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1.
Cell Rep ; 43(2): 113795, 2024 Feb 27.
Article in English | MEDLINE | ID: mdl-38367238

ABSTRACT

Activation of endosomal Toll-like receptor (TLR) 7, TLR9, and TLR11/12 is a key event in the resistance against the parasite Toxoplasma gondii. Endosomal TLR engagement leads to expression of interleukin (IL)-12 via the myddosome, a protein complex containing MyD88 and IL-1 receptor-associated kinase (IRAK) 4 in addition to IRAK1 or IRAK2. In murine macrophages, IRAK2 is essential for IL-12 production via endosomal TLRs but, surprisingly, Irak2-/- mice are only slightly susceptible to T. gondii infection, similar to Irak1-/- mice. Here, we report that upon T. gondii infection IL-12 production by different cell populations requires either IRAK1 or IRAK2, with conventional dendritic cells (DCs) requiring IRAK1 and monocyte-derived DCs (MO-DCs) requiring IRAK2. In both populations, we identify interferon regulatory factor 5 as the main transcription factor driving the myddosome-dependent IL-12 production during T. gondii infection. Consistent with a redundant role of DCs and MO-DCs, mutations that affect IL-12 production in both cell populations show high susceptibility to infection in vivo.


Subject(s)
Interleukin-1 Receptor-Associated Kinases , Toxoplasmosis , Animals , Mice , Dendritic Cells , Interferon Regulatory Factors/genetics , Interleukin-12
2.
Sci Rep ; 13(1): 19614, 2023 11 10.
Article in English | MEDLINE | ID: mdl-37950057

ABSTRACT

Ras guanine nucleotide exchange factor member 1b (RasGEF1b) of the RasGEF/CDC25 domain-containing family is preferentially expressed by macrophages. However, information is lacking about its role in macrophage function. In this study, we generated mice with ubiquitous deletion of Rasgef1b and used RNA-seq-based transcriptomics to compare the global gene expression in wild-type and knock-out primary bone-marrow-derived macrophages under basal conditions and after lipopolysaccharide (LPS) treatment. Transcriptional filtering identified several genes with significantly different transcript levels between wild-type and knock-out macrophages. In total, 49 and 37 differentially expressed genes were identified at baseline and in LPS-activated macrophages, respectively. Distinct biological processes were significantly linked to down-regulated genes at the basal condition only, and largely included chemotaxis, response to cytokines, and positive regulation of GTPase activity. Importantly, validation by RT-qPCR revealed that the expression of genes identified as down-regulated after LPS stimulation was also decreased in the knock-out cells under basal conditions. We used a luciferase-based reporter assay to showcase the capability of RasGEF1b in activating the Serpinb2 promoter. Notably, knockdown of RasGEF1b in RAW264.7 macrophages resulted in impaired transcriptional activation of the Serpinb2 promoter, both in constitutive and LPS-stimulated conditions. This study provides a small collection of genes that shows relative expression changes effected by the absence of RasGEF1b in macrophages. Thus, we present the first evidence that RasGEF1b mediates the regulation of both steady-state and signal-dependent expression of genes and propose that this GEF plays a role in the maintenance of the basal transcriptional level in macrophages.


Subject(s)
Cytokines , Lipopolysaccharides , Animals , Mice , Chemotaxis , Cytokines/genetics , Cytokines/metabolism , Lipopolysaccharides/pharmacology , Lipopolysaccharides/metabolism , Macrophages/metabolism , Transcriptome
3.
Article in English | MEDLINE | ID: mdl-32695765

