Lipophilic gold(I) complexes with 1,3,4-oxadiazol-2-thione or 1,3-thiazolidine-2-thione moieties: synthesis and their cytotoxic and antimicrobial activities.

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.

Correction to: Lipophilic gold(I) complexes with 1,3,4-oxadiazol-2-thione or 1,3-thiazolidine-2-thione moieties: synthesis and their cytotoxic and antimicrobial activities.

This article has been corrected. One of the author names was given incorrect. Please find in this erratum the correct author name: "Heloiza Diniz Nicolella" that should be regarded as final by the reader.

Novel antitumor adamantane-azole gold(I) complexes as potential inhibitors of thioredoxin reductase.

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.

Quinic acid derivatives inhibit dengue virus replication in vitro.

BACKGROUND: Dengue is the most prevalent arboviral disease in tropical and sub-tropical areas of the world. The incidence of infection is estimated to be 390 million cases and 25,000 deaths per year. Despite these numbers, neither a specific treatment nor a preventive vaccine is available to protect people living in areas of high risk. RESULTS: With the aim of seeking a treatment that can mitigate dengue infection, we demonstrated that the quinic acid derivatives known as compound 2 and compound 10 were effective against all four dengue virus serotypes and safe for use in a human hepatoma cell line (Huh7.5). Both compounds were non-virucidal to dengue virus particles and did not interfere with early steps of the dengue virus life cycle, including binding and internalization. Experiments using a replicon system demonstrated that compounds 2 and 10 impaired dengue virus replication in Huh7.5 cells. Additionally, the anti-dengue virus effects of the quinic acid derivatives were preserved in human peripheral blood mononuclear cells. CONCLUSIONS: Taken together, these data suggest that quinic acid derivatives represent a novel chemical class of active compounds that could be used to combat dengue virus infection.

Synthesis, characterization, cytotoxic and antitubercular activities of new gold(I) and gold(III) complexes containing ligands derived from carbohydrates.

Novel gold(I) and gold(III) complexes containing derivatives of D-galactose, D-ribose and D-glucono-1,5-lactone as ligands were synthesized and characterized by IR, (1)H, and (13)C NMR, high resolution mass spectra and cyclic voltammetry. The compounds were evaluated in vitro for their cytotoxicity against three types of tumor cells: cervical carcinoma (HeLa) breast adenocarcinoma (MCF-7) and glioblastoma (MO59J) and one non-tumor cell line: human lung fibroblasts (GM07492A). Their antitubercular activity was evaluated as well expressed as the minimum inhibitory concentration (MIC90) in µg/mL. In general, the gold(I) complexes were more active than gold(III) complexes, for example, the gold(I) complex (1) was about 8.8 times and 7.6 times more cytotoxic than gold(III) complex (8) in MO59J and MCF-7 cells, respectively. Ribose and alkyl phosphine derivative complexes were more active than galactose and aryl phosphine complexes. The presence of a thiazolidine ring did not improve the cytotoxicity. The study of the cytotoxic activity revealed effective antitumor activities for the gold(I) complexes, being more active than cisplatin in all the tested tumor cell lines. Gold(I) compounds (1), (2), (3), (4) and (6) exhibited relevant antitubercular activity even when compared with first line drugs such as rifampicin.

A new copper(II) complex containing long-chain aliphatic hydrazide and 1,10-phenanthroline upregulates ADP hydrolysis in triple-negative breast cancer cells.

