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Azithromycin (AZM) is a well-known macrolide-type antibiotic that has been used in the treatment of infections and inflammations. Knowledge of the predominant molecular structure in solution is a prerequisite for an understanding of the interactions of the drug in biological media. Experimental structural determination can be carried out for samples in solid-state (X-ray diffraction technique) and gas phase (electron diffraction experiment). In solution, spectroscopic methods can be used to extract valuable information which combined with quantum chemical calculations can lead to the determination of the preferred molecular structures to be observed when a given solute is dissolved in each solvent. That is precisely the aim of this work. We used experimental NMR chemical shift data (in CDCl more...

Flavivirus is a genus that comprises more than 70 viruses with common characteristics and causes many of the most prevalent infections in the world. These viruses affect more people than any other genus. However, compared to other viral diseases, priorities are low in the context of public health perhaps due to their prevalence in developing countries. A safe and efficacious vaccine would be the ideal way to prevent diseases caused by Flavivirus spp., however, the treatment of most of these infections is still nonspecific and symptomatic. Natural products and their derivatives are emerging as candidates in the treatment of flaviviral diseases and are the scope of the present review. Natural products are molecules obtained through biological processes of living organisms and have several applications, many being in human and veterinary medicine and in agriculture. It is possible to obtain these compounds from secondary metabolites produced by plants, animals, and microorganisms. Many countries, such as Brazil, rely on traditional medicine for economic and geographic reasons. The use of medicinal plant compounds and their derivatives are among the main therapeutic resources for the population mainly in primary health care. These molecules play an important role to combat various types of pathogenic microorganisms, for example, bacteria, fungi, and viruses. With respect to antiviral activity, these compounds are promising candidates to combat Flavivirus spp. more...

Dermatomycoses are infections caused by fungi and yeasts and the drug treatment is considered expensive and extensive. Researchers are synthesizing new organic compounds in order to obtain more effective molecules that provide reduced adverse effects. Our research group has synthesized and evaluated the biological activities of aminoalcohol and diamine derivatives, which were considered active against human pathogenic fungi. Therefore, the objective of this study was to evaluate the in vitro antifungal activity of aminoalcohols and diamine derivatives against fungi and yeasts that cause dermatomycoses. The minimum inhibitory concentrations (MICs) and the minimum fungicidal concentration (MFC) of aminoalcohol (1–4) and diamine (5–13) derivatives was determined against Trichophyton mentagrophytes, T. rubrum, Epidermophyton floccosum, and Candida albicans according to protocols from the Clinical and Laboratory Standards Institute. All molecules exhibited fungicidal activity against the evaluated fungal strains, with the MIC and MFC ranging between 0.12 and 1000 μg/mL for filamentous fungi and 0.6 and 1250 μg/mL for yeasts. The best activity was attributed to diamines compared to aminoalcohols, with an emphasis on molecules 6 and 7. These results demonstrate the antifungal potential of the evaluated aminoalcohols and diamines against the four primary fungal species that cause dermatomycoses. more...

This work describes the synthesis, characterization and in vitro anticancer activity of two platinum(II) complexes of the type [Pt(L1)

Experimental autoimmune encephalomyelitis (EAE) is one of the main animal models used for the study of Multiple Sclerosis (MS). Long-chain lipophilic amino alcohols with immunoregulatory activities have already been studied in some models of inflammatory diseases, but the action of these compounds in EAE and MS is still unknown. In this study, we investigated whether the lipophilic amino alcohol 4b would act to improve the clinical signs of EAE and reduce the demyelination process and the neuroinflammatory parameters in the spinal cord, as well as the inflammatory process in the inguinal lymph nodes, of C57Bl/6 mice induced with EAE after stimulation with MOG35-55 and pertussis toxin. The 4b treatment (1.0 mg/kg/day) was orally administered, starting on the day of onset of clinical signs of the disease (10th) and ending on the 20th day after immunization. This treatment was able to reduce the cell count on the inguinal lymph nodes, the migration of inflammatory cells into the central nervous system (CNS), as well as the processes of microgliosis, astrogliosis, and the production of chemokines and pro-inflammatory cytokines, thus increasing the IL-10 anti-inflammatory cytokine levels in EAE mice. The inhibition of Akt phosphorylation in the CNS of EAE mice after treatment with 4b indicates that the immunoregulatory action of 4b is related to the PI3K/Akt signaling pathway. Our results indicate the immunoregulatory efficacy of the new compound 4b in the control of some inflammatory parameters and in the glial proliferation. In addition, 4b was able to reduce the demyelination of neurons and the worsening of clinical signs of EAE as effectively as the compound FTY720, the first oral drug approved by the FDA for the treatment of MS. more...

Flavonoids are natural products widely recognized for their plurality of applications such as antiviral, antiproliferative, antitumor activities and, antioxidant properties. The flavanone naringenin is presented in citrus fruits and has been studied to combat recurrent diseases that still lack effective treatment. Research groups have been investing efforts to the development of new, safe and active candidates to combat these agents or conditions and despite good results recently reported against the Zika virus (ZIKV) and tumor cells, the use of citrus naringenin is limited due to its low bioavailability. Structural exchanges through functionalization, for example, attaching lipophilic groups instead of hydroxyl groups, can further enhance biological properties. Here, the synthesis and characterization of regioselective naringenin mono-7-O-ethers and both mono and di-fatty acid esters, structurally lipophilic ones were demonstrated. Finally, in vitro studies of anti-ZIKV action and antiproliferative activities against melanoma (B16–F10) and breast carcinoma (4T1) cells showed the ether derivatives were actives, with IC50 ranging from 6.76, 18.5 and 22.6 μM to 28.53, 45.1 and 32.3 μM referring to ZIKV, B16–F10 and 4T1 cell lines, respectively. The lipophilic ethers present the ability to inhibit selectively ZIKV-replication in human cells and inhibitions. This class of modifications in flavonoid molecules could be further explore in the future development of specific anti-ZIKV compounds. more...