ABSTRACT

In this communication, it was evaluated the production of fatty acid ethyl ester (FAAE) from the free fatty acids of babassu oil catalyzed by lipase from Rhizomucor miehei (RML) immobilized on magnetic nanoparticles (MNP) coated with 3-aminopropyltriethoxysilane (APTES), Fe3O4@APTES-RML or RML-MNP for short. MNPs were prepared by co-precipitation coated with 3-aminopropyltriethoxysilane and used as a support to immobilize RML (immobilization yield: 94.7 ± 1.0%; biocatalyst activity: 341.3 ± 1.2 U p -NPB/g), which were also activated with glutaraldehyde and then used to immobilize RML (immobilization yield: 91.9 ± 0.2%; biocatalyst activity: 199.6 ± 3.5 U p -NPB/g). RML-MNP was characterized by X-Ray Powder Diffraction (XRPD), Fourier Transform-Infrared (FTIR) spectroscopy and Scanning Electron Microscope (SEM), proving the incorporation and immobilization of RML on the APTES matrix. In addition, the immobilized biocatalyst presented at 60°C a half-life 16-19 times greater than that of the soluble lipase in the pH range 5-10. RML and RML-MNP showed higher activity at pH 7; the immobilized enzyme was more active than the free enzyme in the pH range (5-10) analyzed. For the production of fatty acid ethyl ester, under optimal conditions [40°C, 6 h, 1:1 (FFAs/alcohol)] determined by the Taguchi method, it was possible to obtain conversion of 81.7 ± 0.7% using 5% of RML-MNP.

4.
3 Biotech ; 10(6): 254, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32426206

ABSTRACT

In this work, the concept of lipase cocktail has been proposed in the ultrasound-assisted hydrolysis of coconut oil. Lipase from Thermomyces lanuginosus (TLL), lipase from Rhizomucor miehei (RML), and lipase B from Candida antarctica (CALB) were evaluated as biocatalysts in different combinations. The best conversion (33.66%) was achieved using only RML; however, the best lipase cocktail (75% RML and 25% CALB) proposed by the triangular response surface was used to achieve higher conversions. At the best lipase cocktail, reaction parameters [temperature, biocatalyst content and molar ratio (water/oil)] were optimized by a Central Composite Design, allowing to obtain more than 98% of conversion in the hydrolysis of coconut oil in 3 h of incubation at 37 kHz, 300 W and 45 °C by using 20% of the lipase cocktail (w/w) and a molar ratio of 7.5:1 (water/oil). The lipase cocktail retained about 50% of its initial activity after three consecutive cycles of hydrolysis. To the authors' knowledge, up to date, this communication is the first report in the literature for the ultrasound-assisted hydrolysis of coconut oil catalyzed by a cocktail of lipases. Under ultrasound irradiation, the concept of lipase cocktail was successfully applied, and this strategy could be useful for the other types of reactions using heterogeneous substrates.

5.
Int J Mol Sci ; 20(22)2019 Nov 19.
Article in English | MEDLINE | ID: mdl-31752306

ABSTRACT

The synthesis of ethyl butyrate catalyzed by lipases A (CALA) or B (CALB) from Candida antarctica immobilized onto magnetic nanoparticles (MNP), CALA-MNP and CALB-MNP, respectively, is hereby reported. MNPs were prepared by co-precipitation, functionalized with 3-aminopropyltriethoxysilane, activated with glutaraldehyde, and then used as support to immobilize either CALA or CALB (immobilization yield: 100 ± 1.2% and 57.6 ± 3.8%; biocatalysts activities: 198.3 ± 2.7 Up-NPB/g and 52.9 ± 1.7 Up-NPB/g for CALA-MNP and CALB-MNP, respectively). X-ray diffraction and Raman spectroscopy analysis indicated the production of a magnetic nanomaterial with a diameter of 13.0 nm, whereas Fourier-transform infrared spectroscopy indicated functionalization, activation and enzyme immobilization. To determine the optimum conditions for the synthesis, a four-variable Central Composite Design (CCD) (biocatalyst content, molar ratio, temperature and time) was performed. Under optimized conditions (1:1, 45 °C and 6 h), it was possible to achieve 99.2 ± 0.3% of conversion for CALA-MNP (10 mg) and 97.5 ± 0.8% for CALB-MNP (12.5 mg), which retained approximately 80% of their activity after 10 consecutive cycles of esterification. Under ultrasonic irradiation, similar conversions were achieved but at 4 h of incubation, demonstrating the efficiency of ultrasound technology in the enzymatic synthesis of esters.


