Synthesis of pure aromatic, aliphatic, and araliphatic diselenides

Organodiselenides are potential building blocks for a new class of self-assembled monolayers e.g. on coinage metals. For this, the diselenides have to be extremely pure and in particular must not contain any traces of higher organoselenides. Several strategies for the preparation of organodiselenides were compared in their efficiency in particular regarding the purity of the products. It could be shown that most literature-established procedures generate significant amounts of triselenides which are hard to detect with conventional analytic methods. While in case of the aromatic diselenides the direct synthesis via the corresponding Grignard reagent resulted in pure diselenides, the preparation of the aliphatic and araliphatic derivatives required a more indirect route through the corresponding selenocyanates.     

An investigation of in vitro cytotoxicity and apoptotic potential of aromatic diselenides

A target synthesis of a library of symmetric aromatic diselenides was attempted with the aim of generating anticancer lead compounds. Out of thirteen screened molecules (1–13) against a panel of human cancer cell lines, compound 8 exhibited highest cell growth inhibition in Human leukemia HL-60 cells with IC₅₀ value of 8 μM. Compound 8 had a good pro-apoptotic potential as evidenced from several apoptotic protocols like DNA cell cycle analysis and monitoring of apoptotic bodies formation using phase contrast and nuclear microscopy with Hoechst 33,258. Also, 8 significantly inhibits S phase of the cell cycle and eventually trigger apoptosis in HL-60 cells through mitochondrial dependent pathway substantiated by the loss of mitochondrial potential. A theoretical investigation of DNA binding ability of 8 showed that it selectively bind to minor groove of DNA, where it is stabilized by hydrogen bonding and hydrophobic interactions.     

Triazolopyridyl ketones as a novel class of antileishmanial agents. DNA binding and BSA interaction

A new series of triazolopyridyl pyridyl ketones has been synthetized by regioselective lithiation of the corresponding [1,2,3]triazolo[1,5-a]pyridine at 7 position followed by reaction with different electrophiles. The in vitro antileishmanial activity of these compounds was evaluated against Leishmania infantum, Leishmania braziliensis, Leishmania guyanensis and Leishmania amazonensis. Compounds 6 and 7 were found to be the most active leishmanicidal agents. Both of them showed activities at micromolar concentration against cultured promastigotes of Leishmania spp. (IC₅₀ = 99.8–26.8 μM), without cytotoxicity on J774 macrophage cells. These two compounds were also tested in vivo in a murine model of acute infection by L. infantum. The triazolopyridine derivative 6 was effective against both spleen and liver parasites forms, while 7 was inactive against liver parasites. Mechanistic aspects of the antileishmanial activity were investigated by means of DNA binding studies (UV-titration and viscosimetry). Results have revealed that these active ligands are able to interact strongly with DNA [K_b = 1.14 × 10⁵ M⁻¹ (6) and 3.26 × 10⁵ M⁻¹ (7)]. Moreover, a DNA groove binding has been proposed for both 6 and 7. To provide more insight on the mode of action of compounds 6 and 7 under biological conditions, their interaction with bovine serum albumin (BSA) was monitored by fluorescence titrations and UV–visible spectroscopy. The quenching constants and binding parameters were determined. Triazolopyridine ketones 6 and 7 have exhibited significant affinity towards BSA [K_b = 2.5 × 10⁴ M⁻¹ (6) and 1.9 × 10⁴ M⁻¹ (7)]. Finally, to identify the binding location of compounds 6 and 7 on the BSA, competitive binding experiments were carried out, using warfarin, a characteristic marker for site I, and ibuprofen as one for site II. Results derived from these studies have indicated that both compounds interact at BSA site I and, to a lesser extent, at site II.     

Direct synthesis of C3-mono-functionalized oxindoles from N-unprotected 2-oxindole and their antileishmanial activity

A novel approach for the synthesis of unprecedented C3-mono-functionalized indolin-2-ones is reported, starting from 2-oxindole and chalcones. The reactions proceed regioselectively under mild conditions, without di- and tri-alkylated side products. The new compounds have been evaluated in vitro for their antiproliferative effects against the protozoan Leishmania infantum. Interestingly, they appear able to kill L. infantum promastigotes and amastigotes, without significant cytotoxic effects.     