The drugs currently used to treat leishmaniases have limitations concerning cost, efficacy, and safety, making the search for new therapeutic approaches urgent. We found that the gold(I)-derived complexes were active against L. infantum and L. braziliensis intracellular amastigotes with IC50 values ranging from 0.5 to 5.5 μM. All gold(I) complexes were potent inhibitors of trypanothione reductase (TR), with enzyme IC50 values ranging from 1 to 7.8 μM. Triethylphosphine-derived complexes enhanced reactive oxygen species (ROS) production and decreased mitochondrial respiration after 2 h of exposure, indicating that gold(I) complexes cause oxidative stress by direct ROS production, by causing mitochondrial damage or by impairing TR activity and thus accumulating ROS. There was no cross-resistance to antimony; in fact, SbR (antimony-resistant mutants) strains were hypersensitive to some of the complexes. BALB/c mice infected with luciferase-expressing L. braziliensis or L. amazonensis and treated orally with 12.5 mg/kg/day of AdT Et (3) or AdO Et (4) presented reduced lesion size and parasite burden, as revealed by bioimaging. The combination of (3) and miltefosine allowed for a 50% reduction in miltefosine treatment time. Complexes 3 and 4 presented favorable pharmacokinetic and toxicity profiles that encourage further drug development studies. Gold(I) complexes are promising antileishmanial agents, with a potential for therapeutic use, including in leishmaniasis caused by antimony-resistant parasites. more...

Stem bark, root bark, and leaf extracts of Erythroxylum pungens were subjected to phytochemical analysis. N,N-dimethyltryptamine (DMT) was isolated and characterized from E. pungens roots. This unprecedented result is remarkable since no indole alkaloid has been previously reported from Erythroxylaceae so far. Eleven known tropane alkaloids were identified by their mass spectra and 3-(2-methylbutyryloxy)tropan-6,7-diol as well as 3-(2-methylbutyryloxy)nortropan-6,7-diol were isolated and characterized based on mass spectrometry, 1H, 13C, COSY, and NOESY NMR analysis. The complete NMR data are reported for the first time. Inverse Structure-based and Ligand-Based virtual screening were carried out to identify possible targets for 3-(2-methylbutyryloxy)tropan-6,7-diol. The level of cytotoxicity of this tropane alkaloid aliphatic ester was discrete with potencies on the order of 0.3–1.0 mg/mL and better results against HeLa (50% cell viability reduction). Otherwise, atropine (0.3 mg/mL), a Solanaceae tropane alkaloid, and DMT (0.5 mg/mL) from E. pungens roots impaired at 50% the cell viability against HeLa, SiHa, PC3, and 786-0. This study stimulates scientific investigation of the impact of edaphoclimatic features in a semi-arid environment on tropane alkaloid biosynthesis. more...

We report here the characterization of two new polymeric copper(II) complexes containing 2-chlorobenzhydrazide (2-CH) and two N,N-donor ligands, namely, 1,10-phenanthroline (phen) and 4-4′-dimethoxy-2-2′-bipyridine (dmb). The structure of a new polymeric copper(II) complex in which a perchlorate anion acts as a bridge ligand is discussed in detail. In both complexes, spectral data reveals a bidentate coordination mode for hydrazide, perchlorate and N,N-donor ligand. These metal complexes and their free ligands were evaluated for their trypanocidal and cytotoxic activities and the complex with 1,10-phenanthroline has been much more active than benznidazole, a drug used in the treatment of Chagas disease. Keywords: Copper(II) complexes, Crystal structure, Trypanosoma cruzi, Cytotoxic activity more...

The citrus naringenin (NAR) is a bioactive flavanone that represents an important platform for the development of new drugs. Bioavailability is a limiting factor to proceed with clinical studies and the insertion of lipophilic groups to the flavanone skeleton is a strategy for improving the biological response. However, side reactions, such as ring-opening isomerization of the pyranone ring, often compromise the efficiency of the reaction. Here, we discuss the NAR reactivity, evaluating the chemo- and regioselective conditions, and the factors that lead to ring-opening isomerization. The mechanistic studies were performed by density functional theory (DFT), thermodynamic properties and real-time 1H and 13C NMR monitoring. In addition, we explore the conformational space of NAR through molecular dynamics (MD) simulation. Mechanistic studies of flavanone isomerization, as well as thermodynamic properties, have not yet been reported in the literature. more...

The preparation and synthesis of PLLA/PMMA blend nanoparticles by miniemulsion/solvent evaporation, miniemulsion polymerization, and seeded emulsion polymerization strategies is herein presented. We evaluate the effect of nanoparticle preparation technique and blend ratio over nanoparticle morphology and blend miscibility, and our results indicate that the nanoparticle processing method can greatly influence the final morphology characteristics of blend nanoparticles. By miniemulsion/solvent evaporation, miscible blend and homogeneous nanoparticles were obtained, and an increase in PMMA content led to a concomitant increase of nanoparticle size. Miniemulsion polymerization, on the other hand, resulted in an immiscible blend with a core-shell-like morphology nanoparticles. Under the conditions used, seeded emulsion polymerization led to the formation of secondary smaller particles of pure PMMA in addition to miscible PLLA/PMMA blend nanoparticles. PLLA/PMMA nanoparticles were further used to encapsulate a hydrophobic drug with high entrapment efficiency, showing to be a promising hydrophobic compound carrier. more...