Subject(s)
Butyrates/metabolism , Candida/metabolism , Enzymes, Immobilized/chemistry , Enzymes, Immobilized/metabolism , Fungal Proteins/metabolism , Lipase/metabolism , Magnetite Nanoparticles/chemistry , Biocatalysis , Esterification/physiology , Glutaral/metabolism , Ultrasonic Waves
6.
Int J Mol Sci ; 20(16)2019 Aug 17.
Article in English | MEDLINE | ID: mdl-31426510

ABSTRACT

In this communication, lipase A from Candida antarctica (CALA) was immobilized by covalent bonding on magnetic nanoparticles coated with chitosan and activated with glutaraldehyde, labelled CALA-MNP, (immobilization parameters: 84.1% ± 1.0 for immobilization yield and 208.0 ± 3.0 U/g ± 1.1 for derivative activity). CALA-MNP biocatalyst was characterized by X-ray Powder Diffraction (XRPD), Fourier Transform Infrared (FTIR) spectroscopy, Thermogravimetry (TG) and Scanning Electron Microscope (SEM), proving the incorporation of magnetite and the immobilization of CALA in the chitosan matrix. Besides, the immobilized biocatalyst showed a half-life 8-11 times higher than that of the soluble enzyme at pH 5-9. CALA showed the highest activity at pH 7, while CALA-MNP presented the highest activity at pH 10. The immobilized enzyme was more active than the free enzyme at all studied pH values, except pH 7.


Subject(s)
Candida/enzymology , Chitosan/chemistry , Lipase/metabolism , Magnetite Nanoparticles/chemistry , Enzyme Stability , Enzymes, Immobilized/metabolism , Fungal Proteins/metabolism
7.
Curr Top Med Chem ; 18(17): 1465-1474, 2018.
Article in English | MEDLINE | ID: mdl-30129412

ABSTRACT

BACKGROUND: Breast cancer is a major cause of death among women worldwide. Treatment for breast cancer involves the surgical removal of cancer tissue, followed by chemotherapy. Although the treatment is efficient, especially when the cancer is detected early, recurrence is common and is often resistant to the previous treatment. Therefore, a constant search for efficient and novel drugs for the treatment of breast cancer is mandatory. Recently, triazole derivatives have shown promising effects against different types of cancer, revealing these molecules as putative anticancer drugs. EXPERIMENTAL: We have synthesized a series of naphthotriazolyl-4-oxoquinoline derivatives and tested their activity against a human breast cancer cell line. Among the compounds tested, we identified a molecule that killed the human breast cancer cell line MCF-7 with minimal effects on its noncancer counterpart, MCF10A. This effect was seen after 24 hours of treatment and persisted for additional 24 hours after treatment withdrawal. After 1 hour of treatment, the compound, here named 12c, promoted a decrease in cell glucose consumption and lactate production. Moreover, the cells treated with 12c for 1 hour showed diminished intracellular ATP levels with unaltered mitochondrial potential and increased reactive oxygen species production. Additionally, apoptosis was triggered after treatment with the drug for 1 hour. All of these effects are only observed with MCF-7 cells, and not MCF10A. These data show that 12c has selective activity against breast cancer cells and is a potential candidate for a novel anticancer drug. RESULTS AND CONCLUSION: The naphthotriazolyl-4-oxoquinoline derivatives were obtained in good to moderate yields, and one of them, 12c, exhibited strong and selective antitumor properties. The antitumor mechanism involves inhibition of glycolysis, diminished intracellular ATP levels, induction of ROS production and triggering of apoptosis. These effects are all selective for cancer cells, since noncancer cells are unaffected, and these effects can only be attributed to the whole molecule, as different pharmacophoric groups did not reproduce these effects.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Quinolones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Molecular Structure , Quinolones/chemical synthesis , Quinolones/chemistry , Reactive Oxygen Species/analysis , Reactive Oxygen Species/metabolism , Structure-Activity Relationship
8.
Eur J Med Chem ; 156: 1-12, 2018 Aug 05.
Article in English | MEDLINE | ID: mdl-30006155

