Abstract 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. leishmaniasis design synthesis hydrazidebased hydrazide based hybrids activities N1,4Dioxo1,4dihydronaphthalen2yl3,5dimethoxybenzohydrazide N14Dioxo14dihydronaphthalen2yl35dimethoxybenzohydrazide NDioxodihydronaphthalenyldimethoxybenzohydrazide N 1,4 Dioxo dihydronaphthalen 2 yl 3,5 dimethoxybenzohydrazide 1 4 3 5 (13 IC50 IC (IC5 183 83 1.8 µM 965 9 65 9.6 µM. . 4BromoN1,4dioxo1,4dihydronaphthalen2ylbenzohydrazide 4BromoN14dioxo14dihydronaphthalen2ylbenzohydrazide BromoNdioxodihydronaphthalenylbenzohydrazide Bromo dioxo benzohydrazide 16 (16 1216 12 12.1 LLCMK2 LLCMK LLC MK2 MK LLC-MK SI 95.28. 9528 95.28 95 28 95.28) Furthermore studies cruzain CPB28 CPB CPB2 8 CPB2. targets N1 4Dioxo1 4dihydronaphthalen2yl3 5dimethoxybenzohydrazide 14 1, 35 3, (1 IC5 (IC 18 1. 96 6 9. 4BromoN1 4dioxo1 4dihydronaphthalen2ylbenzohydrazide BromoN ylbenzohydrazide 121 12. 952 95.2 4Dioxo dihydronaphthalenyl 4dihydronaphthalen2yl ( 4BromoN 4dioxo dihydronaphthalenylbenzohydrazide 95.

Resumo Objetivo Avaliar os resultados obtidos do tratamento cirúrgico das fraturas maleolares do tornozelo associadas a lesão da sindesmose tibiofibular distal (STFD) submetidas a procedimento cirúrgico convencional de fixação da fratura e fixação da STFD pelo suture button (SB). Métodos Avaliou-se retrospectivamente 49 pacientes com uma média de idade de 45 anos e seguimento médio de 34,1 meses. A avaliação clínica e funcional foi baseada na escala visual analógica (EVA) e na escala American Foot and Ankle Society Score (AOFAS, na sigla em inglês) para tornozelo e retropé, retorno às atividades da rotina e retorno ao esporte. Resultados As médias pós-operatórias das escalas AOFAS e EVA foram, respectivamente, 97,06 (índice de confiança [IC 95%: 95,31 - 98,81] e 0,16 [IC 95% 0,04 - 0,29]. Todos os pacientes retornaram às atividades prévias do cotidiano, sendo que apenas 12 apresentaram algum sintoma residual. Não se verificou instabilidade pós-operatória em nenhum paciente. Ao todo, 46 pacientes retornaram às atividades desportivas e, destes, apenas 1 não retornou ao nível prévio à lesão. Apenas dois pacientes apresentaram alterações relacionadas ao SB. Não houve relato de insatisfação. Conclusão Em fraturas maleolares do tornozelo com lesão da STFD, a fixação da sindesmose com o SB demonstrou excelentes resultados pós-operatórios. Nível de Evidência IV, série de casos retrospectiva.

Abstract Objective To evaluate the results obtained from the surgical treatment of malleolar ankle fractures associated with distal tibiofibular syndesmosis (DTFS) injury submitted to conventional surgical procedure for fracture fixation and DTFS fixation by suture button (SB). Methods Forty-nine patients were retrospectively evaluated, with a mean age of 45 years old and a mean follow-up of 34.1 months. Clinical and functional evaluation was based on the visual analogue scale (VAS) and on the American Foot and Ankle Society Score (AOFAS) for ankle and hindfoot, return to routine activities, and return to sport. Results The postoperative mean AOFAS and VAS were, respectively, 97.06 (confidence interval [CI 95%: 95.31-98.81] and 0.16 [CI 95% 0,04 - 0,29]. All patients returned to previous daily activities, and only 12 showed some residual symptom. There was no postoperative instability in any patient. Forty-six patients returned to sports activities and, of these, only 1 did not return to the level prior to the injury. Only two patients presented SB-related alterations. There was no report of dissatisfaction. Conclusion In malleolar fractures of the ankle with DTFS injury, the fixation of syndesmosis with SB demonstrated excellent postoperative results. Level of Evidence IV, retrospective case series.

