RESUMEN
New anti-infective agents are urgently needed to fight microbial resistance. Methicillin-resistant Staphylococcus aureus (MRSA) strains are particularly responsible for complicated pathologies that are difficult to treat due to their virulence and the formation of persistent biofilms forming a complex protecting shell. Parasitic infections caused by Trypanosoma brucei and Leishmania mexicana are also of global concern, because of the mortality due to the low number of safe and effective treatments. Female inflorescences of hop produce specialized metabolites known for their antimicrobial effects but underexploited to fight against drug-resistant microorganisms. In this study, we assessed the antimicrobial potential of phenolic compounds against MRSA clinical isolates, T. brucei and L. mexicana. By fractionation process, we purified the major prenylated chalcones and acylphloroglucinols, which were quantified by UHPLC-UV in different plant parts, showing their higher content in the active flowers extract. Their potent antibacterial action (MIC < 1 µg/mL for the most active compound) was demonstrated against MRSA strains, through kill curves, post-antibiotic effects, anti-biofilm assays and synergy studies with antibiotics. An antiparasitic activity was also shown for some purified compounds, particularly on T. brucei (IC50 < 1 to 11 µg/mL). Their cytotoxic activity was assessed both on cancer and non-cancer human cell lines.
Asunto(s)
Antiinfecciosos/química , Productos Biológicos/química , Humulus/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antiinfecciosos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Biopelículas/efectos de los fármacos , Productos Biológicos/farmacología , Humanos , Leishmania mexicana/efectos de los fármacos , Leishmania mexicana/patogenicidad , Staphylococcus aureus Resistente a Meticilina/química , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Pruebas de Sensibilidad Microbiana , Enfermedades Parasitarias/tratamiento farmacológico , Enfermedades Parasitarias/parasitología , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma brucei brucei/patogenicidadRESUMEN
In the present study, a series of new esters of secochiliolide acid (SA), a diterpene isolated from Nardophyllum bryoides, were synthesized in good yield. All compounds were evaluated for their in vitro antiparasitic properties (on Plasmodium falciparum and Trypanosoma brucei brucei) and cytotoxicity (on WI38, normal mammalian cells). They displayed moderate antitrypanosomal activity with IC50 values between 2.55 and 18.14 µm, with selectivity indices >10, and low antiplasmodial effects with IC50 > 29 µm. The only exception was the n-hexyl ester of SA, which showed a strong and selective antiplasmodial activity (IC50 = 1.99 µm and selectivity index = 117.0). The in vivo antimalarial efficacy of this compound was then assessed according to the 4-day suppressive test of Peters in mice. An intraperitoneal treatment at 50 mg kg-1 day-1 induced a slight parasitaemia reduction by 56% which was statistically significant on day 4 post-infection and an increase in the survival time.
Asunto(s)
Antimaláricos/química , Antiprotozoarios/química , Diterpenos/química , Ésteres/química , Propionatos/química , Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Antiprotozoarios/aislamiento & purificación , Antiprotozoarios/farmacología , Asteraceae/química , Asteraceae/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Humanos , Extractos Vegetales/química , Plasmodium falciparum/efectos de los fármacos , Propionatos/aislamiento & purificación , Propionatos/farmacología , Trypanosoma brucei brucei/efectos de los fármacosRESUMEN
In this work, a series of hybrid compounds were tested as antiparasitic substances. These hybrids were prepared from bile acids and a series of antiparasitic Cinchona alkaloids by the formation of a covalent C-C bond via a decarboxylative Barton-Zard reaction between the two entities. The bile acids showed only weak antiparasitic properties, but all the hybrids exhibited high in vitro activities (IC50: 0.48-5.39 µM) against Trypanosoma brucei. These hybrids were more active than their respective parent alkaloids (up to a 135 fold increase in activity), and displayed good selectivity indices. Aditionally, all these compounds inhibited the in vitro growth of a chloroquine-sensitive strain of Plasmodium falciparum (3D7: IC50: 36.1 nM to 8.72 µM), and the most active hybrids had IC50s comparable to that of artemisinin (IC50: 36 nM). Some structure-activity relationships among the group of 48 hybrids are discussed. The increase in antiparasitic activity may be explained by an improvement in bioavailability, since the more lipophilic derivatives showed the lowest IC50s.
Asunto(s)
Antimaláricos/farmacología , Ácidos y Sales Biliares/farmacología , Alcaloides de Cinchona/farmacología , Plasmodium falciparum/efectos de los fármacos , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Antimaláricos/síntesis química , Antimaláricos/química , Ácidos y Sales Biliares/química , Alcaloides de Cinchona/química , Relación Dosis-Respuesta a Droga , Conformación Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/químicaRESUMEN
A series of 16 hybrids of Cinchona alkaloids and bile acids (4a-h, 5a-h) was prepared by means of a Barton-Zard decarboxylation reaction. Quinine, quinidine, cinchonine and cinchonidine were functionalized at position C-2 of the quinoline nucleus by radical attack of a norcholane substituent. The newly synthesized hybrids were evaluated in vitro for their antitrypanosomal, antileishmanial and antiplasmodial activities, along with their cytotoxicity against WI38, a normal human fibroblast cell line. Seven compounds (4d, 4f, 4h, 5b, 5d, 5f, 5h) showed promising trypanocidal activity with IC50 values in the same range as the commercial drug suramine. Moreover all the 16 hybrids showed antiplasmodial activity (IC50 ≤ 6 µg/ml), particularly those containing a nor-chenodeoxycholane moiety (4b, 4d, 4f, 4h, 5b, 5d, 5f, 5h) with IC50 values comparable to those of the natural alkaloids, and selectivity indices in the range of 5.6-15.7.