ABSTRACT

Antibiotic resistance has emerged as a serious global public health problem and lately very few antibiotics have been discovered and introduced into clinical practice. Therefore, there is an urgent need for the development of antibacterial compounds with new mechanism of action, especially those capable of evading known resistance mechanisms. In this work two series of glycoconjugate and non-glycoconjugate amino compounds derived from of isoquinoline-5,8-dione and 1,4-naphthoquinone and their halogenated derivatives were synthesized and evaluated for antimicrobial activity against Gram-positive (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228, S. simulans ATCC 27851) and Gram-negative bacteria (E. coli ATCC 25922, Proteus mirabilis ATCC 15290, K. pneumoniae ATCC 4352 and P. aeruginosa ATCC 27853) strains of clinical importance. This study revealed that glycoconjugate compounds derived from halogeno-substituted naphthoquinones were more active against Gram-negative strains, which cause infections whose treatment is even more difficult, according to the literature. These molecules were also more active than isoquinoline-5,8-dione analogues with minimum inhibitory concentration (MIC = 4-32 µg/mL) within Clinical and Laboratory Standard Institute MIC values (CLSI 0.08-256 µg/mL). Interestingly the minimal bactericidal concentration (MBC) values of the most active compounds were equal to MIC classifying them as bactericidal agents against Gram-negative bacteria. Sixteen compounds among eighteen carbohydrate-based naphthoquinones tested showed no hemolytic effects on health human erythrocytes whereas more susceptibility to hemolytic cleavage was observed when using non-glycoconjugate amino compounds. In silico Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) evaluation also pointed out that these compounds are potential for oral administration with low side effects. In general, this study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials more effective against Gram-negative bacteria.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Isoquinolines/chemistry , Isoquinolines/pharmacology , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Amino Sugars/chemical synthesis , Amino Sugars/chemistry , Amino Sugars/pharmacology , Amino Sugars/toxicity , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/toxicity , Bacterial Infections/drug therapy , Halogenation , Hemolysis/drug effects , Humans , Isoquinolines/chemical synthesis , Isoquinolines/toxicity , Naphthoquinones/chemical synthesis , Naphthoquinones/toxicity
9.
Reprod Biomed Online ; 36(3): 277-284, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29361453

ABSTRACT

Vitamin D receptor-knockout mice fail to produce mature oocytes, indicating vitamin D is crucial for folliculogenesis in mice. However, the actions of vitamin D during folliculogenesis remain unknown. This prospective study aimed to assess whether follicular fluid (FF) vitamin D (25OHD3) concentrations are related to specific responses to ovarian stimulation. Women undergoing ovarian stimulation for IVF participated in the study. FF 25OHD3 concentrations were assessed in the first follicle aspirate on oocyte retrieval day. Oestradiol and progesterone concentrations were assessed on the trigger day. K-means grouping analysis showed that 25OHD3 FF concentrations clustered into a higher and lower group (mean ± SEM 17.4 ± 6.61 ng/ml and 35.5 ± 7.17 ng/ml, respectively, P < 0.001). The clusters were analysed according to the oestradiol and progesterone concentrations, follicle number and size and resulting oocyte number and maturity. The FF 25OHD3 concentrations were no different among the infertility diagnoses. The lower 25OHD3 group had more follicles (≥16.0 mm, P = 0.009) and higher serum oestradiol concentrations (P < 0.03) on the day of HCG administration. In this study, lower follicular 25OHD3 concentrations predicted a better response to ovarian stimulation shown by a greater production of larger follicles and higher serum oestradiol concentrations.


