Design, synthesis and identification of novel molecular hybrids based on naphthoquinone aromatic hydrazides as potential trypanocide and leishmanicidal agents.

In pursuit of potential agents to treat Chagas disease and leishmaniasis, we report the design, synthesis, and identification novel naphthoquinone hydrazide-based molecular hybrids. The compounds were subjected to in vitro trypanocide and leishmanicidal activities. N'-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-3,5-dimethoxybenzohydrazide (13) showed the best performance against Trypanosoma cruzi (IC50 1.83 µM) and Leishmania amazonensis (IC50 9.65 µM). 4-Bromo-N'-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzohydrazide (16) exhibited leishmanicidal activity (IC50 12.16 µM). Regarding trypanocide activity, compound 13 was low cytotoxic to LLC-MK2 cells (SI = 95.28). Furthermore, through molecular modeling studies, the cysteine proteases cruzain, rhodesain and CPB2.8 were identified as the potential biological targets.

Chemotherapeutic Mechanism of Action of the Synthetic Resorcinolic Methyl 3,5-dimethoxy-2-octanoylbenzoate.

Resorcinolic lipids are described as potential examples of selective chemotherapeutic adjuvants that can enhance the effects of cyclophosphamide (CYC) while promoting cell death without causing DNA damage. Therefore, the current study attempted to describe how the resorcinolic lipid methyl 3,5-dimethoxy-2-octanoylbenzoate (AMS35BB) interacted with DNA (DNA docking) and how this compound affected genetic toxicology models and other biological characteristics when combined with CYC. We observed that AMS35BB, used alone (7.5 and 10 mg/kg), increases the frequency of genomic damage (comet assay) but not chromosomal damage (micronuclei assay), lowers phagocytosis, and promotes cell death in Swiss male mice. When used in association with CYC, AMS35BB can reduce the risk of genomic damage by up to 33.8% as well as chromosomal damage, splenic phagocytosis, cell death, and lymphocyte frequency. Molecular docking showed that AMS35BB had a higher affinity than the active metabolite of CYC for binding to the DNA double helix major groove. As a result, AMS35BB has the potential to be both an adjuvant when used in association with CYC and a therapeutic candidate for the development of a selective chemotherapeutic drug.

Investigation of the Potential Targets behind the Promising and Highly Selective Antileishmanial Action of Synthetic Flavonoid Derivatives.

Leishmaniases are among the neglected tropical diseases that still cause devastating health, social, and economic consequences to more than 350 million people worldwide. Despite efforts to combat these vector-borne diseases, their incidence does not decrease. Meanwhile, current antileishmanial drugs are old and highly toxic, and safer presentations are unaffordable to the most severely affected human populations. In a previous study by our research group, we synthesized 17 flavonoid derivatives that demonstrated impressive inhibition capacity against rCPB2.8, rCPB3, and rH84Y. These cysteine proteases are highly expressed in the amastigote stage, the target form of the parasite. However, although these compounds have been already described in the literature, until now, the amastigote effect of any of these molecules has not been proven. In this work, we aimed to deeply analyze the antileishmanial action of this set of synthetic flavonoid derivatives by correlating their ability to inhibit cysteine proteases with the action against the parasite. Among all the synthesized flavonoid derivatives, 11 of them showed high activity against amastigotes of Leishmania amazonensis, also providing safety to mammalian host cells. Furthermore, the high production of nitric oxide by infected cells treated with the most active cysteine protease B (CPB) inhibitors confirms a potential immunomodulatory response of macrophages. Besides, considering flavonoids as multitarget drugs, we also investigated other potential antileishmanial mechanisms. The most active compounds were selected to investigate another potential biological pathway behind their antileishmanial action using flow cytometry analysis. The results confirmed an oxidative stress after 48 h of treatment. These data represent an important step toward the validation of CPB as an antileishmanial target, as well as aiding in new drug discovery studies based on this protease.

Catalyst- and metal-free C(sp2)-H bond selenylation of (N-hetero)-arenes using diselenides and trichloroisocyanuric acid at room temperature.

In this paper, we report an eco-friendly approach for the C(sp2)-H bond selenylation of imidazopyridines and other N-heteroarenes as well as simple arenes at ambient temperature. This new protocol consists of the reaction between (N-hetero)-arenes and the diorganyl-diselenides and trichloroisocyanuric acid (TCCA)-ethanol reagent system. In a short reaction time, the desired selenylated products were obtained regioselectively in good yields, with tolerance for a wide range of functional groups.

