Synthesis and antiprotozoal activity of 4-arylcoumarins.

A large series of 4-arylcoumarins was synthesized by Suzuki-Miyaura cross-coupling reaction and evaluated for antiprotozoal activity against Plasmodium falciparum and Leishmania donovani. Several compounds were found to strongly inhibit the proliferation of human cell line and/or parasites. The 4-(3,4-dimethoxyphenyl)-6,7-dimethoxycoumarin exhibit a potent activity on L. donovani amastigotes with a selectivity index (SI=265) twice than amphotericin B (SI=140).

Alternative and complementary antileishmanial treatments: assessment of the antileishmanial activity of 27 Lebanese plants, including 11 endemic species.

Aqueous, methanolic, and dichloromethane extracts from 27 Lebanese plants were investigated for their in vitro immunomodulatory and antileishmanial activities as compared to their toxicity against human cells. Extracts from yellow chamomile (Anthemis tinctoria), white larkspur (Consolida rigida), Syrian broom (Cytisus syriacus), coast spurge (Euphorbia paralias), shield fibigia (Fibigia clypeata), Auchers golden-drop (Onosma aucheriana), shell-flower sage (Salvia multicaulis), snowy woundwort (Stachys nivea), Palestine woundwort (Stachys palaestina), and polium-leaved speedwell (Veronica polifolia) exhibited interesting antileishmanial activities on the intracellular amastigote form of the parasite, while several extracts from A. tinctoria, F. clypeata, and O. aucheriana were shown to induce nitrous oxide (NO) production by human macrophages. Further experiments should be performed in order to purify and characterize the chemical compounds responsible for these activities.

[Anti-leishmaniasis activity of some extracts isolated from Nigella damascena (Ranunculaceae)]. / Actiunea antileishmaniazica a unor extracte obtinute din specia Nigella damascena (Ranunculaceae).

UNLABELLED: Nigella damascena L. (Ranunculaceae) originates from Magreb's countries (Morocco, Algeria, Tunisia, Egypt) and from the Middle Orient (Syria). In these countries the seeds are venerated by all the Muslim people and thus they are quoted in the Koran for their therapeutic effects. MATERIALS AND METHODS: We evaluated the effects of different extracts isolated from Nigellae damascenae semen and Nigellae damascenae herba on three types of cells: THP1 cells (human monocytes which were used for evaluating the toxicity of the extracts) and two different forms of Leishmania infatum: promastigote cells and amastigote cells. RESULTS: Dichlormethanic extracts isolated from Nigellae damascenae semen and Nigellae damascenae herba were active on Leishmania promastigotes. CONCLUSIONS: Dichlormethanic extracts could be an alternative to the therapy based on pentamidine and amphotericin B.

Synthesis and antileishmanial activity of 6-mono-substituted and 3,6-di-substituted acridines obtained by acylation of proflavine.

Two new series of diaminoacridinic derivatives obtained from proflavine and N-(6-amino-3-acridinyl)acetamide were synthesised and assessed for their cytotoxic and antileishmanial activities. Two compounds, N-[6-(acetylamino)-3-acridinyl]acetamide and N-[6-(benzoylamino)-3-acridinyl]benzamide demonstrated highly specific antileishmanial properties against the intracellular amastigote form of the parasite. Structure-activity relationships established that the antiproliferative activity against human cells was greatly enhanced by the presence of a benzoylamino group in 6-mono-substituted acridines, while the presence of two acetylamino or benzoylamino groups in 3,6-di-substituted acridines strongly increased the specificity of the molecules for Leishmania parasite, suggesting that symmetric conformations could preferentially interfere with Leishmania metabolism.

Antileishmanial activity of quinovic acid glycosides and cadambine acid isolated from Nauclea diderrichii.

Nine quinovic acid glycosides and the alkaloid cadambine acid isolated from N. diderrichii, an evergreen endemic plant of West and Central Africa, were assessed for their in vitro antileishmanial activity against Leishmania infantum. Four quinovic acid glycosides and cadambine acid revealed a strong antileishmanial activity (IC (50) = 1 microM) highly specific for the intracellular amastigote form of the parasite. Quinovic acid glycosides were shown to inhibit parasite internalisation by interfering with promastigotes while cadambine acid exerted immunomodulatory activity by inducing NO production in human macrophages. The association of cadambine acid with amphotericin B demonstrated an interesting synergism, suggesting that cadambine acid could be used as a complement of such conventional therapy.

In vitro antileishmanial activity of diphyllin isolated from Haplophyllum bucharicum.

Diphyllin isolated from Haplophyllum bucharicum Litv. (Rutaceae), an endemic plant of Uzbekistan, displayed a moderate antiproliferative activity towards human monocytes (IC50 = 35.2 microM) and Leishmania promastigotes (IC50 = 14.4 microM), by a mechanism of action that involved interaction with macromolecules and resulted in cell cycle arrest in the S-phase and inhibition of protein synthesis. In the intracellular amastigote form of the parasite, diphyllin exerted a strong specific inhibitory activity (IC50 = 0.2 microM) resulting from the inhibition of parasite internalization within macrophages. This property was mainly due to modulation of macrophage phagocytosis and, to a lesser extent, it also involved interference with surface molecules of the promastigote membrane.

Synthesis and antileishmanial activity of (1,3-benzothiazol-2-yl) amino-9-(10H)-acridinone derivatives.

