ABSTRACT
Aim: The design, synthesis, docking studies and evaluation of the in vitro antifungal and cytotoxic properties of eugenol (EUG) containing 1,2,3-triazole derivatives are reported. Most of the derivatives have not been reported.Materials & methods: The EUG derivatives were synthesized, molecular docked and tested for their antifungal activity.Results: The compounds showed potent antifungal activity against Trichophyton rubrum, associated with dermatophytosis. Compounds 2a and 2i exhibited promising results, with 2a being four-times more potent than EUG. The binding mode prediction was similar to itraconazole in the lanosterol-14-α-demethylase wild-type and G73E mutant binding sites. Additionally, the pharmacokinetic profile prediction suggests good gastrointestinal absorption and potential oral administration.Conclusion: Compound 2a is a promising antifungal agent against dermatophytosis caused by T. rubrum.
[Box: see text].
ABSTRACT
BACKGROUND: The current treatments for Chagas disease (CD) include benznidazole and nifurtimox, which have limited efficacy and cause numerous side effects. Triazoles are candidates for new CD treatments due to their ability to eliminate T. cruzi parasites by inhibiting ergosterol synthesis, thereby damaging the cell membranes of the parasite. METHODS: Eleven synthetic analogs of the kinase inhibitor SRPIN340 containing a triazole core (compounds 6A-6K) were screened in vitro against the Tulahuen strain transfected with ß-galactosidase, and their IC50, CC50, and selectivity indexes (SI) were calculated. Compounds with an SI > 50 were further evaluated in mice infected with the T. cruzi Y strain by rapid testing. RESULTS: Eight compounds were active in vitro with IC50 values ranging from 0.5-10.5 µg/mL. The most active compounds, 6E and 6H, had SI values of 125.2 and 69.6, respectively. These compounds also showed in vivo activity, leading to a reduction in parasitemia at doses of 10, 50, and 250 mg/kg/day. At doses of 50 and 250 mg/kg/day, parasitemia was significantly reduced compared to infected untreated animals, with no significant differences between the effects of 6E and 6H. CONCLUSIONS: This study identified two new promising compounds for CD chemotherapy and confirmed their activity against T. cruzi.
Subject(s)
Chagas Disease , Triazoles , Trypanocidal Agents , Trypanosoma cruzi , Trypanosoma cruzi/drug effects , Animals , Triazoles/pharmacology , Chagas Disease/drug therapy , Trypanocidal Agents/pharmacology , Mice , Inhibitory Concentration 50 , Parasitic Sensitivity Tests , ThiazolesABSTRACT
Aim: This study aimed to enhance the aqueous dissolution of SRPK inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340).Materials & Methods: A complex with p-sulfonic calix[6]arene (Host) and SRPIN340 (Guest) was prepared, studied via 1H nuclear magnetic resonance (NMR) and theoretical calculations and biologically evaluated on cancer cell lines.Results & conclusion: The 1:1 host (H)/guest (G) complex significantly enhanced the aqueous dissolution of SRPIN340, achieving 64.8% water solubility as determined by 1H NMR quantification analysis. The H/G complex reduced cell viability by 75% for HL60, â¼50% for Nalm6 and Jurkat, and â¼30% for B16F10 cells. It exhibited greater cytotoxicity than free SRPIN340 against Jurkat and B16F10 cells. Theoretical studies indicated hydrogen bond stabilization of the complex, suggesting broader applicability of SRPIN340 across diverse biological systems.
[Box: see text].
Subject(s)
Antineoplastic Agents , Calixarenes , Cell Survival , Calixarenes/chemistry , Calixarenes/pharmacology , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Cell Survival/drug effects , Phenols/chemistry , Phenols/pharmacology , Mice , Magnetic Resonance Spectroscopy , Animals , Sulfonic Acids/chemistry , Sulfonic Acids/antagonists & inhibitors , Sulfonic Acids/pharmacology , Cell Line, Tumor , Molecular Structure , Drug Screening Assays, Antitumor , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Cell Proliferation/drug effects , Piperidines/chemistry , Piperidines/pharmacologyABSTRACT
This study explores the stabilization by niobic acid, of Pt, Ni, Pd, and Au nanoparticles (NPs) for the efficient microheterogeneous catalysis of NaBH4 hydrolysis for hydrogen production. Niobic acid is the most widely studied Nb2O5 polymorph, and it is employed here for the first time for this key reaction relevant to green energy. Structural insights from XRD, Raman, and FTIR spectroscopies, combined with hydrogen production data, reveal the role of niobic acid's Brønsted acidity in its catalytic activity. The supported NPs showed significantly higher efficiency than the non-supported counterparts regarding turnover frequency, average hydrogen production rate, and cost. Among the tested NPs, PtNPs and NiNPs demonstrate the most favorable results. The data imply mechanism changes during the reaction, and the kinetic isotope assay indicates a primary isotope effect. Reusability assays demonstrate consistent yields over five cycles for PtNPs, although catalytic efficiency decreases, likely due to the formation of reaction byproducts.
