RESUMEN
Several harmful bacteria have evolved resistance to conventional antibiotics due to their extensive usage. FtsZ, a principal bacterial cell division protein, is considered as an important drug target to combat resistance. We identified a caffeoyl anilide derivative, (E)-N-(4-(3-(3,4-dihydroxyphenyl)acryloyl)phenyl)-1-adamantylamide (compound 11) as a new antimicrobial agent targeting FtsZ. Compound 11 caused cell elongation in Mycobacterium smegmatis, Bacillus subtilis, and Escherichia coli cells, indicating that it inhibits cell partitioning. Compound 11 inhibited the assembly of Mycobacterium smegmatis FtsZ (MsFtsZ), forming short and thin filaments in vitro. Interestingly, the compound increased the rate of GTP hydrolysis of MsFtsZ. Compound 11 also impeded the assembly of Mycobacterium tuberculosis FtsZ. Fluorescence and absorption spectroscopic analysis suggested that compound 11 binds to MsFtsZ and produces conformational changes in FtsZ. The docking analysis indicated that the compound binds at the interdomain cleft of MsFtsZ. Further, it caused delocalization of the Z-ring in Mycobacterium smegmatis and Bacillus subtilis without affecting DNA segregation. Notably, compound 11 did not inhibit tubulin polymerization, the eukaryotic homolog of FtsZ, suggesting its specificity on bacteria. The evidence indicated that compound 11 exerts its antibacterial effect by impeding FtsZ assembly and has the potential to be developed as a broad-spectrum antimicrobial agent.
Asunto(s)
Antibacterianos , Proteínas del Citoesqueleto , Proteínas del Citoesqueleto/química , Antibacterianos/química , División Celular , Proliferación Celular , Proteínas Bacterianas/químicaRESUMEN
Acquired immunodeficiency syndrome patients face great socio-economic difficulties in obtaining treatment. There is an urgent need for new, safe, and cheap anti-HIV agents. Traditional medicinal plants are a valuable source of novel anti-HIV agents and may offer alternatives to expensive medicines in future. Various medicinal plants or plant-derived natural products have shown strong anti-HIV activity and are under various stages of clinical development in different parts of the world. The present study was directed towards assessment of anti-HIV activity of various extracts prepared from Indian medicinal plants. The plants were chosen on the basis of similarity of chemical constituents with reported anti-HIV compounds or on the basis of their traditional usage as immunomodulators. Different extracts were prepared by Soxhlet extraction and liquid-liquid partitioning. Ninety-two extracts were prepared from 23 plants. Anti-HIV activity was measured in a human CD4+ T-cell line, CEM-GFP cells infected with HIV-1NL4.3. Nine extracts of 8 different plants significantly reduced viral production in CEM-GFP cells infected with HIV-1NL4.3. Aegle marmelos, Argemone mexicana, Asparagus racemosus, Coleus forskohlii, and Rubia cordifolia demonstrated promising anti-HIV potential and were investigated for their active principles.
Asunto(s)
Fármacos Anti-VIH/farmacología , VIH/efectos de los fármacos , Extractos Vegetales/farmacología , Plantas Medicinales/química , Aegle/química , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/química , Argemone/química , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , Línea Celular , Línea Celular Tumoral , Coleus/química , VIH/crecimiento & desarrollo , Humanos , Extractos Vegetales/efectos adversos , Extractos Vegetales/química , Rubia/químicaRESUMEN
Naturally occurring protoberberine alkaloids, berberine and berberrubine along with 9-substituted derivatives of berberine were assessed for the anti-human immunodeficiency virus (HIV) activity. Berberine was found to be the most active compound with an EC(50) of 0.13 µM against HIV-1 NL4.3 virus in CEM-GFP cell lines. Berberrubine and two other compounds were found to be less active than berberine, at the same time they were less toxic than berberine. Enzyme based assay suggested that the anti-HIV activity of berberine and its analogs might be due to RTase inhibitory activity and some additional mechanisms.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Berberina/síntesis química , Berberina/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/toxicidad , Berberina/análogos & derivados , Berberina/toxicidad , Productos Biológicos/química , Línea Celular , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , VIH-1/enzimología , HumanosRESUMEN
Designing multi-functional ligands is a recent strategy by which multiple targets can be inhibited by a single entity. A series of caffeoyl-anilide compounds based on structures of various integrase and CCR-5 inhibitors have been designed and synthesized as anti-HIV agents in the present study. Most of the compounds exhibited potent anti-HIV activity at micromolar concentration in CEM-GFP CD4+ T cells infected with HIV-1NL4.3 virus. Compound 14 showed a lower EC(50) and better TI as compared to AZT. Mechanism based studies suggest that these compounds inhibit either one or in some cases, both the targets. The experimental data and the docking results showed that these compounds are potential inhibitors for both HIV-1 IN and CCR5.
Asunto(s)
Acetanilidas/síntesis química , Acetanilidas/farmacología , Anilidas/síntesis química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5 , Ácidos Cafeicos/síntesis química , Ácidos Cafeicos/farmacología , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , Acetanilidas/química , Anilidas/análisis , Anilidas/farmacología , Fármacos Anti-VIH/química , Ácidos Cafeicos/química , Diseño de Fármacos , Inhibidores de Integrasa VIH/química , VIH-1/fisiología , Ligandos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosAsunto(s)
Fármacos Anti-VIH , Productos Biológicos , Alcaloides/química , Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/aislamiento & purificación , Fármacos Anti-VIH/farmacología , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , VIH/química , VIH/efectos de los fármacos , VIH/metabolismo , Estructura Molecular , Fenoles/química , Fenoles/aislamiento & purificación , Fenoles/farmacología , Terpenos/química , Terpenos/aislamiento & purificación , Terpenos/farmacologíaRESUMEN
Various extracts of the aerial parts of Coleus forskohlii (Labiatae) were prepared and evaluated at their non cytotoxic concentration against HIV-1 NL4-3. Chloroform, ethyl acetate and n-butanol extracts showed 45.6, 66.5 and 37.7% inhibition of HIV, respectively in CEM-GFP cells infected with HIV-1(NL4-3) at 5 microg/mL. Four diterpenes, 1-deoxyforskolin, 1,9-dideoxyforskolin, forskolin and isoforskolin were isolated from the chloroform extract and tested against the virus. Six semi-synthetic derivatives of forskolin have been prepared to study SAR. 1-Deoxyforskolin and forskolin were found to be active against HIV(NL4-3). This is first report of anti HIV activity of this plant and its isolated constituents.