(1,3-Benzothiazol-2-yl) amino-9-(10H)-acridinone derivatives were synthesized via a procedure based on the Ullman reaction and were assessed for their in vitro antileishmanial and anti-HIV activities. Two derivatives, 4-(6-nitro-benzothiazol-2-ylamino)-10H-acridin-9-one and 1-(6-amino-benzothiazol-2-ylamino)-10H-acridin-9-one, revealed a selective antileishmanial activity, mainly due to amastigote-specific toxicity. Results suggested that:the addition of a benzothiazole group on a parent amino-9-(10H)-acridinone ring could enhance antileishmanial abilities, the presence of a 6-amino-benzothiazole group on position 2 amino chain or a 6-nitro-benzothiazole group on position 4 amino chain was essential for specific anti-amastigote properties.

Antiparasitic activity of highly conjugated pyrimidine-2,4-dione derivatives.

4-[2-(1,3-Dimethyl-5-nitro-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)vinyl]benzaldehyde was synthesized in four steps from 6-methyl-1H,3H-pyrimidine-2,4-dione. This aldehyde was functionalized by various substituted anilines or substituted benzylamines. Antiparasitic activities of the corresponding azomethines were assessed against Plasmodium falciparum, Trichomonas vaginalis and Leishmania infantum compared to their toxicity versus human cells.

In vitro activities of 7-substituted 9-chloro and 9-amino-2-methoxyacridines and their bis- and tetra-acridine complexes against Leishmania infantum.

9-Chloro and 9-amino-2-methoxyacridines bearing different substituents in position 7, as well as their corresponding unsubstituted dimeric and tetrameric complexes, were investigated for in vitro antiproliferative properties against Leishmania infantum compared to toxicity towards human monocytes. The results clearly confirmed that several compounds of the 2-methoxyacridine series, together with their corresponding dimeric and tetrameric derivatives, had strong in vitro antiparasitic properties. Antileishmanial activity was shown to depend on the nature of both 7- and 9-substituted groups in monoacridines, while it varied according to the nature of the 9-substituted group and the length of the linker among bis- and tetra-acridines. The effects of acridine derivatives on DNA synthesis raised the hypothesis that DNA metabolism constituted their main target in Leishmania promastigotes; however, secondary effects on other biochemical pathways, including protein and lipid metabolism, were observed, suggesting that acridine compounds could be considered multitarget drugs.

In vivo excitotoxicity induced by ouabain, a Na+/K+-ATPase inhibitor.

The susceptibility of immature rat brain to neurotoxicity of N-methyl-D-aspartate (NMDA) has provided a widely used paradigm to study excitotoxicity relevant to acute neurodegenerative diseases such as cerebral ischemia. In this study, excitotoxicity was induced via injection of ouabain (1 mM/0.5 microL), a Na+/K+ -ATPase-inhibitor, into neonatal rat brain and compared with NMDA injection. The aim of the study was to induce excitotoxicity secondary to cellular membrane depolarization, thereby more closely mimicking the pathophysiologic processes of ischemia-induced brain injury where NMDA-receptor overstimulation by glutamate follows, not precedes, membrane depolarization. Na+/K+ -ATPase-inhibition caused an acute, 40% +/- 8% decrease of the apparent diffusion coefficient (ADC) of water, as measured using diffusion-weighted magnetic resonance imaging (MRI), and resulted in infarctlike lesions as measured using T2-weighted MRI and histology up to 2 weeks later. Localized one- and two-dimensional 1H-magnetic resonance spectroscopy (MRS) demonstrated that the early excitotoxic diffusion changes were not accompanied by an overall metabolic disturbance. Furthermore, 31P-MRS demonstrated that energy depletion is not a prerequisite for ADC decrease or excitotoxic cell death. Treatment with the NMDA-antagonist MK-801 (1 mg/kg) attenuated the volume of tissue exhibiting a decreased ADC (P < 0.005), demonstrating that the ouabain-induced injury is indeed excitotoxic in nature. The authors argue that, compared with NMDA-injection, ouabain-induced excitotoxicity elicits more appropriate glutamate-receptor overstimulation and is better suited to detect relevant neuroprotection in that it is more sensitive to attenuation of synaptic glutamate levels.

1,3-Diphenylpyrazoles: synthesis and antiparasitic activities of azomethine derivatives.

1,3-Diphenylpyrazole-4-carboxaldehyde and 1-(4-nitrophenyl)-3-phenylpyrazole-4-carboxaldehyde were obtained from the appropriated phenylhydrazones via the Vilsmeier-Haack reaction. These two aldehydes were functionalized by various substituted anilines or substituted benzylamines. Antiparasitic activities of the corresponding azomethines were assessed. In the most cases, nitrated compounds were found to be more efficient than non-nitrated ones against Plasmodium falciparum, Trichomonas vaginalis and Leishmania infantum.

In vitro activities of position 2 substitution-bearing 6-nitro- and 6-amino-benzothiazoles and their corresponding anthranilic acid derivatives against Leishmania infantum and Trichomonas vaginalis.

6-Nitro- and 6-amino-benzothiazoles bearing different chains in position 2 and their corresponding anthranilic acid derivatives were investigated for their in vitro antiparasitic properties against parasites of the species Leishmania infantum and Trichomonas vaginalis compared to their toxicity towards human monocytes. Biological investigations established that the antiprotozoal properties depended greatly on the chemical structure of the position 2 substitution-bearing group. Compound C1, 2-[(2-chloro-benzothiazol-6-yl) amino] benzoic acid, demonstrated an interesting antiproliferative activity towards parasites of the species T. vaginalis, while compound C11, 2-([2-[(2-hydroxyethyl) amino]-benzothiazol-6-yl] amino) benzoic acid, exhibited a promising activity against parasites of the species L. infantum in their intracellular amastigote form. Additional experiments established that compound C11, which was poorly toxic against the promastigote and the extracellular amastigote forms of the parasite, could improve host-protective mechanisms against Leishmania by preventing parasite internalization by macrophages and stimulating NO production, by means of a mechanism synergistically enhanced by the presence of gamma interferon.