ABSTRACT
A series of 19 novel eugenol derivatives containing a 1,2,3-triazole moiety was synthesized via a two-step process, with the key step being a copper(I)-catalyzed azide-alkyne cycloaddition reaction. The compounds were assessed for their antifungal activities against Colletotrichum gloeosporioides, the causative agent of papaya anthracnose. Triazoles 2k, 2m, 2l, and 2n, at 100 ppm, were the most effective, reducing mycelial growth by 88.3, 85.5, 82.4, and 81.4%, respectively. Molecular docking calculations allowed us to elucidate the binding mode of these derivatives in the catalytic pocket of C. gloeosporioides CYP51. The best-docked compounds bind closely to the heme cofactor and within the channel access of the lanosterol (LAN) substrate, with crucial interactions involving residues Tyr102, Ile355, Met485, and Phe486. From such studies, the antifungal activity is likely attributed to the prevention of substrate LAN entry by the 1,2,3-triazole derivatives. The triazoles derived from natural eugenol represent a novel lead in the search for environmentally safe agents for controlling C. gloeosporioides.
Subject(s)
Carica , Colletotrichum , Eugenol , Fungicides, Industrial , Molecular Docking Simulation , Plant Diseases , Triazoles , Colletotrichum/drug effects , Eugenol/pharmacology , Eugenol/chemistry , Carica/chemistry , Fungicides, Industrial/pharmacology , Fungicides, Industrial/chemistry , Fungicides, Industrial/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacology , Triazoles/chemical synthesis , Plant Diseases/microbiology , Plant Diseases/prevention & control , Structure-Activity Relationship , Drug Design , Fungal Proteins/chemistry , Molecular StructureABSTRACT
Methicillin-resistant Staphylococcus aureus (MRSA) is widely recognized as a causative agent for various infections acquired in healthcare settings as well as in the community. Given the limited availability of effective antimicrobial agents to combat MRSA infections, there is an increasing need to explore alternative therapeutic strategies. This study aimed to assess the antimicrobial, anti-adhesive, anti-biofilm properties, and toxicity of 175 newly synthesized compounds, belonging to seven different classes, against MRSA. Initially, the compounds underwent screening for antimicrobial activity using the agar diffusion method. Subsequently, active compounds underwent further evaluation to determine their minimum inhibitory concentrations through microdilution. Anti-biofilm and anti-adhesive properties were assessed using the crystal violet method, while toxicity was tested using the alternative infection model Galleria mellonella. Among the tested compounds, two xanthenodiones exhibited the most promising activities, displaying bactericidal effects along with anti-adhesive and anti-biofilm properties. Moreover, the observed non-toxicity in G. mellonella larvae suggests that these compounds hold significant potential as alternative therapeutic options to address the escalating challenge of MRSA resistance in both hospital and community settings.
Subject(s)
Anti-Bacterial Agents , Biofilms , Methicillin-Resistant Staphylococcus aureus , Microbial Sensitivity Tests , Moths , Methicillin-Resistant Staphylococcus aureus/drug effects , Biofilms/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Animals , Moths/drug effects , Moths/microbiology , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Bacterial Adhesion/drug effects , Larva/drug effects , Larva/microbiologyABSTRACT
Aim: The assessment of the antileishmanial potential of 22 vanillin-containing 1,2,3-triazole derivatives against Leishmania braziliensis is reported. Materials & methods: Initial screening was performed against the parasite promastigote form. The most active compound, 4b, targeted parasites within amastigotes (IC50 = 4.2 ± 1.0 µmol l-1), presenting low cytotoxicity and a selective index value of 39. 4D quantitative structure-activity relationship and molecular docking studies provided insights into structure-activity and biological effects. Conclusion: A vanillin derivative with significant antileishmanial activity was identified. Enhanced activity was linked to increased electrostatic and Van der Waals interactions near the benzyl ring of the derivatives. Molecular docking indicated the inhibition of the Leishmania amazonensis sterol 14α-demethylase, using Leishmania infantum sterol 14α-demethylase as a model, without affecting the human isoform. Inhibition was active site competition with lanosterol.