Subject(s)
Estradiol/blood , Follicular Fluid/metabolism , Ovarian Follicle/cytology , Progesterone/blood , Vitamin D/metabolism , Adult , Female , Fertilization in Vitro , Humans , Ovarian Follicle/metabolism , Ovulation Induction , Prospective Studies
10.
Article in English | MEDLINE | ID: mdl-28439500

ABSTRACT

Sepsis is a severe syndrome that arises when the host response to an insult is exacerbated, leading to organ failure and frequently to death. How a chronic infection that causes a prolonged Th1 expansion affects the course of sepsis is unknown. In this study, we showed that mice chronically infected with Toxoplasma gondii were more susceptible to sepsis induced by cecal ligation and puncture (CLP). Although T. gondii-infected mice exhibited efficient control of the bacterial burden, they showed increased mortality compared to the control groups. Mechanistically, chronic T. gondii infection induces the suppression of Th2 lymphocytes via Gata3-repressive methylation and simultaneously induces long-lived IFN-γ-producing CD4+ T lymphocytes, which promotes systemic inflammation that is harmful during CLP. Chronic T. gondii infection intensifies local and systemic Th1 cytokines as well as nitric oxide production, which reduces systolic and diastolic arterial blood pressures after sepsis induction, thus predisposing the host to septic shock. Blockade of IFN-γ prevented arterial hypotension and prolonged the host lifespan by reducing the cytokine storm. Interestingly, these data mirrored our observation in septic patients, in which sepsis severity was positively correlated to increased levels of IFN-γ in patients who were serologically positive for T. gondii. Collectively, these data demonstrated that chronic infection with T. gondii is a critical factor for sepsis severity that needs to be considered when designing strategies to prevent and control the outcome of this devastating disease.


Subject(s)
Coinfection/pathology , Sepsis/complications , Sepsis/pathology , Toxoplasmosis/complications , Animals , Disease Models, Animal , Interferon-gamma/metabolism , Mice , Nitric Oxide/metabolism , Th1 Cells/immunology , Th2 Cells/immunology
11.
ALTEX ; 32(1): 59-63, 2015.
Article in English | MEDLINE | ID: mdl-25490698

ABSTRACT

In veterinary medicine, surgical education and training require the development of abilities that can be acquired in practical classes using currently available models such as cadaver training. Limited availability of cadavers, undesirable changes in tissue texture and the absence of bleeding are the main disadvantages of cadaver-based training compared to training in live animals. This study proposes a chemical cadaver preservation method aimed at overcoming the aforementioned limitations. Blood circulation could be reproduced in preserved cadavers, thereby enabling satisfactory simulation-based training of several surgical procedures, from incision to suture and including hemostatic techniques. The model in this study introduces a high-fidelity simulation training alternative to prepare students for the practice of surgery. In this manner, surgical interventions would be restricted to surgical cases and healthy animals would not be submitted to surgical procedures exclusively for learning purposes.


Subject(s)
Embalming/methods , Surgery, Veterinary/education , Animal Testing Alternatives , Animals , Brazil , Cadaver , Education, Veterinary/methods , Hemostatic Techniques
12.
Curr Microbiol ; 65(4): 455-60, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22773252

ABSTRACT

Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis, which remains a serious public health problem. The emergence of resistant bacterial strains has continuously increased and new treatment options are currently in need. In this work, we identified a new potential aldehyde-arylhydrazone-oxoquinoline derivative (4e) with interesting chemical structural features that may be important for designing new anti-TB agents. This 1-ethyl-N'-[(1E)-(5-nitro-2-furyl)methylene]-4-oxo-1,4-dihydroquinoline-3-carbohydrazide (4e) presented an in vitro active profile against M. tuberculosis H37Rv strain (minimum inhibitory concentration, MIC = 6.25 µg/mL) better than other acylhydrazones described in the literature (MIC = 12.5 µg/mL) and close to other antitubercular agents currently on the market. The theoretical analysis showed the importance of several structural features that together with the 5-nitro-2-furyl group generated this active compound (4e). This new compound and the analysis of its molecular properties may be useful for designing new and more efficient antibacterial drugs.