Copper can be opportunely complexed to modulate oncogenic pathways, being a promising strategy for cancer treatment. Herein, three new copper(II) complexes containing long-chain aliphatic hydrazides and 1,10-phenanthroline (1,10-phen), namely, [Cu(octh)(1,10-phen)(H2O)](NO3)21, [Cu(dech)(1,10-phen)(H2O)](NO3)22 and [Cu(dodh)(1,10-phen)(H2O)](NO3)2.H2O 3 (where octh = octanoic hydrazide, dech = decanoic hydrazide, dodh = dodecanoic hydrazide) were successfully prepared and characterized by several physical-chemical methods. Furthermore, X-ray structural analysis of complex 2 indicated that the geometry around the copper(II) ion is distorted square-pyramidal, in which hydrazide and 1,10-phenanthroline act as bidentate ligands. A water molecule in the apical position completes the coordination sphere of the metal ion. All new copper(II) complexes were cytotoxic to breast cancer cell lines (MCF7, MDA-MB-453, MDA-MB-231, and MDA-MB-157) and selective when compared to the non tumor lineage MCF-10A. In particular, complex 2 showed half-maximal inhibitory concentration (IC50) values ranging between 2.7 and 13.4 µM in MDA-MB231 cells after 24 and 48 h of treatment, respectively. Furthermore, this complex proved to be more selective for tumor cell lines when compared to doxorubicin and docetaxel. Complex 2 inhibited the clonogenicity of MDA-MB231 cells, increasing adenosine diphosphate (ADP) hydrolysis and upregulating ecto-nucleoside triphosphate diphosphohydrolase 1 (ENTPD1) transcriptional levels. In this sense, we suggest that the inhibitory effect on cell proliferation may be related to the modulation of adenosine monophosphate (AMP) levels. Thus, a novel copper(II) complex with increased cytotoxic effects and selectivity against breast cancer cells was obtained, contributing to medicinal chemistry efforts toward the development of new chemotherapeutic agents.

Anticancer and antileishmanial in vitro activity of gold(I) complexes with 1,3,4-oxadiazole-2(3H)-thione ligands derived from δ-D-gluconolactone.

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.

Flavonoids as Molecules With Anti-Zika virus Activity.

Zika virus (ZIKV) is an arthropod-born virus that is mainly transmitted to humans by mosquitoes of the genus Aedes spp. Since its first isolation in 1947, only a few human cases had been described until large outbreaks occurred on Yap Island (2007), French Polynesia (2013), and Brazil (2015). Most ZIKV-infected individuals are asymptomatic or present with a self-limiting disease and nonspecific symptoms such as fever, myalgia, and headache. However, in French Polynesia and Brazil, ZIKV outbreaks led to the diagnosis of congenital malformations and microcephaly in newborns and Guillain-Barré syndrome (GBS) in adults. These new clinical presentations raised concern from public health authorities and highlighted the need for anti-Zika treatments and vaccines to control the neurological damage caused by the virus. Despite many efforts in the search for an effective treatment, neither vaccines nor antiviral drugs have become available to control ZIKV infection and/or replication. Flavonoids, a class of natural compounds that are well-known for possessing several biological properties, have shown activity against different viruses. Additionally, the use of flavonoids in some countries as food supplements indicates that these molecules are nontoxic to humans. Thus, here, we summarize knowledge on the use of flavonoids as a source of anti-ZIKV molecules and discuss the gaps and challenges in this area before these compounds can be considered for further preclinical and clinical trials.

The terpenic diamine GIB24 inhibits the growth of Trypanosoma cruzi epimastigotes and intracellular amastigotes, with proteomic analysis of drug-resistant epimastigotes.

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.

A new lipophilic amino alcohol, chemically similar to compound FTY720, attenuates the pathogenesis of experimental autoimmune encephalomyelitis by PI3K/Akt pathway inhibition.

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.

Impact of the carbon chain length of novel platinum complexes derived from N-alkyl-propanediamines on their cytotoxic activity and cellular uptake.

This work describes the synthesis and characterization of four new ligands derived from 1,3-propanediamine in addition to the preparation and characterization of their respective platinum(II) complexes by reaction with K(2)PtCl(4). These ligands were obtained by the reaction of the corresponding alkyl mesylate with 1,3-propanediamine. We have prepared compounds having different carbon chains lengths in an attempt to correlate this factor, which influences the lipophilicity of the compounds, with cytotoxic activity. Octanol/water partition coefficients, the effect of the four complexes on the growth of two tumoral cell lines, and their cellular uptake were investigated. Increasing lipophilicity enhances the rate of cellular uptake and, consequently, the cytotoxic activity.