Subject(s)
Antiprotozoal Agents , Benzaldehydes , Quantitative Structure-Activity Relationship , Humans , Molecular Docking Simulation , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Triazoles/pharmacology , Sterols , Structure-Activity RelationshipABSTRACT
ABSTRACT Background: The current treatments for Chagas disease (CD) include benznidazole and nifurtimox, which have limited efficacy and cause numerous side effects. Triazoles are candidates for new CD treatments due to their ability to eliminate T. cruzi parasites by inhibiting ergosterol synthesis, thereby damaging the cell membranes of the parasite. Methods: Eleven synthetic analogs of the kinase inhibitor SRPIN340 containing a triazole core (compounds 6A-6K) were screened in vitro against the Tulahuen strain transfected with β-galactosidase, and their IC50, CC50, and selectivity indexes (SI) were calculated. Compounds with an SI > 50 were further evaluated in mice infected with the T. cruzi Y strain by rapid testing. Results: Eight compounds were active in vitro with IC50 values ranging from 0.5-10.5 µg/mL. The most active compounds, 6E and 6H, had SI values of 125.2 and 69.6, respectively. These compounds also showed in vivo activity, leading to a reduction in parasitemia at doses of 10, 50, and 250 mg/kg/day. At doses of 50 and 250 mg/kg/day, parasitemia was significantly reduced compared to infected untreated animals, with no significant differences between the effects of 6E and 6H. Conclusions: This study identified two new promising compounds for CD chemotherapy and confirmed their activity against T. cruzi.
ABSTRACT
The present investigation aimed to develop inclusion complexes (ICs) from Psidium gaudichaudianum (GAU) essential oil (EO) and its major compound ß-caryophyllene (ß-CAR), and to evaluate their herbicidal (against Lolium multiflorum and Bidens pilosa) and cytogenotoxic (on Lactuca sativa) activities. The ICs were obtained using 2-hydroxypropyl-ß-cyclodextrin (HPßCD) and they were prepared to avoid or reduce the volatility and degradation of GAU EO and ß-CAR. The ICs obtained showed a complexation efficiency of 91.5 and 83.9% for GAU EO and ß-CAR, respectively. The IC of GAU EO at a concentration of 3000 µg mL-1 displayed a significant effect against weed species B. pilosa and L. multiflorum. However, the ß-CAR IC at a concentration of 3000 µg mL-1 was effective only on L. multiflorum. In addition, the cytogenotoxic activity evaluation revealed that there was a reduction in the mitotic index and an increase in chromosomal abnormalities. The produced ICs were able to protect the EO and ß-CAR from volatility and degradation, with a high thermal stability, and they also enabled the solubilization of the EO and ß-CAR in water without the addition of an organic solvent. Therefore, it is possible to indicate the obtained products as potential candidates for commercial exploration since the ICs allow the complexed EO to exhibit a more stable chemical constitution than pure EO under storage conditions.
Subject(s)
Herbicides , Oils, Volatile , Psidium , 2-Hydroxypropyl-beta-cyclodextrin/chemistry , Herbicides/pharmacology , Herbicides/analysis , Oils, Volatile/chemistry , Plant Leaves/chemistry , Psidium/chemistry , SolubilityABSTRACT
Leishmaniasis is a group of infectious diseases caused by protozoan parasites that belong to the genus Leishmania. Currently, there is no human vaccine, and the available treatments are associated with toxicity, high cost, and the emergence of resistant strains. These factors highlight the need to identify new antileishmanial candidates. In this study, we synthesized twenty-four methoxylated cinnamides containing 1,2,3-triazole fragments and evaluated their antileishmanial activity against the Leishmania braziliensis species, which is the main etiological agent responsible for American Tegumentary Leishmaniasis (ATL). The cinnamides were synthetically prepared using nucleophilic acyl substitution and copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. The compounds were characterized using infrared, nuclear magnetic resonance, and high-resolution mass spectrometry techniques. We performed preliminary studies to evaluate the biological activity of these compounds against L. braziliensis promastigotes and axenic amastigotes. Compound 28, N-((1-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-1H-1,2,3-triazole-4-yl) methyl)-3,4-dimethoxy cinnamide, demonstrated relevant antileishmanial activity with low toxicity in murine cells. The selectivity index values for this compound were superior compared with data obtained using amphotericin B. Furthermore, this cinnamide derivative reduced the infection percentage and number of recovered amastigotes in L. braziliensis-infected macrophages. It also induced an increase in reactive oxygen species production, depolarization of the mitochondrial potential, and disruption of the parasite membrane. Taken together, these findings suggest that this synthetic compound holds potential as an antileishmanial candidate and should be considered for future studies in the treatment of ATL.
