RESUMEN
The in vitro activity against Leishmania spp. of five novel designed compounds, phenalenone derivatives, is described in this study. Previous works have shown that some phenalenones present leishmanicidal activity, some of which could induce programmed cell death events in L. amazonensis parasites. In this research, we focused on the determination of the programmed cell death evidence by detecting the characteristic features of the apoptosis-like process, such as phosphatidylserine exposure and mitochondrial membrane potential, among others. The results showed that the new derivatives have comparable or better activity and selectivity than the commonly prescribed anti-leishmanial drug. This result was obtained by inducing stronger mitochondrial depolarization or more intense phosphatidylserine exposure than miltefosine, highlighting compound 8 with moreover 9-times better selectivity index. In addition, the new five molecules activated the apoptosis-like process in the parasite. All the signals observed were indicative of the death process that the parasites were undergoing.
Asunto(s)
Antiprotozoarios/farmacología , Leishmania/efectos de los fármacos , Fenalenos/farmacología , Antiprotozoarios/química , Apoptosis/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Fenalenos/química , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologíaRESUMEN
A collection of N-substituted quinolin-2(1H)-ones were screened against a panel of clinically relevant protozoa (Leishmania, Trypanosoma and Acanthamoeba). Three quinolin-2(1H)-one compounds were identified as selective anti-Acanthamoeba agents. Further assessment revealed that these compounds were active against both trophozoite and cyst forms of A. castellanii Neff, and caused protozoa death via apoptosis. The data presented herein identify N-acyl quinolin-2(1H)-ones as a promising new class of selective anti-Acanthamoeba agents.
Asunto(s)
Queratitis por Acanthamoeba/tratamiento farmacológico , Acanthamoeba/efectos de los fármacos , Antiprotozoarios/farmacología , Leishmania/efectos de los fármacos , Quinolonas/farmacología , Trypanosoma/efectos de los fármacos , Acanthamoeba/aislamiento & purificación , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Leishmania/aislamiento & purificación , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Quinolonas/síntesis química , Quinolonas/química , Relación Estructura-Actividad , Trypanosoma/aislamiento & purificaciónRESUMEN
BACKGROUND: The in vitro activity against Leishmania spp. of a novel group of compounds, phenalenone derivatives, is described in this study. Previous studies have shown that some phenalenones present leishmanicidal activity, and induce a decrease in the mitochondrial membrane potential in L. amazonensis parasites, so in order to elucidate the evidence of programmed cell death occurring inside the promastigote stage, different assays were performed in two different species of Leishmania. METHODS: We focused on the determination of the programmed cell death evidence by detecting the characteristic features of the apoptosis-like process, such as phosphatidylserine exposure, mitochondrial membrane potential, and chromatin condensation among others. RESULTS: The results showed that four molecules activated the apoptosis-like process in the parasite. All the signals observed were indicative of the death process that the parasites were undergoing. CONCLUSIONS: The present results highlight the potential use of phenalenone derivatives against Leishmania species and further studies should be undertaken to establish them as novel leishmanicidal therapeutic agents.
Asunto(s)
Antiprotozoarios/química , Antiprotozoarios/farmacología , Apoptosis/efectos de los fármacos , Leishmania/efectos de los fármacos , Fenalenos/química , Fenalenos/farmacología , Humanos , Leishmania/citología , Leishmania/crecimiento & desarrollo , Leishmaniasis/parasitología , Estadios del Ciclo de Vida/efectos de los fármacos , Estructura MolecularRESUMEN
Screening of a designed collection of mono-substituted amino-1H-phenalen-1-ones against promastigote forms of L. donovani and L. amazonensis, identified seven compounds with anti-leishmanial activities comparable or better than the commonly prescribed anti-leishmanial drug, miltefosine. Structure-activity analysis revealed that appendages containing a basic tertiary nitrogen were favored, and that the position of the appendage also affected their potency. Like miltefosine, several of these active compounds significantly reduced the mitochondrial membrane potential in promastigotes. Further studies in amastigotes of L. amazonensis revealed that compounds 14, 15 and 33 were more active and more selective than miltefosine, with sub-micromolar potencies and selectivity indices >100.
Asunto(s)
Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Diseño de Fármacos , Leishmania donovani/efectos de los fármacos , Fenalenos/síntesis química , Fenalenos/farmacología , Antiprotozoarios/química , Técnicas de Química Sintética , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/parasitología , Leishmania donovani/fisiología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Fenalenos/químicaRESUMEN
Acanthamoeba is an opportunistic pathogen which is the causal agent of a sight-threatening ulceration of the cornea known as Acanthamoeba keratitis (AK) and, more rarely, an infection of the central nervous system called "granulomatous amoebic encephalitis" (GAE). The symptoms of AK are non-specific, and so it can be misdiagnosed as a viral, bacterial, or fungal keratitis. Furthermore, current therapeutic measures against AK are arduous, and show limited efficacy against the cyst stage of Acanthamoeba. 1H-Phenalen-1-one (PH) containing compounds have been isolated from plants and fungi, where they play a crucial role in the defense mechanism of plants. Natural as well as synthetic PHs exhibit a diverse range of biological activities against fungi, protozoan parasites or human cancer cells. New synthetic PHs have been tested in this study and they show a potential activity against this protozoa.
Asunto(s)
Acanthamoeba castellanii/efectos de los fármacos , Amebicidas/farmacología , Fenalenos/farmacología , Amebicidas/química , Amebicidas/toxicidad , Anfotericina B/farmacología , Anfotericina B/toxicidad , Permeabilidad de la Membrana Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Células MCF-7/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Fenalenos/química , Fenalenos/toxicidadRESUMEN
A set of derivatives encompassing structural modifications on the privileged phenalenone scaffold were assessed for their antiplasmodial activities against a strain of chloroquine sensitive Plasmodium falciparum F32. Two compounds exhibited considerable effects against the malaria parasite (IC50 ≤ 1 µg/mL), one of which maintained the same level of activity in a chloroquine-resistant strain. This is the first record of antiplasmodial activity on this type of scaffold, providing a new structural motif as a new lead for antimalarial activity.
Asunto(s)
Antimaláricos/farmacología , Fenalenos/química , Fenalenos/farmacología , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/química , Cloroquina/farmacología , Eritrocitos/parasitología , Humanos , Concentración 50 InhibidoraRESUMEN
A set of derivatives encompassing structural modifications on the privileged phenalenone scaffold were assessed for their antiparasitic activities against the most clinically relevant forms of trypanosomiasis and leishmaniasis. Several compounds exhibited leishmanicidal effects at levels comparable or better than the reference drug pentamidine, while the parent phenalenone was shown to have a level of activity against Trypanosoma cruzi comparable to the marketed drug benznidazole.