RESUMO Objetivo: comparar o uso de solução alcoólica de clorexidina 0,5% e de álcool 70% na antissepsia da pele para bloqueios do neuroeixo. Método: ensaio clínico randomizado de não inferioridade, com dois braços paralelos. Foram selecionados 70 pacientes candidatos à bloqueio do neuroeixo, randomicamente alocados para o grupo A (n=35), em que a antissepsia foi realizada com clorexidina alcoólica 0,5%, ou para o grupo B (n=35), em que se utilizou álcool etílico hidratado 70%. Foram coletadas, com swab, amostras para cultura em três momentos: antes da antissepsia, dois minutos após aplicação do antisséptico, e imediatamente após a punção. As amostras foram semeadas em três meios de cultura e foi contabilizado o número de unidades formadoras de colônias (UFC) por cm². Resultados: não houve diferença entre os grupos quanto à idade, ao sexo, ao índice de massa corporal, ao tempo para realização do bloqueio ou tipo de bloqueio. Também não houve diferenças entre os grupos na contagem de UFC/cm² antes da antissepsia. Constatou-se menor crescimento bacteriano no grupo B dois minutos após aplicação do antisséptico (p=0,048), mas não houve diferença entre os grupos quanto ao número de UFC/cm² ao final da punção. Conclusão: o álcool 70% mostrou-se mais efetivo em reduzir o número de UFC/cm² após dois minutos, e não houve diferença entre os dois grupos quanto à colonização da pele ao final do procedimento. Esses resultados sugerem que o álcool 70% pode ser opção para antissepsia da pele antes de bloqueios do neuroeixo. Registro ensaio clínico: ClinicalTrials.gov, NCT02833376.

ABSTRACT Objective: to compare the use of 0.5% alcoholic chlorhexidine and 70% alcohol in skin antisepsis for neuraxial blocks. Method: this is a non-inferiority randomized clinical trial, with two parallel arms. Seventy patients who were candidates for neuraxial block were randomly allocated to group A (n = 35), in whom antisepsis was performed with 0.5% alcoholic chlorhexidine, or to group B (n = 35), in whom we used 70% hydrated ethyl alcohol. Swabs were harvested for culture at three times: before antisepsis, two minutes after application of the antiseptic, and immediately after puncture. The samples were sown in three culture media and the number of colony forming units (CFU) per cm² was counted. Results: there was no difference between the groups regarding age, sex, body mass index, time to perform the block or type of block. There were no differences between groups in the CFU/cm² counts before antisepsis. There was less bacterial growth in group B two minutes after application of the antiseptic (p = 0.048), but there was no difference between the groups regarding the number of CFU/cm² at the end of the puncture. Conclusion: 70% alcohol was more effective in reducing the number of CFU/cm² after two minutes, and there was no difference between the two groups regarding skin colonization at the end of the procedure. These results suggest that 70% alcohol may be an option for skin antisepsis before neuraxial blocks. Trial registration: ClinicalTrials.gov, NCT02833376.

Abstract 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).

Natural and synthetic sulfur-bearing organic compounds have many applications in medicinal chemistry. This article reports the preparation of amphiphilic β-hydroxy sulfides, sulfoxides, and sulfones derived from cardanol and glycerol. Thiolysis of cardanol epoxide 3 with various thiols (4a-4j) in ethanol or water yielded the corresponding β-hydroxy sulfides 5a-5j (61-95%). Treatment with 30% H2O2 in acetic acid at ambient temperature completely converted these products into β-hydroxy sulfoxides 6a-6j and sulfones 7a, 7c-7f, 7h-7j. The synthesized compounds were characterized by 1H nuclear magnetic resonance (NMR), 13C NMR, high-resolution mass spectroscopy (HRMS) and performed the in vitro evaluation antimicrobial activities against standard strains of Staphylococcus aureus and Escherichia coli. Compounds 5a, 5d-5f, and 5h-5j proved moderately active against S. aureus. None of the compounds were active against E. coli. β-Hydroxy-sulfides 5a-5j were also evaluated for antioxidant properties but failed to exhibit significant activity.

