RESUMEN
Three simplified "non-natural" natural taxanes, related to taxuspine X, were synthetized and assayed as P-glycoprotein (P-gp) inhibitors. One of them (6) proved to be a very efficient P-gp inhibitor with an IC50 = 7.2 × 10(-6) M. In addition, to rationalize biological data, a pharmacophoric model was built through a ligand-based approach. This model represents the first example of a pharmacophore, which describes interactions of taxanes with P-gp.
RESUMEN
A small family of S-DABO cytosine analogs (S-DABOCs) has been synthesized and biologically evaluated as HIV-1 inhibitor both on wild type (wt) and drug-resistant mutants leading to the identification of an interesting compound (5d). Molecular modeling studies have been finally performed in order to rationalize the results.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Citosina/análogos & derivados , Fármacos Anti-VIH/química , Citosina/síntesis química , Citosina/química , Citosina/farmacología , VIH-1/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos MolecularesRESUMEN
Among the FDA approved drugs for the treatment of AIDS, non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of first-line anti-HIV-1 therapy because of the less-severe adverse effects associated with NNRTIs administration in comparison to therapies based on other anti-HIV-1 agents. In this contest, 3,4-dihydro-2-alkoxy-6-benzyl-4-oxypyrimidines (DABOs) have been the object of many studies aimed at identifying novel analogues endowed with potent inhibitory activity towards HIV-1 wild type and especially drug-resistant mutants. Accordingly, based on the encouraging results obtained from the biological screening of our internal collection of S-DABO derivatives, we started with the systematic functionalization of the pyrimidine scaffold to identify the minimal required structural features for RT inhibition. Herein, we describe how the combination of synthetic, biological, and molecular modeling studies led to the identification of two novel subclasses of S-DABO analogues: S-DABO cytosine analogues (S-DABOCs) and 4-dimethyamino-6-vinylpyrimidines (DAVPs).
Asunto(s)
Diseño de Fármacos , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/síntesis química , Transcriptasa Inversa del VIH/genética , VIH-1/genética , Humanos , Mutación , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
Since their discovery in 1992, 3,4-dihydro-2-alkoxy-6-benzyl-4-oxypyrimidines (DABOs) have been subjected to many structural modifications in order to obtain better non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of AIDS. Herein, we report a straightforward and versatile route for the synthesis of novel C-6 arylmethyl-functionalized S-DABO, a poorly explored class of derivatives. Finally, biological evaluation of the synthesized derivatives led to the identification of a promising anti-HIV-1 lead compound.