Straightforward synthesis of cytosporone analogs AMS35AA and AMS35BB.

Cytosporones, a class of octaketide resorcinolic lipids, have drawn the attention of researchers for exhibiting a number of notable biological properties. Herein, we describe routes to synthesize the bioactive synthetic resorcinolic lipids AMS35AA and AMS35BB with excellent overall yields using 3,5-dimethoxybenzoic acid as the starting material. The methods proved remarkably efficient to achieve the target compounds and comprise the synthesis of AMS35AA catalyzed by ascorbic acid (vitamin C).

l-Hypaphorine and d-hypaphorine: Specific antiacetylcholinesterase activity in rat brain tissue.

Acetylcholinesterase (AChEis) inhibitors are used to treat neurodegenerative diseases like Alzheimer's disease (AD). l-Hypaphorine (l-HYP) is a natural indole alkaloid that has been shown to have effects on the central nervous system (CNS). The goal of this research was to synthesize l-HYP and d-HYP and test their anticholinesterasic properties in rat brain regions. l-HYP suppressed acetylcholinesterase (AChE) activity only in the cerebellum, whereas d-HYP inhibited AChE activity in all CNS regions studied. No cytotoxic effect on normal human cells (HaCaT) was observed in the case of l-HYP and d-HYP although an increase in cell proliferation. Molecular modeling studies revealed that d-HYP and l-HYP have significant differences in their binding mode positions and interact stereospecifically with AChE's amino acid residues.

S-(4-Methoxyphenyl)-4-methoxybenzenesulfonothioate as a Promising Lead Compound for the Development of a Renal Carcinoma Agent.

Organosulfur compounds show cytotoxic potential towards many tumor cell lines. Disulfides and thiosulfonates act through apoptotic processes, inducing proteins associated with apoptosis, endoplasmic reticulum stress, and the unfolded protein response. Three p-substituted symmetric diaryl disulfides and three diaryl thiosulfonates were synthesized and analyzed for inhibition of tubulin polymerization and for human cancer cell cytotoxic activity against seven tumor cell lines and a non-tumor cell line. S-(4-methoxyphenyl)-4-methoxybenzenesulfonothioate (6) exhibited inhibition of tubulin polymerization and showed the best antiproliferative potential, especially against the 786-0 cell line, being six times more selective as compared with the non-tumor cell line. In addition, compound 6 was able to activate caspase-3 after 24 and 48 h treatments of the 786-0 cell line and induced cell-cycle arrest in the G2/M stage at the highest concentration evaluated at 24 and 48 h. Compound 6 was able to cause complete inhibition of proliferation, inducing the death of 786-0 cells, by increasing the number of cells at G2/M and greater activation of caspase-3.

A potent larvicidal agent against Aedes aegypti mosquito from cardanol.

Cardanol is a constituent of Cashew Nut Shell Liquid that presents larvicidal activity against Aedes aegypti. The isolation of cardanol is somewhat troublesome, however, in this work we describe an efficient and inexpensive method to obtain it as a pure material. The compound was used as starting material to make chemical transformation leading to saturated cardanol, epoxides and, halohydrins. These derivatives were tested for toxicity against Aedes aegypti larvae. The results showed that iodohydrins are very promising compounds for making commercial products to combat the vector mosquito larvae presenting a LC50 of 0.0023 ppm after 72 h of exposure.

A potent larvicidal agent against Aedes aegypti mosquito from cardanol

ABSTRACT Cardanol is a constituent of Cashew Nut Shell Liquid that presents larvicidal activity against Aedes aegypti. The isolation of cardanol is somewhat troublesome, however, in this work we describe an efficient and inexpensive method to obtain it as a pure material. The compound was used as starting material to make chemical transformation leading to saturated cardanol, epoxides and, halohydrins. These derivatives were tested for toxicity against Aedes aegypti larvae. The results showed that iodohydrins are very promising compounds for making commercial products to combat the vector mosquito larvae presenting a LC50 of 0.0023 ppm after 72 h of exposure.

Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity.