The synthesis of novel amino alcohol derivatives based on cardanol and glycerol were achieved in good yields and characterized by 1H and 13C NMR (nuclear magnetic resonance) and MS (mass spectrometry). In addition, we evaluated the in vitro antimicrobial activity against Gram-positive (Staphylococcus aureus, standard and clinical strains), Gram-negative (Escherichia coli) and M. tuberculosis bacterial strains. The bioassay results indicated that four compounds showed activity against S. aureus, including the clinical resistant strain, with MIC (minimum inhibitory concentration) ranging from 3.90 to 15.60 µg mL-1 and M. tuberculosis, with MIC90 (minimum inhibitory concentration required to inhibit the growth of 90% of organisms) ranging from 3.18 to 7.36 µg mL-1.

Abstract The increased incidence of cancer and its high treatment costs have encouraged the search for new compounds to be used in adjuvant therapies for this disease. This study discloses the synthesis of (Z)-4-((1,5-dimethyl-3-oxo-2-phenyl-2,3dihydro-1H-pyrazol-4-yl) amino)-4-oxobut-2-enoic acid (IR-01) and evaluates not only the action of this compound on genetic integrity, increase in splenic phagocytosis and induction of cell death but also its effects in combination with the commercial chemotherapeutic agents doxorubicin, cisplatin and cyclophosphamide. IR-01 was designed and synthesized based on two multifunctionalyzed structural fragments: 4-aminoantipyrine, an active dipyrone metabolite, described as an antioxidant and anti-inflammatory agent; and the pharmacophore fragment 1,4-dioxo-2-butenyl, a cytotoxic agent. The results indicated that IR-01 is an effective chemoprotector because it can prevent clastogenic and/or aneugenic damage, has good potential to prevent genomic damage, can increase splenic phagocytosis and lymphocyte frequency and induces cell death. However, its use as an adjuvant in combination with chemotherapy is discouraged since IR-01 interferes in the effectiveness of the tested chemotherapeutic agents. This is a pioneer study as it demonstrates the chemopreventive effects of IR-01, which may be associated with the higher antioxidant activity of the precursor structure of 4-aminoantipyrine over the effects of the 1,4-dioxo-2-butenyl fragment.

Abstract Chemotherapy is one of the major approaches for the treatment of cancer. Therefore, the development of new chemotherapy drugs is an important aspect of medicinal chemistry. Chemotherapeutic agents include isocoumarins, which are privileged structures with potential antitumoral activity. Herein, a new 3-substituted isocoumarin was synthesized from 2-iodo-3,5-dimethoxy-benzoic acid and oct-1-yne in a cross-coupling Sonogashira reaction followed by a copper iodide-catalyzed intramolecular cyclization as key step using MeOH/Et3N as the solvent system. The present study also evaluated the leukometry, phagocytic activity, genotoxic potential and cell death induction of three different doses (5 mg/kg, 10 mg/kg and 20 mg/kg) of this newly synthesized isocoumarin, alone and in combination with the commercial chemotherapeutic agents cyclophosphamide (100 mg/kg) and cisplatin (6 mg/kg) in male Swiss mice. The results suggest that the isocoumarin has genotoxicity and causes cell death. Noteworthy, this new compound can increase splenic phagocytosis and lymphocyte frequency, which are related to immunomodulatory activity. When combined with either cyclophosphamide or cisplatin, chemopreventive activity led to a reduction in the effects of both chemotherapeutic drugs. Thus, the new isocoumarin is not a candidate for chemotherapeutic adjuvant in treatments using cyclophosphamide or cisplatin. Nevertheless, the compound itself is an important prototype for the development of new antitumor drugs.

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.

Abstract Cardanol is an effective antioxidant and is a compound with antimutagenic and antitumoral activity. Here, we evaluated the genotoxic and mutagenic potential of saturated side chain cardanol and its effects in combination with cyclophosphamide in preventing DNA damage, apoptosis, and immunomodulation. Swiss mice were treated with cardanol (2.5, 5 and 10 mg/kg) alone or in combination with cyclophosphamide (100 mg/kg). The results showed that cardanol is an effective chemopreventive compound, with damage reduction percentages that ranged from 18.9 to 31.76% in the comet assay and from 45 to 97% in the micronucleus assay. Moreover, cardanol has the ability to reduce the frequency of apoptosis induced by cyclophosphamide. The compound did not show immunomodulatory activity. A final interpretation of the data showed that, despite its chemoprotective capacity, cardanol has a tendency to induce DNA damage. Hence, caution is needed if this compound is used as a chemopreventive agent. Also, this compound is likely not suitable as an adjuvant in chemotherapy treatments that use cyclophosphamide.

