In vitro 4-Aryloxy-7-chloroquinoline derivatives are effective in mono- and combined therapy against Leishmania donovani and induce mitocondrial membrane potential disruption.

The present study evaluates in vitro the effect of two synthetic compounds of the 7-chloro-4-aryloxyquinoline series, QI (C17H12ClNO3) and QII (C18H15ClN4O2S), on Leishmania donovani parasites. The results obtained demonstrate that these compounds are able to inhibit the proliferation of L. donovani promastigotes in a dose-dependent way (QI IC50 = 13.03 ±â€¯3.4 and QII IC50 = 7.90 ±â€¯0.6 µM). Likewise, these compounds significantly reduced the percentage of macrophage infection by amastigotesand the number of amastigotes within macrophage phagolysosomes, the clinical relevant phase of these parasites. Compound QI showed an IC50 value of 0.66 ±â€¯0.2 µM, while for derivative QII, the corresponding IC50 was 1.02 ±â€¯0.17 µM. Interestingly, the amastigotes were more susceptible to the drug treatment when compared to promastigotes. Furthermore, no cytotoxic effect of these compounds was observed on the macrophage cell line at the concentrations tested. The combination of these compounds with miltefosine and amphotericin B on both parasite morphotypes was evaluated. The isobolograms showed a synergistic effect for both combinations; with a Fractional Inhibitory Concentration (FIC) Index lower than 1 for promastigotes and less than 0.3 for intracellular amastigotes. The effect of QI and QII on mitochondrial membrane potential was also studied. The combination of quinolone derivatives compounds with miltefosine and amphotericin B showed 5-8-fold stronger depolarization of membrane mitochondrial potential when compared to drugs alone. The present work validates the combination of drugs as an effective alternative to potentiate the action of anti-Leishmania agents and points to the quinoline compounds studied here as possible leishmanicidal drugs.

In vitro phenotypic screening of 7-chloro-4-amino(oxy)quinoline derivatives as putative anti-Trypanosoma cruzi agents.

In this study, a series of 22 pre-synthesized 7-chloro-4-amino(oxy)quinoline derivatives was assayed in vitro as potential antichagasic agents. A primary screening against Trypanosoma cruzi epimastigotes and a non-specific cytotoxicity assay on murine fibroblasts were simultaneously performed, resulting quinolines 3, 7 and 12 with great selectivity (SI) on the extracellular parasite (SI7, SI3, SI12 and SIBZ >9.44). Therefore, the activity of these derivatives was evaluated on intracellular amastigotes, achieving derivative 7 the best SI (SI=12.73). These results, supported by the in silico prediction of a good oral bioavailability and a suitable risk profile, propose the 4-amino-7-chloroquinoline scaffold as a potential template for designing trypanocidal prototypes.

Aberraciones cromosomales en bulbos de cebolla Allium cepa inducidas pormoléculas híbridas 4-aminoquinolínicas / Chromosomal aberrations in Allium cepa onion bulbs induced by 4-aminoquinoline hybrid molecules

Se estudiaron las propiedades toxicológicas de los trescompuestos híbridos quinolin-tiazolidinona (FR-72 y FR-121), y acridinepoxiisoindolindiona(FR-154) aplicándolos en el test de las raíces debulbos de cebolla Allium cepa. Las moléculas FR-72, FR-121 y FR-154 fueron sintetizadas de novo según protocolos experimentalesdescritos. Los bulbos de Allium cepa (2n = 16) limpios y sanos,previamente sumergidos en el agua destilada, se secaron con papeltoalla y se colocaron directamente en los tubos de ensayo llenos conla sustancia a evaluar. Los experimentos se realizaron a temperaturaambiente 20 ± 2°C y se mantuvieron en oscuridad. El periodo deexposición de los bulbos fue de 120 horas y las raíces que se utilizaronpara el montaje de genotoxicidad eran en promedio de 2 a 2.5 cmde longitud. La evaluación del comportamiento de las tres moléculasquinolínicas sobre la inhibición del crecimiento promedio de las raícesde bulbos de cebolla Allium cepa se realizó con los tres parámetrosde bioactividad (CE50, IM, ACs) en diferentes concentraciones. Lassustancias evaluadas pueden considerarse aneugénicas, ya que actúana nivel de estructuras celulares y moleculares e impiden la fijación delas fibras del huso acromático, por ende ocasionan el desplazamientode cromosomas en anafase o pérdidas de cromosomas, llegandoincluso a ser inductoras de la apoptosis al sobrepasar la capacidadhomeostática de la célula. El análisis preliminar indicó que la moléculaFR-121 a concentración 10-6 M y la molécula FR-154 a concentración10-3 M resultaron ser potentes agentes fitotóxicos provocando diversasaberraciones claustogénicas y aneugénicas...