Four gold(I) complexes conceived as anticancer agents were synthesized by reacting [Au(PEt3 )Cl] and [Au(PPh3 )Cl] with ligands derived from δ-d-gluconolactone. The ligands' structure was designed to combine desired biological properties previously reported for each group. Ligands were synthesized from δ-d-gluconolactone via ketal protection and hydrazide formation followed by cyclization with CS2 to produce the novel oxadiazolidine-2-thione 7 and 8. Increasing of the ligands' lipophilicity via ketal protection proved useful since all four gold(I) complexes showed anticancer and antileishmanial properties. The IC50 values are at low micromolar range, varying from 2 to 3 μm for the most active compounds. The free D-gluconate 1,3,4 oxadiazole-derived ligands were neither toxic nor presented anticancer or antileishmanial properties. Triethylphosphine-derived compounds 9 and 10 were more selective against B16-F10 melanoma cell line. Although similar in vitro antileishmanial activity was observed for the gold(I) precursors themselves and their derived complexes, the latter were three times less toxic for human THP-1 macrophage cell line; this result is attributed to an isomeric variation of the D-gluconate ligand and the oxadiazole portion, which was one of the key concepts behind this work. These findings should encourage further research on gold(I) complexes to develop novel compounds with potential application in cancer and leishmaniasis chemotherapy. more...

Three medicinal plants with recognized anti-inflammatory potential, identified as “erva de São João“ (Ageratum conyzoides), “Tanchagem“ (Plantago major) and “ Bardana“ (Arctium lappa L.) were obtained from a medicinal herbs company located in Teófilo Otoni city (Minas Gerais State, Brazil). The dry plant material obtained in packages was submitted to the chemical procedures to prepare the crude extracts by maceration according to the Brazilian pharmacopoeia legislation. After extraction, the samples were subjected to 1H NMR, TLC and Capillary Electrophoresis analysis by co-injection of authentic patterns of phenolic acids and flavonoids to identify the major compounds and classes of secondary metabolites present in each material and then their chemical and biological potential was assessed by DPPH free radical inhibition assay and antimicrobial against E. coli. The results obtained allow us to conclude that the phytopreparation was effective in the extraction of compounds with antioxidant potential and the three species presented a high concentration of flavonoids and other phenolics that is compatible with the chemosystematic data. The screening obtained by 1H NMR spectroscopy, TLC and Capillary Electrophoresis with ultraviolet detection analysis provided us a qualitative profile of the phytochemicals present in each material. None of the extracts were active against Escherichia coli by antibacterial disk diffusion assay at concentration of 1 mg/ml. more...

In this paper, density functional theory calculations of nuclear magnetic resonance (NMR) chemical shifts for l-quebrachitol isomer, previously studied in our group, are reported with the aim of investigating in more detail the water solvent effect on the prediction of 1H NMR spectra. In order to include explicit water molecules, 20 water-l-quebrachitol configurations obtained from Monte Carlo simulation were selected to perform geometry optimizations using the effective fragment potential method encompassing 60 water molecules around the solute. The solvated solute optimized geometries were then used in B3LYP/6-311+G(2d,p) NMR calculations with PCM-water. The inclusion of explicit solvent in the B3LYP NMR calculations resulted in large changes in the 1H NMR profiles. We found a remarkable improvement in the agreement with experimental NMR profiles when the explicit hydrated l-quebrachitol structure is used in B3LYP 1H NMR calculations, yielding a mean absolute error (MAE) of only 0.07 ppm, much lower tha... more...

Crotalaria genus belongs to the subfamily Papilionoideae comprising about 600 species spread throughout tropical, neotropical and subtropical regions. In this study, seeds of Crolatalaria pallida were used to the isolation of usaramine, a pyrrolizidine alkaloid. Thus, Pseudomonas aeruginosa and Staphylococcus epidermidis were utilized as strains to test some activities of this alkaloid, such as antibiofilm and antibacterial. Meanwhile, monocrotaline obtained from Crotalaria retusa seeds, was used as the starting material for synthesis of necine base derivatives with anti-Trichomonas vaginalis potential. Alkaloids were characterized by 1D and 2D NMR techniques and GC–MS analysis. Usaramine demonstrated a highlighted antibiofilm activity against S. epidermidis by reducing more than 50% of biofilm formation without killing the bacteria, thus it could be assumed as a prototype for the development of new antibiofilm molecules for pharmaceutical and industrial purposes. Monocrotaline activity against T. vaginalis was evaluated and results indicated inhibition of 80% on parasite growth at 1 mg/mL, in addition, neither cytotoxicity against vaginal epithelial cells nor hemolytic activity were observed. On the other hand, retronecine showed no anti-T. vaginalis activity while azido-retronecine was more active than monocrotaline killing 85% of the parasites at 1 mg/mL. In conclusion, pyrrolizidine alkaloids are suggested as promising prototypes for new drugs especially for topical use. more...