We have devised a procedure for the synthesis of analogs of combretastatin A-4 (CA-4) containing sulfur and selenium atoms as spacer groups between the aromatic rings. CA-4 is well known for its potent activity as an inhibitor of tubulin polymerization, and its prodrugs combretastatin A-4 phosphate (CA-4P) and combretastatin A-1 phosphate (CA-1P) are being investigated as antitumor agents that cause tumor vascular collapse in addition to their activity as cytotoxic compounds. Here we report the preparation of two sulfur analogs and one selenium analog of CA-4. All synthesized compounds, as well as several synthetic intermediates, were evaluated for inhibition of tubulin polymerization and for cytotoxic activity in human cancer cells. Compounds 3 and 4 were active at nM concentration against MCF-7 breast cancer cells. As inhibitors of tubulin polymerization, both 3 and 4 were more active than CA-4 itself. In addition, 4 was the most active of these agents against 786, HT-29 and PC-3 cancer cells. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA-4 to tubulin within the colchicine site.

SYNTHESIS AND BIOLOGICAL ACTIVITY OF SULFUR COMPOUNDS SHOWING STRUCTURAL ANALOGY WITH COMBRETASTATIN A-4.

We extended our previous exploration of sulfur bridges as bioisosteric replacements for atoms forming the bridge between the aromatic rings of combretastatin A-4. Employing coupling reactions between 5-iodo-1,2,3-trimethoxybenzene and substituted thiols, followed by oxidation to sulfones with m-CPBA, different locations for attaching the sulfur atom to ring A through the synthesis of nine compounds were examined. Antitubulin activity was performed with electrophoretically homogenous bovine brain tubulin, and activity occurred with the 1,2,3-trimethoxy-4-[(4-methoxyphenyl)thio]benzene (12), while the other compounds were inactive. The compounds were also tested for leishmanicidal activity using promastigote forms of Leishmania braziliensis (MHOM/BR175/M2904), and the greatest activity was observed with 1,2,3-trimethoxy-4-(phenylthio)benzene (10) and 1,2,3-trimethoxy-4-[(4-methoxyphenyl) sulfinyl]benzene (15).

(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone inhibits tubulin polymerization, induces G2/M arrest, and triggers apoptosis in human leukemia HL-60 cells.

(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a known cytotoxic compound belonging to the phenstatin family. However, the exact mechanism of action of PHT-induced cell death remains to be determined. The aim of this study was to investigate the mechanisms underlying PHT-induced cytotoxicity. We found that PHT displayed potent cytotoxicity in different tumor cell lines, showing IC50 values in the nanomolar range. Cell cycle arrest in G2/M phase along with the augmented metaphase cells was found. Cells treated with PHT also showed typical hallmarks of apoptosis such as cell shrinkage, chromatin condensation, phosphatidylserine exposure, increase of the caspase 3/7 and 8 activation, loss of mitochondrial membrane potential, and internucleosomal DNA fragmentation without affecting membrane integrity. Studies conducted with isolated tubulin and docking models confirmed that PHT binds to the colchicine site and interferes in the polymerization of microtubules. These results demonstrated that PHT inhibits tubulin polymerization, arrests cancer cells in G2/M phase of the cell cycle, and induces their apoptosis, exhibiting promising anticancer therapeutic potential.

Synthesis method for thiosulfonate and report of its insecticidal activity in Anagasta kuehniella (Lepidoptera: Pyralidae).

Insect pests have caused economic losses valued at billions of dollars in agricultural production. Anagasta kuehniella (Zeller), the Mediterranean flour moth, is of major economic importance as a flour and grain feeder and is often a severe pest in flourmills. This study provides a suitable route for the direct preparation of thiosulfonates 2 and 3 from thiols, under mild conditions, with good yields; these thiosulfonates were tested for their regulatory effect on insect growth. The chronic ingestion of thiosulfonates resulted in a significant reduction in larval survival and weight. In addition, the tryptic activity of larvae was sensitive to these thiosulfonates. Results suggest that thiosulfonates 2 and 3 have a potential antimetabolic effect when ingested by A. kuehniella. The use of AgNO(3)/BF(3)·OEt(2) and Al(H(2)PO(4))(3)/HNO(3) provides a suitable route for the direct preparation of thiosulfonates from thiols under mild conditions with good yields. These thiosulfonates were toxic for A. kuehniella larvae, suggesting their potential as biotechnological tools.

The filler content of the dental composite resins and their influence on different properties.