Subject(s)
Antitubercular Agents/isolation & purification , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Aldehydes/chemistry , Aldehydes/isolation & purification , Aldehydes/pharmacology , Antitubercular Agents/chemistry , Hydrazones/chemistry , Hydrazones/isolation & purification , Hydrazones/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Quinolones/chemistry , Quinolones/isolation & purification , Quinolones/pharmacology
13.
Nat Prod Res ; 26(4): 364-9, 2012.
Article in English | MEDLINE | ID: mdl-21432719

ABSTRACT

Luehea candicans Mart. et Zucc. (Tiliaceae) is known as 'açoita-cavalo' and is one of the most important medicinal plants found in the Brazilian cerrado. The crude methanolic extracts of the branches and leaves and their fractions were evaluated using the following cancer cell lines: MCF-7 (breast), NCI-ADR (breast expressing the multidrug resistance phenotype), NCI-460 (lung), UACC-62 (melanoma), 786-0 (kidney), OVCAR (ovarian), PCO-3 (prostate), HT-29 (colon) and K-562 (leukaemia). The crude methanolic extracts from the branches (B) and leaves (L) were able to inhibit the growth of the K-562 and 786-0 cell lines in a dose-dependent manner, with GI(50) values of 8.1 and 5.4 µg mL(-1), respectively. The hexane (L1), chloroform (L2) and methanol (L4) fractions derived from extract L showed a high selectivity and pronounced cytostatic activity against 786-0 (GI(50) ~ 40 µg mL(-1)). A significant amount of lupeol was isolated from fraction L2. The chloroform (B2) and methanol (B3) fractions derived from extract (B) exhibited less selectivity, showing the highest cytostatic activity against K-562, NCI-ADR, OVCAR, MCF-7 and NCI-460 cells, with GI(50) values between 27 and 40 µg mL(-1). Lupeol, betulin, a mixture of steroids, (-)-epicatechin, vitexin and liriodendrin were isolated from these active fractions.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Malvaceae/chemistry , Plant Extracts/pharmacology , Plants, Medicinal/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Brazil , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , HT29 Cells/drug effects , Humans , K562 Cells/drug effects , Male , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Pentacyclic Triterpenes/isolation & purification , Plant Leaves/chemistry , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology
14.
Bioorg Med Chem ; 19(18): 5605-11, 2011 Sep 15.
Article in English | MEDLINE | ID: mdl-21840219

ABSTRACT

Tuberculosis treatment remains a challenge that requires new antitubercular agents due to the emergence of multidrug-resistant Mycobacterium strains. This paper describes the synthesis, the antitubercular activity and the theoretical analysis of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (8a-b, 8e-f, 8i-j and 8n-o) and new analogues (8c-d, 8g-h, 8l-m and 8p-q). These derivatives were synthesized in good yields and some of them showed a promising antitubercular profile. Interestingly the N-acylhydrazone (NAH) 8n was the most potent against the Mycobacterium tuberculosis H37Rv strain (MIC=2.5 µg/mL) similar to or better than the current drugs on the market. The theoretical structure-activity relationship study suggested that the presence of the furyl ring and the electronegative group (NO(2)) as well as low lipophilicity and small volume group at R position are important structural features for the antitubercular profile of these molecules. NMR spectra, IR spectra and elemental analyses of these substances are reported.


Subject(s)
Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Hydrazines/pharmacology , Mycobacterium tuberculosis/drug effects , Triazoles/chemistry , Antitubercular Agents/chemistry , Dose-Response Relationship, Drug , Hydrazines/chemical synthesis , Hydrazines/chemistry , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship
15.
Bioorg Med Chem ; 19(6): 1860-5, 2011 Mar 15.
Article in English | MEDLINE | ID: mdl-21376603