This work describes the synthesis and total characterization of five novel PtII complexes of the type trans-[Pt(L)2(PPh3)2] (L = 5-alkyl-1,3,4-oxadiazol-2-thione derivatives and PPh3 = triphenylphosphine). These PtII complexes were characterized by elemental analysis, conductivity measurements, mass spectrometry, FT-IR, multinuclear NMR spectroscopy and X-ray diffraction crystallography. According to X-ray diffraction data, all complexes exhibited distorted square-planar geometry, in which two 5-alkyl-1,3,4-oxadiazol-2-thione derivatives coordinate a platinum ion through the sulfur atom with two triphenylphosphine molecules completing the coordination sphere. The isomerization of the platinum complexes was also investigated in deuterated chloroform solution by 31P{1H} and 195Pt{1H} NMR spectroscopy. In all cases, the trans-isomer was found according to the observed coupling constants (J). more...

The effect of N-geranyl-ethane-1,2-diamine dihydochloride (GIB24), a synthetic diamine, was assayed against different developmental forms of the parasitic protozoan Trypanosoma cruzi (strain Dm28c). The compound was effective against culture epimastigote forms (IC50/24h = 5.64 μM; SI = 16.4) and intracellular amastigotes (IC50/24h = 12.89 μM; SI = 7.18), as detected by the MTT methodology and by cell counting, respectively. Incubation of epimastigotes for 6h with 6 μM GIB24 (IC50/24h value) resulted in significant dissipation of the mitochondrial membrane potential, prior to permeabilization of the plasma membrane. Rounded epimastigotes with cell size reduction were observed by scanning electron microscopy. These morpho-physiological changes induced by GIB24 suggest an incidental death process. Treatment of infected Vero cells did not prevent the intracellular amastigotes from completing the intracellular cycle. However, there was a decrease in the number of released parasites, increasing the ratio amastigotes/trypomastigotes. Proteomic analysis of 15 μM GIB24 resistant epimastigotes indicated that the compound acts mainly on mitochondrial components involved in the Krebs cycle and in maintaining the oxidative homeostasis of the parasites. Our data suggest that GIB24 is active against the main morphological forms of T. cruzi. more...

Made available in DSpace on 2019-10-06T16:48:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-01-01 Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) In order to improve the previously observed antichagasic activity of Cu(II) complexes containing 2-chlorobenzhydrazide (2-CH), we report herein the synthesis and anti-Trypanosoma cruzi activity of novel copper complexes containing 2-methoxybenzhydrazide (2-MH), 4-methoxybenzhydrazide (4-MH) and three α-diimine ligands, namely, 1,10-phenanthroline (phen), 2,2-bipyridine (bipy) and 4-4′-dimethoxy-2-2′-bipyridine (dmb). Two of these complexes showed higher in vitro anti-Trypanosoma cruzi activity when compared to benznidazole, the main drug used in Chagas disease treatment. One of them, the copper complex with 4-MH and dmb, [Cu(4-MH)(dmb)(ClO 4 ) 2 ], exhibited a higher selectivity index than that recommended for preclinical studies. Considering this observation, complex [Cu(4-MH)(dmb)(ClO 4 ) 2 ] was selected for preliminary in vivo assays, which verified that this compound was able to reduce parasitemia by 64% at the peak of infection. Further investigations were performed on all compounds. The Cu(II) complexes bind to ct-DNA with K b values in the range of 10 3 –10 4 M –1 , with [Cu(4-MH)(dmb)(ClO 4 ) 2 ] showing the highest K b value (1.45 × 10 4 M –1 ). Molecular docking simulations predicted that [Cu(4-MH)(dmb)(ClO 4 ) 2 ] binds in the minor groove of the double helix of ct-DNA and forms one hydrogen bond. Instituto de Química Universidade Federal de Uberlândia, Campus Santa Mônica Departamento de Análises Clínicas Toxicológicas e Bromatológicas Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS) Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo Departamento de Química Universidade Federal de Juiz de Fora Juiz de Fora-MG Instituto de Física de São Carlos Universidade de São Paulo UNESP - Universidade Estadual Paulista Instituto de Química Departamento de Física Instituto de Ciências Exatas Naturais e Educação Universidade Federal do Triângulo Mineiro UNESP - Universidade Estadual Paulista Instituto de Química FAPEMIG: APQ-00330-14 more...

Gold complexes that could act as antitumor agents have attracted great attention. Heterocyclic compounds and their metal complexes display a broad spectrum of pharmacological properties. The present study reports the preparation and characterization of four novel gold(I) complexes containing tertiary phosphine and new ligands 5-adamantyl-1,3-thiazolidine-2-thione, 3-methyladamantane-1,3,4-oxadiazole-2-thione. Spectroscopic data suggest that gold is coordinated to the exocyclic sulfur atom in all cases, as confirmed by X-ray crystallographic data obtained for complex (1) and supported by quantum-mechanical calculations. The cytotoxicity of the compounds has been evaluated in comparison to cisplatin and auranofin in three different tumor cell lines, colon cancer (CT26WT), metastatic skin melanoma (B16F10), mammary adenocarcinoma (4T1) and kidney normal cell (BHK-21). The gold complexes were more active than their respective free ligands and able to inhibit the thioredoxin reductase (TrxR) enzyme, even in the presence of albumin. Molecular modeling studies were carried out to understand the interaction between the compounds and the TrxR enzyme, considered as a potential target for new compounds in cancer treatment. The docking results show that the adamantane ring is essential to stabilize the ligand-enzyme complex prior the formation of covalent bond with gold center. The structure of the new gold compounds was established on the basis of spectroscopic data, DFT calculations and X-ray diffraction. TrxR inhibition was evaluated and the results correlated with the assays in tumor cells, suggesting the TrxR as possible target for these compounds. more...