The purpose of this study was to compare the inorganic content and morphology of one nanofilled and one nanohybrid composite with one universal microhybrid composite. The Vickers hardness, degree of conversion and scanning electron microscope of the materials light-cured using LED unit were also investigated. One nanofilled (Filtek™ Supreme XT), one nanohybrid (TPH®(3)) and one universal microhybrid (Filtek™ Z-250) composite resins at color A(2) were used in this study. The samples were made in a metallic mould (4 mm in diameter and 2 mm in thickness). Their filler weight content was measured by thermogravimetric analysis (TG). The morphology of the filler particles was determined using scanning electron microscope equipped with a field emission gun (SEM-FEG). Vickers hardness and degree of conversion using FT-IR spectroscopy were measured. Filtek™ Z-250 (microhybrid) composite resin shows higher degree of conversion and hardness than those of Filtek™ Supreme XT (nanofilled) and TPH®(3) (nanohybrid) composites, respectively. The TPH(3)® (nanohybrid) composite exhibits by far the lowest mechanical property. Nanofilled composite resins show mechanical properties at least as good as those of universal hybrids and could thus be used for the same clinical indications as well as for anterior restorations due to their high aesthetic properties.

Assessment of genotoxic effects of (4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone in human lymphocytes.

(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) belongs to the phenstatin family. This compound has been studied due to its potent cytotoxicity and ability to inhibit tubulin assembly. The present study aimed to evaluate the mutagenic potential of PHT in human lymphocytes. PHT displayed cytotoxicity in human lymphocytes with an IC50 value of 5.68 µM, and therefore, concentrations of 0.25, 0.5, 1.0, 2.0, and 4.0 µM were used for all protocols. The alkaline comet assay and chromosome aberration (CA) analysis were performed in different phases of the cell cycle (G1, G1/S, transition, and G2), to evaluate the DNA-damaging and clastogenic effects of PHT, respectively. CA analysis was carried out in the presence or absence of colchicine to evaluate the action of PHT in the mitotic phase. PHT was cytotoxic and significantly reduced the mitotic index with drug exposure in all phases of cell cycle. Interestingly, it induced an increase in mitotic index in experimental protocols without colchicine, corroborating its action as an antitubulin agent. It also induced DNA damage and was clastogenic with drug exposure in all phases of the cell cycle, in the presence or absence of colchicine. In conclusion, PHT induces DNA damage and exerts clastogenic effects in human lymphocytes.

In vitro cytotoxic activity of Brazilian Middle West plant extracts

Cytotoxic activity of eight plant extracts, native from the Mid-West of Brazil comprising Cerrado, Pantanal and semideciduous forest, was evaluated for MDA-MB-435, SF-295, and HCT-8 cancer cell strains. A single 100 µg.mL-1 dose of each extract was employed with 72 h of incubation for all tests. Doxorubicin (1 µg.mL-1) was used as the positive control and the MTT method was used to detect the activity. Cytotoxicity of distinct polarities was observed in thirty extracts (46 percent), from different parts of the following species: Tabebuia heptaphylla (Vell.) Toledo, Bignoniaceae, Tapirira guianensis Aubl., Anacardiaceae, Myracrodruon urundeuva Allemão, Anacardiaceae, Schinus terebinthifolius Raddi, Anacardiaceae, Gomphrena elegans Mart., Amaranthaceae, Attalea phalerata Mart. ex Spreng., Arecaceae, Eugenia uniflora L., Myrtaceae, and Annona dioica A. St.-Hil., Annonaceae. Extracts of at least two tested cell strains were considered to be highly active since their inhibition rate was over 75 percent.

Investigation of the photodynamic effects of curcumin against Candida albicans.

This study describes the association of curcumin with light emitting diode (LED) for the inactivation of Candida albicans. Suspensions of Candida were treated with nine curcumin concentrations and exposed to LED at different fluences. The protocol that showed the best outcomes for Candida inactivation was selected to evaluate the effect of the preirradiation time (PIT) on photodynamic therapy (PDT) effectiveness, the uptake of curcumin by C. albicans cells and the possible involvement of singlet oxygen in the photodynamic action. Curcumin-mediated PDT was also assessed against biofilms. In addition to the microbiological experiments, similar protocols were tested on a macrophage cell line and the effect was evaluated by Methyltetrazolium assay (MTT) and SEM analysis. The optical properties of curcumin were investigated as a function of illumination fluence. When compared with the control group, a statistically significant reduction in C. albicans viability was observed after PDT (P < 0.05), for both planktonic and biofilm cultures. Photodynamic effect was greatly increased with the presence of curcumin in the surrounding media and the PIT of 20 min improved PDT effectiveness against biofilms. Although PDT was phototoxic to macrophages, the therapy was more effective in inactivating the yeast cell than the defense cell. The spectral changes showed a high photobleaching rate of curcumin.