Octocrylene (2-ethylhexyl 2-cyano-3,3-diphenyl-2-propenoate) is present in several sunscreens and is known to work synergistically with UV filters. We prepared eight octocrylene-related compounds to test their photoprotective activities by measuring diffuse transmittance. The compounds had varied photoprotection profiles, with Sun Protection Factors (SPF) ranging from 1 to 5 and UVA Protection Factors (UVAPF) ranging from 1 to 8. Compounds 4, 5, and 7 showed the best protection against UVB sunrays, while compounds 5, 6, and 7 presented the best results for protection from UVA, so compound 7 had the most balanced protection overall. Results for compounds 4, 8, and 9 are reported for the first time in the literature.

An on-line method for Cd and Pb pre-concentration and simultaneous determination in acid digested seafood by inductively coupled plasma optical emission spectrometry (ICP OES) was developed. The on-line pre-concentration was based on the complex formation of the analytes with the ammonium salt of O,O-diethyldithiophosphate (DDTP) and using the Amberlite XAD-4 resin as a solid support in a homemade column. Different conditions of the flow injection system, such as solutions flow rates, nebulizer pressure and eluent concentration were optimized. Three certified reference materials of lobster hepatopancreas, dogfish liver and fish protein, three samples of fish muscle and three samples of shrimp were digested with HNO3, H2O2 and H2SO4 in a microwave system under reflux. DDTP was added in the solutions obtained, and the mixture was injected in the FI system. Calibration curves for Cd and Pb were obtained using the standard solutions in the concentration range 0.05-0.5 µg mL-1 in the digestion medium, submitted to the same pre-concentration procedure. The quantification limits (3.3 x LOD) for 5 min of pre-concentration time were 0.005 mg kg-1 Cd2+ and 0.1 mg kg-1 Pb2+ in the sample of fish or shrimp in natura, considering 1.0 g of the sample in a final volume of 50 mL. The agreement of the obtained concentrations with the certified ones (Student t-test, 95% confidence) and the recoveries of spiked real samples, from 90 to 120%, demonstrated good accuracy. Precision was also adequate, with relative standard deviations from 2 to 13%. The method was accurate, precise and certainly could be applied to the digested samples of different natures.

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).

A method for evaluating inorganic constituents in the grass by ICP OES is proposed. The samples were digested with nitric acid plus hydrogen peroxide in a microwave system. Seventeen samples were collected in the metropolitan area of Curitiba and Castro in the Paraná State, Brazil. The following elements were studied: Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, P, Pb, Sb, Se and Zn. The linear coefficients of the curves were higher than 0.999 and the precision, expressed as the relative standard deviation, which was below 10%, being considered adequate. The accuracy was validated by using the recovery test (recoveries from 80 to 107%) and by the analysis of botanical certified materials. For one sample, two other digestion procedures, using two different mixtures of nitric and hydrochloric acids, produced results in agreement with the adopted procedure. Eleven out of the twenty studied elements could be quantified in real samples. High concentrations of Ca, K, Mg and P, the essential elements for bovines and other animals, were found. The results were evaluated using the principal component analysis that gathered the samples in three groups, according to the areas where the plants were grown.

A busca por herbicidas eficientes e ambientalmente corretos tem sido foco de numerosos estudos sobre a síntese de compostos isolados de fontes naturais. Citosporonas, as quais são lipídeos fenólicos isolados de fungos, apresentam notáveis propriedades biológicas. Este artigo relata a preparação das citosporonas A, B e C, através de uma rota sintética curta e com excelentes rendimentos. Os compostos sintetizados foram avaliados quanto às suas atividades alelopáticas em sementes de alface (Lactuca sativa L). Citosporona A e seu precursor metilado mostraram notável atividade alelopática, inibindo a germinação de sementes e crescimento das plântulas.

The search for efficient, environmentally friendly herbicides has been the focus of numerous studies on the organic synthesis of compounds isolated from natural sources. Cytosporones, which are phenolic lipids isolated from fungi, exhibit noteworthy biological properties. This paper reports the preparation of cytosporones A-C from the same starting material through a short synthetic route, with good yields. All compounds were tested for allelopathic activity on lettuce (Lactuca sativa L) seeds. Cytosporone A and its methylated precursor showed remarkable allelopathic activity, inhibiting seed germination and plantule growth.