Three series of d-galactose derivatives linked to a lipophilic aminoalcohol moiety were synthesized and their antibacterial activity was evaluated against Mycobacterium tuberculosis and representative species of Gram positive and Gram negative bacteria. Five out of the thirteen tested compounds displayed activity against M. tuberculosis, with a minimal inhibitory concentration (MIC) of 12.5 μg/mL and seven compounds were active against the four bacterial strains tested. The best results were obtained for amino alcohols 10 and 11 against Staphylococcus epidermidis (MIC = 2 μg/mL). The antitumor activity was evaluated against three tumor cell lines (MCF-7, HeLa and MO59J) and compared to the normal cell line GM07492A. The results showed that the lowest IC50 values were observed for the amino alcohol 16 against MCF-7 (11.9 μM) and MO59J (10.0 μM). more...

In this study, novel nanobioconjugates based on quantum dots and a PEGylated chitosan derivative (PEG-CHI) have been designed and synthesised by a single-step aqueous route at room temperature. Chitosan was chemically modified by PEGylation aiming to significantly improve its water solubility and used as the capping ligand in the preparation of CdS quantum dot (QD) colloidal systems. UV/Vis and photoluminescence spectroscopy, transmission electron microscopy, dynamic light scattering, and the zeta potential were used to characterise the biopolymer-capped semi-conductor nanocrystals and their relative stability. The results clearly demonstrated that the PEG-CHI derivative is remarkably effective in nucleating and stabilising ultra-small colloidal CdS QDs in aqueous suspensions under acidic, neutral and alkaline media with an average size of approximately 2.0–3.0 nm and simultaneously showing luminescent activity in the visible range. In addition, the results of cell viability analysis in vitro using two cell cultures based on MTT bioassays demonstrated no cytotoxicity of the CdS QD/PEG-chitosan bioconjugates. Thus, based on these findings, it can be envisioned that these bioconjugates have potential use as biocompatible fluorescent biomarkers for nanomedicine applications. more...

Different series of N-alkylated diamines and their derivatives condensed to quinic acid were synthesized and tested for antibacterial properties against Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. The lipophilic chain and carbohydrate moiety modulate the antibacterial activity and the compounds showed a structure-activity relationship. Overall, 11 compounds displayed better activity than chloramphenicol against Gram-positive and Gram-negative bacteria. Monoalkylated amines 2a-h displayed an activity similar to that of ethambutol against Mycobacterium tuberculosis. more...

Human and bovine trichomoniasis are sexually transmitted diseases (STD) caused by Trichomonas vaginalis and Tritrichomonas foetus, respectively. Human trichomoniasis is the most common non-viral STD in the world and bovine trichomoniasis causes significant economic losses to breeders. Considering the significant impact of the infections caused by these protozoa and the treatment failures, the search for new therapeutic alternatives becomes crucial. In this study the effect of diamines and amino alcohols in the in vitro viability of trichomonads was evaluated. Screening demonstrated the high activity of diamine 4 against these protozoa. Although cytotoxicity against HMVII cell line and slight hemolysis were observed in vitro, the compound showed no toxic effect on the Galleria mellonella in vivo model. Importantly, diamine 4 was active against both trichomonads species at 6h and 24h of incubation, and these effects was reverted by putrescine, a polyamine, suggesting competition for the same metabolic pathway. These findings indicate that the mechanism of action of diamine 4 is through the polyamine metabolism, a pathway distinct from that presented by metronidazole, the drug usually used to treat trichomoniasis and to which resistance is widely reported. These data demonstrate the importance of diamines as potential novel candidates as anti-T. vaginalis and anti-T. foetus agents. more...

Novel lipophilic gold(I) complexes containing 1,3,4-oxadiazol-2-thione or 1,3-thiazolidine-2-thione derivatives were synthesized and characterized by IR, high resolution mass spectrometry, and 1H, 13C 31P NMR. The cytotoxicity of the compounds was evaluated considering cisplatin and/or auranofin as reference in different tumor cell lines: colon cancer (CT26WT), metastatic skin melanoma (B16F10), breast adenocarcinoma (MCF-7), cervical carcinoma (HeLa), glioblastoma (M059 J). Normal human lung fibroblasts (GM07492-A) and kidney normal cell (BHK-21) were also evaluated. The gold(I) complexes were more active than their respective free ligands and cisplatin. Furthermore, antibacterial activity was evaluated against Gram-positive bacteria Staphylococcus aureus ATCC 25213, Staphylococcus epidermidis ATCC 12228 and Gram-negative bacteria Escherichia coli ATCC 11229 and Pseudomonas aeruginosa ATCC 27853 and expressed as the minimum inhibitory concentration (MIC). The complexes exhibited lower MIC values when compared to the ligands and chloramphenicol against Gram-positive bacteria and Gram-negative bacteria. Escherichia coli was sensitive one to the action of gold(I) complexes. more...

The isoflavone genistein 1 and some derivatives modulate IL-12, TNF-α and NO production by macrophages and lung cancer cell lines, and improve the clinical signs of experimental autoimmune encephalomyelitis (EAE). Seven genistein derivatives connected at C-6 position of a sugar, such as d-glucose and d-galactose, were synthesized. The ability to modulate macrophage response was evaluated, showing variable inhibition capacity of NO and TNF-α production in J774.A1 and RAW 264.7. Five of the seven compounds were non-cytotoxic; compound 8 was more effective to inhibit NO and TNF-α production, without affecting cell viability. more...