The toxicological properties of three hybridcompounds, quinoline-thiazolidinone (FR-72 and FR-121)and acridin-epoxyisoindolindione (FR-154) were studiedby applying named compounds to the test of the rootsof Allium cepa onion bulbs. Molecules FR-72, FR-121 andFR-154 were synthesized de novo according to describedsynthetic protocols. Clean and healthy bulbs of Alliumcepa (2n = 16), previously immersed in distilled water,were dried with paper towels and placed directly into testtubes filled with the test substance. The experiments werecarried out at room temperature 20 ± 2°C and were keptin darkness. The period of exposure of bulbs was 120hours; the roots used for the genotoxicity evaluation wereon average of 2 to 2.5 cm in length. The evaluation of theeffect of the three quinolinic molecules on the growthof onion roots of Allium cepa bulbs was achieved usingdifferent concentrations of the three growth parameters(EC50, IM, ACs) The evaluated substances performedaneugenic actions, operating at cellular and molecularstructure level and preventing the fixing of mitoticspindle fibers, causing the movement of chromosomesin the anaphase or loss of chromosomes, even inducingapoptosis by exceeding the homeostatic capacity of thecell. The preliminary analysis indicated that molecule FR-121 at 10-6 M concentration and molecule FR-154 at 10-3M concentration, proved to be potent phytotoxic agentscausing various claustogenic and aneugenic aberrations...

Foram estudadas as propriedades toxicológicas dos trêscompostos híbridos, quinolina-tiazolidinona (FR-72 e FR-121)e hidroacridin-epoxiisoindolindiona (FR-154) aplicando-os noteste das raízes de bulbos de cebola Allium cepa. As moléculas FR-72, FR-121 e FR-154 foram sintetizadas de novo de acordo com osprotocolos experimentais já descritos. Os bulbos de Allium cepa (2n= 16) limpos e sádios, previamente imersos em água destilada, foramsecos com papel toalha e colocados diretamente em tubos de ensaio,cheios com a substância de teste. Os experimentos foram realizadosà temperatura ambiente 20 ± 2°C e mantiveram-se na escuridão. Operíodo de exposição dos bulbos foi de 120 horas e as raízes usadaspara a montagem de genotoxicidade tinham, em média, de 2 a 2,5 cmde comprimento. A avaliação do comportamento das três moléculasquinolínicas sobre a inibição do crescimento médio das raízes debulbos de cebola Allium cepa foi realizada com os três parâmetrosde bioatividade (EC50, IM, ACs) em diferentes concentrações. Assubstâncias avaliadas podem se considerar aneugénicas, já queatuam ao nível de estruturas celulares e moleculares, e impedem oestabelecimento de fibras do fuso acromático, provocando assim odeslocamento dos cromossomos na anáfase ou perda de cromossomos,chegando, inclusive, a serem indutoras da apoptose ao ultrapassar acapacidade homeostática da célula. A análise preliminar indicou que amolécula FR-121 em concentração de 10-6 M e a molécula de FR-154em concentração de 10-3 M resultaram ser potentes agentes fitotóxicosprovocando várias aberrações claustogénicas e aneugénicas...

Synthesis and antimalarial activity of new heterocyclic hybrids based on chloroquine and thiazolidinone scaffolds.

A series of new 21 chloroquine heterocyclic hybrids containing either benzylamino fragment or N-(aminoalkyl)thiazolidin-4-one moiety were synthesized and screened for their antimalarial activity against chloroquine (CQ)-sensitive 3D7 and multidrug-resistance Dd2 strains of Plasmodium falciparum. Although no compounds more active than CQ against 3D7 was found; against Dd2 strain, six compounds, four of them with benzylamino fragment, showed an excellent activity, up to 3-fold more active than CQ. Non specific cytotoxicity on J774 macrophages was observed in some compounds whereas only two of them showed liver toxicity on HepG2 cells. In addition, all active compounds inhibited the ferriprotoporphyrin IX biocrystalization process in concentrations around to CQ. In vivo preliminary results have shown that at least two compounds are as active as CQ against Plasmodium berghei ANKA.

Challenges and perspectives of chemical biology, a successful multidisciplinary field of natural sciences.

Objects, goals, and main methods as well as perspectives of chemical biology are discussed. This review is focused on the fundamental aspects of this emerging field of life sciences: chemical space, the small molecule library and chemical sensibilization (small molecule microassays).