Synthesis and biological aspects of mycolic acids: an important target against Mycobacterium tuberculosis.

Mycolic acids are an important class of compounds, basically found in the cell walls of a group of bacteria known as mycolata taxon, exemplified by the most famous bacteria of this group, the Mycobacterium tuberculosis (M. tb.), the agent responsible for the disease known as tuberculosis (TB). Mycolic acids are important for the survival of M. tb. For example, they are able to help fight against hydrophobic drugs and dehydration, and also allow this bacterium to be more effective in the host's immune system by growing inside macrophages. Due to the importance of the mycolic acids for maintenance of the integrity of the mycobacterial cell wall, these compounds become attractive cellular targets for the development of novel drugs against TB. In this context, the aim of this article is to highlight the importance of mycolic acids in drug discovery.

Isolation, spectral characterization, molecular docking, and cytotoxic activity of alkaloids from Erythroxylum pungens O. E. Shulz.

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.

Synthesis of amphiphilic galactopyranosyl diamines and amino alcohols as antitubercular agents.

Mono- and diacylated derivatives of galactopyranosyl amines were obtained from d-galactose, via aminated intermediates prepared by reaction of 6-deoxy-6-iodo-1,2:3,4-di-O-isopropylidene-alpha-d-galactopyranose with 1,3-propanediamine, 1,2-ethanediamine or ethanolamine. Monoacylated derivatives displayed antitubercular activity.

Diamine derivative anti-Trichomonas vaginalis and anti-Tritrichomonas foetus activities by effect on polyamine metabolism.

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.

Fluoroquinolones: an important class of antibiotics against tuberculosis.

Tuberculosis (TB) is a global health problem due to the lack of new drugs in the market and also due to the advent of multidrug resistant strains (MDR). This disease affects around 8 million people and kills almost 3 million people each year and it is estimated that there are 1 billion infected with TB worldwide. Due to this problem fluoroquinolones have attracted much attention as the new class of anti TB drugs due to their fewer toxic side effects, improved pharmacokinetic properties and extensive and potent activity against Gram-positive and Gram-negative bacteria, including resistant strains. In this present review we report fluoroquinolones as a promising new class of anti TB.

Synthesis and biological evaluation against Mycobacterium tuberculosis and Leishmania amazonensis of a series of diaminated terpenoids.

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.

Activity of pyrrolizidine alkaloids against biofilm formation and Trichomonas vaginalis.

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 1mg/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 1mg/mL. In conclusion, pyrrolizidine alkaloids are suggested as promising prototypes for new drugs especially for topical use.

Synthesis, characterization, cytotoxic activity, and cellular accumulation of dinuclear platinum complexes derived from N,N'-di-(2-aminoethyl)-1,3-diamino-2-propanol, aryl substituted N-benzyl-1,4-butanediamines, and N-benzyl-1,6-hexanediamines.

This work describes the synthesis and characterization of six new dinuclear platinum complexes having N,N'-di-(2-aminoethyl)-1,3-diamino-2-propanol, aryl substituted N-benzyl-1,4-butanediamines and N-benzyl-1,6-hexanediamines as ligands. They were prepared by the reaction of cis-[PtCl(2)(DMSO)(2)] (DMSO=dimethyl sulfoxide) with the appropriate ligand in water, except for one of them, which was prepared from K(2)PtCl(4). We also report the cytotoxic activity and cellular accumulation of three of these complexes in a human small-cell lung carcinoma cell line and its resistant subline. Resistant cells exhibited a lesser degree of cross-resistance to these compounds when compared to cisplatin. The accumulation of platinum in both cell lines followed the same pattern, i.e. approximately the same intracellular platinum concentration yielded the same cytotoxic effect independent of the nature of the platinum complex used.

Synthesis of platinum complexes from N-benzyl-2-aminoethanethiol derivatives.

Twelve new platinum(II) complexes, analogs of cisplatin, containing a 2-aminoethanethiol N-substituted by several benzyl groups have been prepared and characterized in good yields. The ligands were obtained by reaction between 2-aminoethanethiol hydrochloride and different benzyl halides