Heterocyclic compounds and their metal complexes display a broad spectrum of pharmacological properties. This work reports the preparation and characterization of four novel gold(I) complexes containing tertiary phosphine and 3-benzyl-1,3-thiazolidine-2-thione, 5-phenyl-1,3,4-oxadiazole-2-thione as ligands. The reaction of chloro(triphenylphosphine)gold(I) and chloro(triethylphosphine)gold(I) with thioamides, 3-benzyl-1,3-thiazolidine-2-thione and 5-phenyl-1,3,4-oxadiazole-2-thione in dichloromethane or dichloromethane/acetone resulted in the formation of the gold(I) complexes of general formula: [SAuPR3]Cl, S = 3-benzyl-1,3-thiazolidine-2-thione, R = Ph or Et and [SAuPR3], S = 5-phenyl-1,3,4-oxadiazole-2-thione, R = Ph or Et. Spectroscopic evidence suggested that gold is coordinated to the exocyclic sulfur atom in all cases and this was confirmed by X-ray crystallographic data obtained for complex (4). The cytotoxicity of the compounds has been evaluated in comparison to cisplatin in two different tumor cell lines, colon cancer (CT26WT) and metastatic skin melanoma (B16F10), and also in a kidney normal cell (BHK-21). The gold complexes showed a better activity than cisplatin and presented a high selectivity index. more...

Nine caffeic and gallic acids derivatives were synthesized and evaluated for their antioxidant activity using the DPPH radical scavenging activity assay and for their antiherpes activity against HSV-1. All compounds displayed higher antioxidant activities than α-tocopherol. The most active antioxidant was compound 8 (IC50 = 177 μM). Five compounds (7, 10, 11, 12 and 14) were found to possess anti-HSV-1 activity with selectivity indices values ranging from 7.0 to 27.1. The most active was compound 10 (IC50 = 15.2 μM; SI = 27.1). more...

Mitoxantrone is an anthracenedione antineoplastic and immunosuppressive agent approved for multiple sclerosis treatment. Novel mono- and disubstituted anthraquinone derivatives, analogues of mitoxantrone, were synthesized through the addition of lipophilic amino alcohols and evaluated for their effect on IL-1β, TNF-α and nitric oxide production by LPS/IFN-γ-stimulated RAW264.7 cells. The disubstituted 1,4-anthracene-9,10-dione 10 showed significant inhibition of nitric oxide, TNF-α and IL-1β production at the concentration of 5 μg/mL, with a much lower cytotoxicity than mitoxantrone. The monosubstituted 3, 4, 11, 12 and 13 also displayed a moderate to good inhibitory capacity on IL-1β production. However, the methylated compounds 11, 12 and 13 failed to inhibit the TNF-α production, and compound 13 was the only one to decrease the production of nitric oxide. None of these derivatives was toxic at the tested concentrations. Compounds 10 and 13 had better inhibitory capacity of the inflammatory mediators analyzed, with reliable viability of the cells. more...

Leishmanicidal and trypanocidal activity of seventeen lipophilic diamines was evaluated in vitro against Leishmania braziliensis, L. chagasi, and Trypanosoma cruzi. Twelve compounds presented anti-Leishmania and six showed anti-T. cruzi amastigote activity. Compound 14 (N-tetradecyl-1,4-butanediamine) was the most active against both L. braziliensis (IC50 = 2.6 μm) and L. chagasi (IC50 = 3.0 μm) which showed a selectivity index (SI) >100. N-decyl-1,6-hexanediamine (compound 9) presented an IC50 = 1.6 μm and SI >187 and was over six times more potent than the reference drug benznidazole against T. cruzi. Treatment of infected or uninfected macrophages with compounds 9 and 14 did not induce significant TNFα and NO production. Four compounds (15, 16, 22, and 23) inhibited 78.9%, 77.7%, 83.7%, and 70.1% of rTRLb activity, respectively, and compound 23 inhibited 73.3% of rTRTc activity at 100 μm. A concentration-dependent effect on mitochondrial membrane depolarization was observed in T. cruzi epimastigotes treated with compound 9, suggesting this mechanism may be involved in the trypanocidal effect. On the contrary, in L. braziliensis promastigotes treated with compound 14, no mitochondrial depolarization was observed. Our results demonstrate that N-decyl-1,6-hexanediamine and N-tetradecyl-1,4-butanediamine are promising molecules for the development of novel leading compounds against T. cruzi and Leishmania spp., particularly given a possible alternative mechanism of action. more...

In this paper, density functional theory calculations of nuclear magnetic resonance (NMR) chemical shifts for l-quebrachitol isomer, previously studied in our group, are reported with the aim of investigating in more detail the water solvent effect on the prediction of more...

This work describes the synthesis of inositol derivatives condensed with 2-mercaptobenzothiazole or 2-mercaptobenzimidazole, potential antimicrobial agents. These compounds were prepared by ring opening of epoxide intermediate (2S,3R-epoxy-1-O-methyl- l-chiro-inositol and 2R,3S-epoxy-1-O-methyl- l-chiro-inositol), which were obtained from l-quebrachitol (1-O-methyl-chiro-inositol). Microwave irradiation was used to promote the condensation reaction. more...

