolo-acridine series has suggested that thiazolo-acridine derivatives could be of great interest. In a continuous attempt to develop DNA-binding molecules and DNA photo-cleavers, 16 new thiazolo[5,4-a]acridines were synthesized and studied for their photo-inducible DNA-intercalative, cytotoxic and mutagenic activities, by use of the DNA methyl-green bioassay, the Alamar Blue viability assay and the Salmonella mutagenicity test using strains TA97a and TA98 with and without metabolic activation and photo-activation. Without photo-activation, one compound showed a DNA-intercalative activity in the DNA major groove while three compounds displayed intercalating properties after photo-activation. In the dark, four molecules possessed cytotoxic activities against a THP1 acute monocytic leukemia cell line while 15 derivatives displayed photo-inducible cytotoxic activity against this cell line. All compounds were mutagenic in strain TA97a with metabolic activation (+S9mix) and 15 molecules were mutagenic in strain TA98 without activation (-S9mix). Study of the quantitative structure-activity relationships (QSAR) from the Salmonella mutagenicity data revealed that several descriptors could describe cytotoxic and mutagenic activities after photo-activation. From the results of the mutagenicity test, four compounds with elevated mutagenic activities were selected for additional experiments. Their capacities to induce single-strand breaks (SSB) and chromosome-damaging effects were monitored by the comet and the micronucleus assays in normal human keratinocytes. Comparison of the minimal genotoxic concentrations showed that two compounds possessed higher capacities to induce SSB after photo-activation. In the micronucleus assay, three molecules were able to induce high numbers of micronuclei following photo-activation. Overall, the results of this study confirm that acridines are predominantly genotoxic via a DNA-intercalating mechanism in the dark, while DNA-adducts were probably induced following photo-activation.
Subject(s)
Acridines/toxicity , DNA Damage , Light , Mutagens/toxicity , Thiazoles/toxicity , Cell Survival/drug effects , Cells, Cultured , Humans , Intercalating Agents/toxicity , Mutagenicity Tests , Quantitative Structure-Activity RelationshipABSTRACT
En el planteo freudiano se inscriben los ensayos incluídos en este libro: todo psicoanálisis es metapsicología, no hay metapsicoanálisis, porque procesa rupturas epistemológicas con la psicología y no por ser una suerte de trasfondo semioscuro de alguna práctica tecnoempírica de la que, se dice, deriva
ABSTRACT
Objeto, castración y fantasía constituyen tres conceptos fundamentales sobre los cuales trabaja la investigación psicoanalítica francesa actual. Green, luego de una exposición de la teoría lacaniana del objeto (a), la discute en la pespectiva del afecto. El trabajo de Freud: Pegan a un niño, es desmontado y minuciosamente analizado por Nassif. Finalmente el texto de Reboul muestra cuál es el precio que el sujeto debe pagar para constituirse como tal: la aceptación de la falta en el Otro