ABSTRACT

In this work, a new series of arysulfonylhydrazine-1H-1,2,3-triazole derivatives were synthesized, and their ability to inhibit the in vitro replication of HSV-1 was evaluated. Among the 1,2,3-triazole derivatives, 1-[(5″-methyl-1″-(4‴-fluorophenylamino)-1H-1,2,3-triazol-4″-yl)carbonyl]-2-(4'-methylphenylsulfonyl)hydrazine and 1-[(5'-methyl-1'-(2″,5″-dichlorophenylamino)-1H-1,2,3-triazol-4'-yl)carbonyl]-2-(phenylsulfonyl)hydrazine, with IC(50) values of 1.30 and 1.26 µM, respectively, displayed potent activity against HSV-1. Because these compounds have low cytotoxicity, their selectivity indices are high. Under the assay conditions, they have better performance than does the reference compound acyclovir. The structures of all of the compounds were confirmed by one- and two-dimensional NMR techniques ((1)H, (13)C-APT, COSY-(1)H×(1)H and HETCOR (1)J(CH)) and by elemental analysis.


Subject(s)
Antiviral Agents/chemical synthesis , Herpesvirus 1, Human/drug effects , Triazoles/chemical synthesis , Animals , Antiviral Agents/chemistry , Antiviral Agents/toxicity , Chlorocebus aethiops , DNA Replication/drug effects , Humans , Magnetic Resonance Spectroscopy , Molecular Conformation , Triazoles/chemistry , Triazoles/toxicity , Vero Cells
16.
Curr Microbiol ; 62(5): 1349-54, 2011 May.
Article in English | MEDLINE | ID: mdl-21225264

ABSTRACT

Herpes simplex virus is an important human pathogen responsible for a range of diseases from mild uncomplicated mucocutaneous infections to life-threatening ones. Currently, the emergence of Herpes simplex virus resistant strains increased the need for more effective and less cytotoxic drugs for Herpes treatment. In this work, we synthesized a series of oxoquinoline derivatives and experimentally evaluated the antiviral activity against acyclovir resistant HSV-1 strain as well as their cytotoxity profile. The most active compound (3b), named here as Fluoroxaq-3b, showed a promising profile with a better cytotoxicity profile than acyclovir. The theoretical analysis of the structure-activity relationship of these compounds revealed some stereoelectronic properties such as lower LUMO energy and lipophilicity, besides a higher polar surface area and number of hydrogen bond acceptor groups as important parameters for the antiviral activity. Fluoroxaq-3b showed a good oral theoretical bioavailability, according to Lipinski rule of five, with a promising profile for further in vivo analysis.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Herpes Simplex/virology , Herpesvirus 1, Human/drug effects , Quinolones/chemistry , Quinolones/pharmacology , Animals , Antiviral Agents/chemical synthesis , Cell Line , Chlorocebus aethiops , Herpes Simplex/drug therapy , Humans , Quinolones/chemical synthesis , Structure-Activity Relationship , Vero Cells
17.
Rev. bras. farmacogn ; 20(1): 23-27, Jan.-Mar. 2010. ilus
Article in Portuguese | LILACS | ID: lil-551257

ABSTRACT

O estudo fitoquímico das folhas de Calycorectes psidiiflorus (O. Berg) Sobral, Myrtaceae, resultou no isolamento e identificação de: sesquiterpeno [8-hidroxicalameneno (1)], triterpenos [α-amirina (2a) e β-amirina (2b)], flavonóide [3-O-α-ramnopiranosil-7-O-bglucopiranosil canferol (3)], e alcalóide [1,2,3,4-tetraidro-1-metil-β-carbolina (4)]. As estruturas das substâncias isoladas foram elucidadas com base nos seus dados de RMN em comparação com os da literatura. A substância 8-hydroxicalameneno apresentou atividade antibacteriana (MIC = 7,8 µg/mL) e antifúngica (MIC = 15,6 µg/mL).


The phytochemical study of Calycorectes psidiiflorus (O. Berg) Sobral leaves resulted in isolation and identification of the sesquiterpene 8-hydroxycalamenene (1), triterpenes α-amyrin (2a) and β-amyrin (2b), flavonoid 3-O-α-rhamnopyranosyl-7-O-β-glucopyranosyl kaempferol (3), and of the alkaloid 1,2,3,4-tetrahydro-1-methyl-β-carboline (4). The structures of the isolated compounds were elucidated based on their spectroscopic NMR data and comparison with those reported in literature. Substance 1 presented antibacterial (MIC = 7.8 µg/mL) and antifungal (MIC = 15.6 µg/ mL) activities.