We report the synthesis of a series of diaminated terpenoids containing, as side-chain of the diamine core, the "head-to-tail" prenyl derivatives, with amino amino spacers of variable length. In vitro biological activity of these compounds was evaluated against Mycobacterium tuberculosis and Leishmania amazonensis, and the structure-activity relationships are discussed. Different biological results were observed depending on the terpenic side-chain length. The best results were obtained for trans,trans-farnesol derivatives. Moreover, these results demonstrated that the stereochemistry of the double bond could play an important role in determining antitubercular and antileishmanial activities of these compounds. more...

The current anticancer and antileishmanial drug arsenal presents several limitations concerning their specificity, efficacy, costs and the emergence of drug-resistant cells lines, which encourages the urgent need to search for new alternatives. Inspired by the fact that gold(I)-based compounds are promising antitumoral and antileishmanial drug candidates, we synthesized novel gold(I) complexes containing phosphine and 5-phenyl-1,3,4-oxadiazole-2-thione and evaluated their anticancer and antileishmanial activities. Synthesis was performed by reacting 5-phenyl-1,3,4-oxadiazole-2-thione derivatives with chloro(triphenylphosphine)gold(I) and chloro(triethylphosphine)gold(I). The novel compounds were characterized by infrared, Raman, 1H, 13C nuclear magnetic resonance, high-resolution mass spectra, and x-ray crystallography. The coordination of the ligands to gold(I) occurred through the exocyclic sulfur atom. All gold(I) complexes were active at low micromolar or nanomolar range with IC50 values ranging from more...

Novel carbohydrate-based hybrids combining chitosan and chemically modified chitosan with CdS inorganic nanoparticles were designed and prepared via aqueous route at room temperature. N,N,N-trimethylchitosan (TM-chitosan) was synthesized aiming at substantially improving the water solubility of chitosan for producing stable colloidal systems. UV–vis spectroscopy, photoluminescence spectroscopy, Nuclear magnetic resonance spectroscopy, Raman spectroscopy, and Fourier transform infrared spectroscopy were used to characterize the synthesis and the relative stability of biopolymer-capped CdS nanocrystals. The results have clearly indicated that chitosan and chitosan-derivative (TM-chitosan) were remarkably effective on nucleating and stabilizing CdS nanoparticles in aqueous suspensions. In addition, the CdS nanocrystals were produced in the so-called “quantum-size confinement regime”, with the calculated average size below 3.5 nm and fluorescent activity in the visible range of the spectra. Therefore, a new single-step process was developed for the bioconjugation of quantum dots with water soluble chemically functionalized carbohydrates at room temperature for potential biomedical applications. more...

Density functional theory (DFT) calculations of 1H NMR chemical shifts for l-quebrachitol isomers were performed using the B3LYP functional employing the 6-31G(d,p) and 6-311 + G(2d,p) basis sets. The effect of the solvent on the B3LYP-calculated NMR spectrum was accounted for using the polarizable continuum model. Comparison is made with experimental 1H NMR spectroscopic data, which shed light on the average uncertainty present in DFT calculations of chemical shifts and showed that the best match between experimental and theoretical B3LYP 1H NMR profiles is a good strategy to assign the molecular structure present in the sample handled in the experimental measurements. Among four plausible O-methyl-inositol isomers, the l-quebrachitol 2a structure was unambiguously assigned based only on the comparative analysis of experimental and theoretical 1H NMR chemical shift data. The B3LYP infrared (IR) spectrum was also calculated for the four isomers and compared with the experimental data, with analysis of the theoretical IR profiles corroborating assignment of the 2a structure. Therefore, it is confirmed in this study that a combined experimental/DFT spectroscopic investigation is a powerful tool in structural/conformational analysis studies. Copyright © 2012 John Wiley & Sons, Ltd. more...

Nanoenabled drug delivery systems against tuberculosis (TB) are thought to control pathogen replication by targeting antibiotics to infected tissues and phagocytes. However, whether nanoparticle (NP)-based carriers directly interact with Mycobacterium tuberculosis and how such drug delivery systems induce intracellular bacterial killing by macrophages is not defined. In the present study, we demonstrated that a highly hydrophobic citral-derived isoniazid analogue, termed JVA, significantly increases nanoencapsulation and inhibits M. tuberculosis growth by enhancing intracellular drug bioavailability. Importantly, confocal and atomic force microscopy analyses revealed that JVA-NPs associate with both intracellular M. tuberculosis and cell-free bacteria, indicating that NPs directly interact with the bacterium. Taken together, these data reveal a nanotechnology-based strategy that promotes antibiotic targeting into replicating extra- and intracellular mycobacteria, which could actively enhance chemotherapy during active TB. more...

Six lycorine derivatives were prepared, characterized, and evaluated for their in vitro anti-Trichomonas vaginalis activity. Compounds bearing an acetyl (2), lauroyl (3), benzoyl (4 and 5), and p-nitrobenzoyl (6 and 7) groups were synthesized. The best activity was achieved with lycorine esterified at C-2 position with lauroyl group. Preliminary structure–activity relationship points that unprotected OH group at C-1 and C-2 is not necessary to the antiparasitic activity, and none of the derivative was less active than lycorine. The lycorine structural requisites required to kill this amitochondriate cell seem to be different in comparison with the derivatives most active against other parasites and tumor cell lines, both mitochondriated cells. This result is an important contribution with our ongoing studies regarding the mechanism of action of the Amaryllidaceae alkaloids on T. vaginalis cell death opening a new perspective to optimize this innovative pharmacological potential. more...