In vitro and in vivo antitumor effects of (4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone.

PURPOSE: (4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a phenstatin analog compound. PHT is a known tubulin inhibitor that has potent cytotoxic activity. In the present study, PHT was synthesized and its antitumor activity was determined using in vitro and in vivo experimental models. METHODS: The in vitro cytotoxic activity of the PHT was determined by the MTT assay. The antimitotic and hemolytic effects were determined based on the inhibition of sea urchin embryo development and lysis of mouse erythrocytes, respectively. In vivo antitumor activity was assessed in mice inoculated with sarcoma 180 cells. RESULTS: In vitro, PHT displayed cytotoxicity in tumor cell lines, showing IC(50) values in the nanomolar range. In addition, it inhibited sea urchin embryo development during all phases examined, first and third cleavage and blastula stage. However, PHT did not induce hemolysis using mouse erythrocytes, suggesting that the cytotoxicity of PHT does not involve membrane damage. The in vivo study demonstrated tumor inhibition rates of 30.9 and 48.2% for PHT at doses of 20 and 40 mg/kg, respectively. In addition, PHT was also able to increase the response elicited by 5-fluorouracil (5-FU) from 33.3 to 55.7%. The histopathological analysis of liver, kidney, and spleen showed that they were just moderately affected by PHT treatment. Neither enzymatic activity of transaminases nor urea levels were significantly affected. Hematological analysis showed leukopenia after 5-FU treatment, but this effect was prevented when 5-FU was combined with PHT. CONCLUSIONS: In conclusion, PHT exhibited in vitro and in vivo antitumor effects without substantial toxicity.

Intraosseous myofibroma simulating an odontogenic lesion.

Myofibroma is a rare benign nodular tumor of the soft tissues, bones, or internal organs, and may affect both children and adults. It is mostly found in the head and neck region, although uncommon in the jaw bones, where only a few lesions have been described. Radiographically, it may appear as a well-defined unilocular radiolucent entity simulating a cystic or odontogenic lesion. Histopathologic findings alone may be insufficient for a final diagnosis, and immunostaining for markers such as vimentin, alpha-smooth muscle actin, desmin and S-100 may be required. Intraosseous myofibroma is a diagnostic challenge and requires careful histopathologic, immunohistochemical and radiographic correlation. The present article describes a conservatively treated intraosseous myofibroma that occurred in a 7-year-old girl. The clinical, radiographic, histopathologic and immunohistochemical features are discussed.

Fotoativação de resina composta utilizando-se laser de argônio em diferentes comprimentos de onda / Photo-activation of composite resin by the use of argon laser at different wavelengths

Muitos fatores promovem influência no processo de fotoativação. Assim, o propósito deste estudo foi avaliar a interferência de diferentes comprimentos de onda e tempos de exposição na dureza, no grau de conversão e alteração de temperatura durante a fotoativação. A resina composta microhíbrida Filtek Z-250 (3M/ESPE) na cor A2 foi utilizada na confecção dos espécimes em matriz metálica (2mm de espessura e 5mm de diâmetro), sendo fotoativadas por laser de argônio (Coerente, Innova 200-20, EUA) em modo standard com intensidade constante por 15, 40 e 60 segundos de exposição para as medidas de dureza Vickers e alteração de temperatura. Para o teste de grau de conversão, os espécimes foram fotoativados durante 10 e 20 segundos. A análise dos valores médios para os diferentes testes foram realizadas pela Análise de Variância (ANOVA) e teste Tukey (p<0,05). Foi observada diferença estatisticamente significante entre os diferentes comprimentos de onda utilizados. O comprimento de onda de 488nm promoveu os maiores valores de dureza e grau de conversão e a menor alteração de temperatura. O comprimento de onda de 488nm foi mais eficiente no processo de fotoativação.