18.
Bioorg Med Chem ; 17(21): 7429-34, 2009 Nov 01.
Article in English | MEDLINE | ID: mdl-19815419

ABSTRACT

The current treatment used against envenomation by Lachesis muta venom still presents several side effects. This paper describes the synthesis, pharmacological and theoretical evaluations of new 1-arylsulfonylamino-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl esters (8a-f) tested against the hemolytic profile of the L. muta snake venom. Their structures were elucidated by one- and two-dimensional NMR techniques ((1)H, APT, HETCOR (1)J(CH) and (n)J(CH), n=2, 3) and high-resolution electrospray ionization mass spectrometry. The series of triazole derivatives significantly neutralized the hemolysis induced by L. muta crude venom presenting a dose-dependent inhibitory profile (IC(50)=30-83 microM) with 1-(4'-chlorophenylsulfonylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl ester (8e) being the most potent compound. The theoretical evaluation revealed the correlation of the antiophidian profile with the coefficient distribution and density map of the Highest Occupied Molecular Orbitals (HOMO) of these molecules. The elucidation of this new series may help on designing new and more efficient antiophidian molecules.


Subject(s)
Crotalid Venoms/toxicity , Triazoles/chemical synthesis , Viperidae/metabolism , Animals , Esters/chemistry , Hemolysis , Humans , Magnetic Resonance Spectroscopy , Rabbits , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship , Thermodynamics , Triazoles/chemistry , Triazoles/pharmacology
19.
Bioorg Med Chem ; 17(15): 5476-81, 2009 Aug 01.
Article in English | MEDLINE | ID: mdl-19581097

ABSTRACT

In the present article, we describe the synthesis, anti-HIV1 profile and molecular modeling evaluation of 11 oxoquinoline derivatives. The structure-activity relationship analysis revealed some stereoelectronic properties such as LUMO energy, dipole moment, number of rotatable bonds, and of hydrogen bond donors and acceptors correlated with the potency of compounds. We also describe the importance of substituents R(2) and R(3) for their biological activity. Compound 2j was identified as a lead compound for future investigation due to its: (i) high activity against HIV-1, (ii) low cytotoxicity in PBMC, (iii) low toxic risks based on in silico evaluation, (iv) a good theoretical oral bioavailability according to Lipinski 'rule of five', (v) higher druglikeness and drug-score values than current antivirals AZT and efavirenz.


Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , HIV-1/drug effects , Quinolones/chemical synthesis , Quinolones/pharmacology , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacokinetics , Cell Survival/drug effects , Chlorocebus aethiops , HIV Infections/drug therapy , HIV-1/growth & development , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Models, Molecular , Molecular Structure , Quinolones/chemistry , Quinolones/pharmacokinetics , Structure-Activity Relationship , Vero Cells
20.
Eur J Med Chem ; 44(9): 3777-83, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19481841

ABSTRACT

This paper describes the antiviral evaluation of new N-amino-1,2,3-triazole derivatives, 1-(substituted-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl esters, 3 and 1-(4-substituted-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid hydrazides, 4, on Cantagalo virus replication. 1-(4-Fluoro-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid hydrazide, 4e, exhibited a significant antiviral effect. Characterization of all compounds was confirmed by IR, (1)H and (13)C spectroscopies and elemental analysis. In addition, molecular structure of 4e was also reported.


Subject(s)
Amitrole/analogs & derivatives , Amitrole/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Vaccinia virus/drug effects , Amitrole/toxicity , Animals , Antiviral Agents/toxicity , Cell Line , Cell Survival/drug effects , Chlorocebus aethiops , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Viral Proteins/analysis , Viral Proteins/metabolism
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