RESUMEN
Justicia gendarussa, a medicinal plant collected in Vietnam, was identified as a potent anti-HIV-1 active lead from the evaluation of over 4500 plant extracts. Bioassay-guided separation of the extracts of the stems and roots of this plant led to the isolation of an anti-HIV arylnaphthalene lignan (ANL) glycoside, patentiflorin A (1). Evaluation of the compound against both the M- and T-tropic HIV-1 isolates showed it to possess a significantly higher inhibition effect than the clinically used anti-HIV drug AZT. Patentiflorin A and two congeners were synthesized, de novo, as an efficient strategy for resupply as well as for further structural modification of the anti-HIV ANL glycosides in the search for drug leads. Subsequently, it was determined that the presence of a quinovopyranosyloxy group in the structure is likely essential to retain the high degree of anti-HIV activity of this type of compounds. Patentiflorin A was further investigated against the HIV-1 gene expression of the R/U5 and U5/gag transcripts, and the data showed that the compound acts as a potential inhibitor of HIV-1 reverse transcription. Importantly, the compound displayed potent inhibitory activity against drug-resistant HIV-1 isolates of both the nucleotide analogue (AZT) and non-nucleotide analogue (nevaripine). Thus, the ANL glycosides have the potential to be developed as novel anti-HIV drugs.
Asunto(s)
Fármacos Anti-VIH/aislamiento & purificación , Fármacos Anti-VIH/farmacología , Glicósidos/aislamiento & purificación , Glicósidos/farmacología , VIH-1/efectos de los fármacos , Género Justicia/química , Lignanos/aislamiento & purificación , Lignanos/farmacología , Plantas Medicinales/química , Inhibidores de la Transcriptasa Inversa/aislamiento & purificación , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/química , Glicósidos/química , VIH-1/genética , Humanos , Lignanos/química , Estructura Molecular , Raíces de Plantas/química , Tallos de la Planta/química , Inhibidores de la Transcriptasa Inversa/química , Vietnam , Zidovudina/farmacologíaRESUMEN
Tuberculosis (TB) is a highly contagious disease mainly caused by Mycobacterium tuberculosis H37 RV . Antitubercular (anti-TB) bioassay-guided isolation of the CHCl3 extract of the leaves and stems of the medicinal plant Ardisia gigantifolia led to the isolation of two anti-TB 5-alkylresorcinols, 5-(8Z-heptadecenyl) resorcinol (1) and 5-(8Z-pentadecenyl) resorcinol (2). We further synthesized 15 derivatives based on these two natural products. These compounds (natural and synthetic) were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37 RV . Resorcinols 1 and 2 exhibited anti-TB activity with MIC values at 34.4 and 79.2 µm in MABA assay, respectively, and 91.7 and 168.3 µm in LORA assay, respectively. Among these derivatives, compound 8 was found to show improved anti-TB activity than its synthetic precursor (2) with MIC values at 42.0 µm in MABA assay and 100.2 µm in LORA assay. The active compounds should be regarded as new hits for further study as a novel class of anti-TB agents. The distinct structure-activity correlations of the parent compound were elucidated based on these derivatives.