Dihydroperoxides and tetraoxanes derived from symmetrically substituted bis(arylmethyl)acetones were synthesized in modest to good yields using several methods. Three of these compounds exhibit an important in vitro antimalarial activity (1.0 μm ≤ IC50 ≤ 5.0 μm) against blood forms of the human malaria parasite Plasmodium falciparum. more...

Genistein modulates inflammatory responses in part by reducing the production of the pro-inflammatory cytokines IL-12, TNF-α, and nitric oxide, by activated macrophages in response to lipopolysaccharide stimulus. Previous studies have shown that synthetic lipophilic genistein glycosides were significantly more active than hydrophilic glycosides. The aims of this study were to synthesize and to evaluate the effect of novel lipophilic genistein derivatives on IL-12, TNF-α, and nitric oxide production by J774A.1 cells. The results show that the modification of genistein enables the generation of non-cytotoxic compounds with increased IL-12 inhibition. However, these derivatives failed to inhibit TNF-α. The nitric oxide production was notably inhibited by the monoester (2, 3) and monoether (6, 7) compounds in a dose-dependent manner. more...

In this work, 17 new N-acylhydrazone derivatives of amino acids have been evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. The compounds 8b, 8e, 8f, 9a-d, and 10c exhibited an important minimum inhibitory concentration activity between 12.5 and 50 μg/mL, which can be compared with that of the tuberculostatic drug d-cycloserine (20 μg/mL). more...

We have synthesized 10,12-pentacosadyinoic acid (PCDA) + N -[(2-tetradecanamide)-ethyl]-ribonamide (TDER) vesicles to determine the colorimetric response induced by pathogenic bacteria ( Staphylococcus aureus and Escherichia coli ). The addition of bacterial supernatants caused a colorimetric transition in TDER/PCDA vesicles, even in diluted concentrations, indicating that chemical interactions occur between the vesicles and bacterial compounds. Bacterial substrates released from S. aureus induced a greater color change compared to the color change induced by E. coli . S. aureus metabolites also induced a greater color change when TDER/PCDA vesicles were incorporated into the cellulose strips. We determined the energy involved in the interaction between the bacterial substrates and the TDER/PCDA vesicles to be exothermic (and very high) for both bacterial supernatants. In addition, we analyzed the colorimetric transition in the presence of other molecules, using apple juice as a food matrix. Both apple juice and apple juice inoculated with bacterial substrates induced a TDER/PCDA color change; however, the S. aureus supernatant induced a slightly greater color change in the vesicles both in the suspension and in the cellulose strips. TDER/PCDA vesicles show great potential to be used as a biosensor to detect food pathogens in intelligent food packaging. more...

Four diamines and three amino alcohols derived from 1-decanol, 1-dodecanol and 1,2-dodecanediol were evaluated in an in vitro assay against a mixture of trypomastigote and intracellular amastigote forms of Trypanosoma cruzi. Two of these compounds (6 and 7) showed better activity against both proliferative stages of T. cruzi than the positive control benznidazole, three were of similar potency (1, 2 and 5) and two were less active (3 and 4). more...

Two synthetic epoxide derivatives, important intermediates in organic synthesis, were obtained from L-quebrachitol, and their conformations were proposed based on spectroscopic analysis. Density functional theory (DFT) calculations of infrared and NMR spectra were shown to be reliable enough for organic chemistry applications. The observed structures were determined with the aid of the DFT spectroscopic data, stressing the relevance and utility of combined experimental/theoretical studies and also the usefulness of the (13)C NMR B3LYP/6-31G(d,p) calculations. more...

This work reports the preparation of several amino alcohols condensed with d-arabinose, d-glucose, and d-galactose derivatives. These compounds were evaluated in vitro for their cytotoxicity and ability to decrease nitric oxide production in J774A.1 cells. Arabinofuranoside derivatives 5a, 5b and 5c showed a significant inhibition of nitric oxide production (>80% at 5 μg/mL), while the galactopyranoside derivative 8d showed a notable nitric oxide inhibitory activity (126% at 0.5 μg/mL). more...

The fluoroquinolones are an important family of synthetic antimicrobial agents being clinically used over the past thirty years. In addition, some fluoroquinolones have been used in the development of anticancer drugs, and others have demonstrated anti-HIV activity. Furthermore, there has been some additional work investigating the effect of metal ions on biological activity. Aiming to obtain novel palladium(II) and platinum(II) complexes that exhibit biological activity, we have synthesized complexes using fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin, sparfloxacin, and gatifloxacin) as ligands. The compounds were characterized using IR and NMR spectroscopy, thermogravimetric and elemental analyses. The complexes show activity against Mycobacterium tuberculosis strain H(37)Rv. The minimal inhibitory concentration (MIC) of the complexes was determined. more...

Taking in account the increased prevalence of metronidazole-resistant infections, alternative drugs are necessary for the treatment of trichomonosis. We report in this work the preparation and the in vitro anti-trichomonads activity of two diamines 1 and 2, and three different lipophilic amino alcohol derivatives 3, 4 and 5. These compounds were tested for in vitro activity against two isolates of Trichomonas vaginalis and displayed inhibition of the parasite growth. Five concentrations of each compound were tested. The butanediamine derivative 1, at a final concentration of 5.85 microM, presented a cytotoxic effect against 47% of T. vaginalis trophozoites. Furthermore, the cytotoxicity of 1 did not present statistically significant difference when compared to metronidazole in the same range of concentration (0.1-1.5 microg/mL). more...