Immune checkpoint therapy of mesothelioma: Pre-clinical bases and clinical evidences

Treatment with immune-checkpoint blocking monoclonal antibody (mAb) is demonstrating a significant efficacy in different tumor types.Here, we discuss the impact of this promising approach in malignant mesothelioma (MM), a still dreadful disease in which medical treatment has been set on platinum based chemotherapy for decades with unsatisfactory results.     

Design and synthesis of novel substituted quinazoline derivatives as antileishmanial agents

4-(Substituted-benzylidine)-2-substituted-5,6-dihydrobenzo[h]quinazoline (5a–p) and 4-(substituted-benzylidine)-2-substituted-3, 4, 5, 6-tetrahydrobenzo[h]quinazoline (6a–p) have been synthesized from 2-(substituted-benzylidine)tetralone-1(3a–d) and several substituted guanidine sulfates(4a–d).These compounds were tested for their in vitro antileishmanial activity. The compounds 6i, 6f, 6g show promising antileishmanial activity against Leishmania donovani.     

Benzimidazole derivatives endowed with potent antileishmanial activity

Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promastigotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Leishmania species, with IC₅₀ values in the low micromolar/sub-micromolar range. Among the set of 2-(long chain)alkyl benzimidazoles, whose heterocyclic head was quaternised, compound 8 resulted about 100-/200-fold more potent than miltefosine, even if the selectivity index (SI) versus HMEC-1 cells was only moderately improved. In the set of 2-benzyl and 2-phenyl benzimidazoles, bearing a basic side chain in position 1, compound 28 (2-(4-chlorobenzyl)-1-lupinyl-5-trifluoromethylbenzimidazole) was 12-/7-fold more potent than miltefosine, but exhibited a further improved SI. Therefore, compounds 8 and 28 represent interesting hit compounds, susceptible of structural modification to improve their safety profiles.     

The use of herbs against neglected diseases: Evaluation of in vitro leishmanicidal and trypanocidal activity of Stryphnodendron rotundifolium Mart

The evaluation of the leishmanicidal and trypanocidal activity of the hydroalcoholic extract of the bark of Stryphnodendron rotundifolium Mart. (EHCSR) was carried out to find an alternative treatment for parasitic diseases. EHCSR was prepared and used at four different concentrations (1000, 500, 250, 125 μg/mL) in in vitro assays for activity against Leishmania promastigotes using the species Leishmania brasiliensis and Leishmania infantum and for trypanocidal activity using the epimastigotes of Trypanosoma cruzi. We also tested EHCSR for cytotoxicity against adhered cultured Murine J774 fibroblasts. The tests were performed in triplicate, and the percent mortality of parasites, IC₅₀ and percent toxicity were determined. With regard to anti-leishmania activity against L. infantum, there was a mean mortality of 45% at all concentrations, and against L. brasiliensis, a substantial effect was seen at 1000 μg/mL with 56.38% mortality, where the IC₅₀ values were 1338.76 and 987.35 μg/mL, respectively. Trypanocidal activity was notably high at 1000 μg/mL extract with 82.31% mortality of epimastigotes. Cytotoxicity at the highest extract concentrations of 500 and 1000 μg/mL was respectively 75.12% and 94.14%, with IC₅₀ = 190.24 μg/mL. Despite that the extract has anti-parasitic activity, its substantial cytotoxicity against fibroblasts cells makes its systemic use nonviable as a therapeutic alternative.     

In vitro assessment of 3-alkoxy-5-nitroindazole-derived ethylamines and related compounds as potential antileishmanial drugs

Leishmaniasis is a widespread neglected tropical disease complex that is responsible of one million new cases per year. Current treatments are outdated and pose many problems that new drugs need to overcome. With the goal of developing new, safe, and affordable drugs, we have studied the in vitro activity of 12 different 5-nitroindazole derivatives that showed previous activity against different strains of Trypanosoma cruzi in a previous work. T. cruzi belongs to the same family as Leishmania spp., and treatments for the disease it produces also needs renewal. Among the derivatives tested, compounds 1, 2, 9, 10, 11, and 12 showed low J774.2 macrophage toxicity, while their effect against both intracellular and extracellular forms of the studied parasites was higher than the ones found for the reference drug Meglumine Antimoniate (Glucantime®). In addition, their Fe-SOD inhibitory effect, the infection rates, metabolite alteration, and mitochondrial membrane potential of the parasites treated with the selected drugs were studied in order to gain insights into the action mechanism, and the results of these tests were more promising than those found with glucantime, as the leishmanicidal effect of these new drug candidates was higher. The promising results are encouraging to test these derivatives in more complex studies, such as in vivo studies and other experiments that could find out the exact mechanism of action.     

Synthesis and preliminary evaluation of new ursolic and oleanolic acids derivatives as antileishmanial agents

A series of new ursolic and oleanolic acids derivatives was synthesized via ursolic or oleanolic acids, previously extracted from South American Ilex species. These new compounds were tested for in vitro antiparasitic activity on Leishmania amazonensis and Leishmania infantum strains. Some of these compounds showed activity against the promastigote forms of L. amazonensis or L. infantum, with IC₅₀ ranging from 5 to 12 μM. As expected, most of the compounds showed a significant level of cytotoxicity against monocytes (IC₅₀ = 2-50 μM). From a structure-activity relationships point of view, these pharmacological results enlightened mainly the importance of an acetylation at position 3 of the oleanolic acid skeleton in the activity against the L. amazonensis strain, and of a bis-(3-aminopropyl)piperazine moiety on the carboxylic function of ursolic acid against the L. infantum strain.     

New coumestan and coumaronochromone derivatives from Dalbergia boehmii Taub. (Fabaceae)

Chemical investigation of leaves and heartwood of Dalbergia boehmii resulted in the isolation of two new phenolic compounds, designated dalbergestan (1) and dalbergichromone (2), along with eleven known compounds, carpachromene (3), proanthocyanidin A-2 (4); piceatannol (5); biochanin A (6); macckiain (7); homopterocarpin (8); angolensin (9); medicarpin (10); 2′,7-dihydroxy-4′,5′-dimethoxyisoflavone (11); 2′-methoxyformononetin (12); and genistein (13). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses including, IR, UV, 1D and 2D – NMR as well as HRMS data. Some of the isolated compounds were evaluated for their in vitro insulin secretion activity on isolated mice islets, leishmanicidal activity against L. major (DESTO) promastigotes and in vitro cytotoxicity on MCF-7 cell lines. All tested compounds were inactive on glucose-stimulated insulin secretion at stimulatory glucose (20.0 mM) from MIN6 cells. Compounds 3 (IC₅₀, 70.0 μg/ml), 6 (IC₅₀, 60.3 μg/ml), 7 (IC₅₀, 86.5 μg/ml) and 13 (IC₅₀, 62.6 μg/ml) exhibited low leishmanicidal activity while compound 12 (IC₅₀, 56.8 μg/ml) displayed a moderate activity. Compounds 3 and 5 were found to be active against MCF-7 at 50 μM with IC₅₀ value 33.2 ± 3.79 μg/ml and 42.64 ± 5.05 μg/ml respectively.     

Microbial transformation of nandrolone with Cunninghamella echinulata and Cunninghamella blakesleeana and evaluation of leishmaniacidal activity of transformed products

Therapeutic potential of nandrolone and its derivatives against leishmaniasis has been studied. A number of derivatives of nandrolone (1) were synthesized through biotransformation. Microbial transformation of nandrolone (1) with Cunninghamella echinulata and Cunninghamella blakesleeana yielded three new metabolites, 10β,12β,17β-trihydroxy-19-nor-4-androsten-3-one (2), 10β,16α,17β-trihydroxy-19-nor-4-androsten-3-one (3), and 6β,10β,17β-trihydroxy-19-nor-4-androsten-3-one (4), along with four known metabolites, 10β,17β-dihydroxy-19-nor-4-androsten-3-one (5), 6β,17β-dihydroxy-19-nor-4-androsten-3-one (6) 10β-hydroxy-19-nor-4-androsten-3,17-dione (7) and 16β,17β-dihydroxy-19-nor-4-androsten-3-one (8). Compounds 1–8 were evaluated for their anti-leishmanial activity. Compounds 1 and 8 showed a significant activity in vitro against Leishmania major. The leishmanicidal potential of compounds 1–8 (IC₅₀ = 32.0 ± 0.5, >100, 77.39 ± 5.52, 70.90 ± 1.16, 54.94 ± 1.01, 80.23 ± 3.39, 61.12 ± 1.39 and 29.55 ± 1.14 μM, respectively) can form the basis for the development of effective therapies against the protozoal tropical disease leishmaniasis.     

Field evidences for the positive effects of aerosols on tree growth

Theoretical and eddy covariance studies demonstrate that aerosol‐loading stimulates canopy photosynthesis, but field evidence for the aerosol effect on tree growth is limited. Here, we measured in situ daily stem growth rates of aspen trees under a wide range of aerosol‐loading in China. The results showed that daily stem growth rates were positively correlated with aerosol‐loading, even at exceptionally high aerosol levels. Using structural equation modeling analysis, we showed that variations in stem growth rates can be largely attributed to two environmental variables covarying with aerosol loading: diffuse fraction of radiation and vapor pressure deficit (VPD). Furthermore, we found that these two factors influence stem growth by influencing photosynthesis from different parts of canopy. Using field observations and a mechanistic photosynthesis model, we demonstrate that photosynthetic rates of both sun and shade leaves increased under high aerosol‐loading conditions but for different reasons. For sun leaves, the photosynthetic increase was primarily attributed to the concurrent lower VPD; for shade leaves, the positive aerosol effect was tightly connected with increased diffuse light. Overall, our study provides the first field evidence of increased tree growth under high aerosol loading. We highlight the importance of understanding biophysical mechanisms of aerosol‐meteorology interactions, and incorporating the different pathways of aerosol effects into earth system models to improve the prediction of large‐scale aerosol impacts, and the associated vegetation‐mediated climate feedbacks.     

Diversity of natural products of the genera Curvularia and Bipolaris

Covering from 1963 to 2017.This review provides a summary of some secondary metabolites isolated from the genera Curvularia and Bipolaris from 1963 to 2017. The study has a broad objective. First to afford an overview of the structural diversity of these genera, classifying them depending on their chemical classes, highlighting individual examples of chemical structures. Also some information regarding their biological activities are presented. Several of the compounds reported here were isolated exclusively from endophytic and pathogenic strains in culture, while few from other sources such as sea Anemone and fish. Some secondary metabolites of the genus Curvularia and Bipolaris revealed a fascinating biological activities included: anti-malarial, anti-biofouling, anti-larval, anti-inflammatory, anti-oxidant, anti-bacterial, anti-fungal, anti-cancer, leishmanicidal and phytotoxicity. Herein, we presented a bibliography of the researches accomplished on the natural products of Curvularia and Bipolaris, which could help in the future prospecting of novel or new analogues of active metabolites from these two genera.     

Mitracarpus frigidus aerial parts exhibited potent antimicrobial, antileishmanial, and antioxidant effects

The crude extract and the hexane, CH(2)Cl(2), EtOAc, n-BuOH, and hydromethanolic fractions of the aerial parts of Mitracarpus frigidus were evaluated against promastigote forms of two species of Leishmania (L. chagasi and L. amazonensis), 11 strains of bacteria (Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella enterica sorovar Tythimurium, Shigella sonnei, Klebsiella pneumoniae, Escherichia coli, Micrococcus luteus, Enterococcus faecalis, Enterobacter cloacae, Streptococcus pyogenes and Bacillus cereus) and two yeasts (Candida albicans and Cryptococcus neoformans). The antioxidant activity (DPPH radical scavenging activity and reducing power), cytotoxicity against mammalian cells, and the contents of phenolics and flavonoids were determined. Phytochemical analysis of the major groups of phytoconstituents is also reported. All samples showed antioxidant activity which was positively correlated to the content of phenolic compounds. S. sonnei, B. cereus and C. neoformans were susceptible to all extracts tested, except for the n-BuOH and hydromethanolic fractions, which demonstrated no antimicrobial activity. The lowest MIC was recorded for the CH(2)Cl(2) fraction against C. neoformans (MIC of 10 microg/ml), followed by B. cereus, S. sonnei, and E. cloacae (MIC of 20, 39 and 39 microg/ml, respectively). The CH(2)Cl(2) fraction was the most effective against L. chagasi (IC(50) of 6.7 microg/ml), and the hydromethanolic fraction exhibited the best activity against L. amazonensis (IC(50) of 9 microg/ml). A cytotoxic effect on mammalian cells was observed only for the crude extract and CH(2)Cl(2) fraction at the concentrations of 130 and 31 microg/ml, respectively. These results suggest that M. frigidus has interesting antimicrobial, antileishmanial and antioxidant activities.     

Molluscicidal and Leishmanicidal Activity of the Leaf Essential Oil of Syzygium cumini (L.) Skeels from Brazil

The chemical composition and biological potential of the essential oil extracted from Syzygium cumini leaves collected in Brazil were examined. GC/MS Analyses revealed a high abundance of monoterpenes (87.12%) in the oil. Eleven compounds were identified, with the major components being α‐pinene (31.85%), (Z)‐β‐ocimene (28.98%), and (E)‐β‐ocimene (11.71%). To evaluate the molluscicidal effect of the oil, it was tested against Biomphalaria glabrata and the LC₅₀ obtained was 90 mg/l. The essential oil also showed significant activity against Leishmania amazonensis, with an IC₅₀ value equal to 60 mg/l. In addition, to evaluate its toxicity towards a non‐target organism, the essential oil was tested against Artemia salina and showed a LC₅₀ of 175 mg/l. Thus, the essential oil of S. cumini showed promising activity as a molluscicidal and leishmanicidal agent and might be valuable in combating neglected tropical diseases such as schistosomiasis and leishmaniasis. Further research is being conducted with regard to the purification and isolation of the most active essential‐oil compounds.     

Fasciola hepatica: the effects of neuropharmacological agents upon in vitro motility

The effects of a wide range of neuropharmacological agents on the motility in vitro of Fasciola hepatica have been determined using an isometric transducer system. The neuromuscular blocking agents tubocurarine and decamethonium cause a long-term stimulation of the basal activity of the fluke. Acetylcholine causes an inhibition of activity. This effect is mimicked by the cholinergic agonists carbachol and nicotine, antagonised by the cholinergic blocking agents atropine and mecamylamine, and potentiated by eserine, a cholinesterase inhibitor. With nicotine and atropine the effects are accompanied by an increase in muscle tone at a concentration of 1 X 10(-2) M. Noradrenaline and adrenaline also cause some inhibition of activity, an effect antagonised by guanethidine, which blocks the release of noradrenaline. In contrast, dopamine stimulates fluke motility, whilst its antagonist dihydroergotamine causes an inhibition of activity. The monoamine oxidase inhibitors iproniazid and p-chloromercuribenzoic acid induce a stimulation of activity; with the latter there is an increase in muscle tone at a concentration of 1 X 10(-3) M. The amine depleting agents chloroamphetamine and reserpine, and the monoamine uptake inhibitors desipramine and nortriptyline produce an inhibition of fluke activity, as does the serotonin uptake inhibitor fluoxetine. High concentrations of chloroamphetamine (1 X 10(-2) M) and the uptake inhibitors (1 X 10(-3) M and above) also induce an increase in muscle tone. Serotonin causes a marked stimulation of motility. The pharmacological evidence is consistent with a neurotransmitter role of acetylcholine (inhibitory), dopamine (excitatory), and noradrenaline (inhibitory). The status of serotonin is discussed.     

Diabetes abolish cardioprotective effects of remote ischemic conditioning: evidences and possible mechanisms

Journal of Physiology and Biochemistry - Diabetes mellitus significantly hampers the development of cardioprotective response to remote pre/post/perconditioning stimuli by impairing the activation...