ABSTRACT
Background: Chagas disease is a life-threatening illness caused by Trypanosoma cruzi. The involvement of serine-/arginine-rich protein kinase in the T. cruzi life cycle is significant. Aims: To synthesize, characterize and evaluate the trypanocidal activity of diamides inspired by kinase inhibitor, SRPIN340. Material & Methods: Synthesis using a three-step process and characterization by infrared, nuclear magnetic resonance and high-resolution mass spectrometry were conducted. The selectivity index was obtained by the ratio of CC50/IC50 in two in vitro models. The most active compound, 3j, was evaluated using in vitro cytokine assays and assessing in vivo trypanocidal activity. Results: 3j activity in the macrophage J774 lineage showed an anti-inflammatory profile, and mice showed significantly reduced parasitemia and morbidity at low compound dosages. Conclusion: Novel diamide is active against T. cruzi in vitro and in vivo.
ABSTRACT
Lung cancer is the leading cause of cancer mortality worldwide, and malignant melanomas are highly lethal owing to their elevated metastatic potential. Despite improvements in therapeutic approaches, cancer treatments are not completely effective. Thus, new drug candidates are continuously sought. We synthesized mono- and di-methoxylated cinnamic acid esters and investigated their antitumor potential. A cell viability assay was performed to identify promising substances against A549 (non-small-cell lung cancer) and SK-MEL-147 (melanoma) cells. (E)-2,5-dimethoxybenzyl 3-(4-methoxyphenyl)acrylate (4m), a monomethoxylated cinnamic acid derivative, was identified as the lead antitumor compound, and its antitumor potential was deeply investigated. Various approaches were employed to investigate the antiproliferative (clonogenic assay and cell cycle analysis), proapoptotic (annexin V assay), and antimigratory (wound-healing and adhesion assays) activities of 4m on A549 cells. In addition, western blotting was performed to explore its mechanism of action. We demonstrated that 4m inhibits the proliferation of A549 by promoting cyclin B downregulation and cell cycle arrest at G2/M. Antimigratory and proapoptotic activities of 4m on A549 were also observed. The antitumor potential of 4m involved its ability to modulate the mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway once phosphorylated-ERK expression was considerably reduced in response to treatment. Our findings demonstrate that 4m is a promising anticancer drug candidate.
ABSTRACT
In agriculture, the control of fungal infections is essential to improve crop quality and productivity. This study describes the preparation and fungicidal activity evaluation of 12 glycerol derivatives bearing 1,2,3-triazole fragments. The derivatives were prepared from glycerol in four steps. The key step corresponded to the Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction between the azide 4-(azidomethyl)-2,2-dimethyl-1,3-dioxolane (3) and different terminal alkynes (57-91% yield). The compounds were characterized by infrared spectroscopy, nuclear magnetic resonance (1H and 13C), and high-resolution mass spectrometry. The in vitro assessment of the compounds on Asperisporium caricae, that is, the etiological agent of papaya black spot, at 750 mg L-1 showed that the glycerol derivatives significantly inhibited conidial germination with different degrees of efficacy. The most active compound 4-(3-chlorophenyl)-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl)-1H-1,2,3-triazole (4c) presented a 91.92% inhibition. In vivo assays revealed that 4c reduced the final severity (70.7%) and area under the disease severity progress curve of black spots on papaya fruits 10 days after inoculation. The glycerol-bearing 1,2,3-triazole derivatives also present agrochemical-likeness properties. Our in silico study using molecular docking calculations show that all triazole derivatives bind favorably to the sterol 14α-demethylase (CYP51) active site at the same region of the substrate lanosterol (LAN) and fungicide propiconazole (PRO). Thus, the mechanism of action of the compounds 4a-4l may be the same as the fungicide PRO, blocking the entrance/approximation of the LAN into the CYP51 active site by steric effects. The reported results point to the fact that the glycerol derivatives may represent a scaffold to be explored for the development of new chemical agents to control papaya black spot.
Subject(s)
Fungicides, Industrial , Fungicides, Industrial/pharmacology , Triose Sugar Alcohols , Glycerol , Molecular Docking Simulation , Azides/chemistry , Triazoles/chemistryABSTRACT
The control of weeds in agriculture is mainly conducted with the use of synthetic herbicides. However, environmental and human health concerns and increased resistance of weeds to existing herbicides have increased the pressure on researchers to find new active ingredients for weed control which present low toxicity to non-target organisms, are environmentally safe, and can be applied at low concentrations. It is herein described the synthesis of glycerol-fluorinated triazole derivatives and evaluation of their phytotoxic and cytogenotoxic activities. Starting from glycerol, ten fluorinated triazole derivatives were prepared in four steps. The assessment of them on Lactuca sativa revealed that they present effects on phytotoxic and cytogenotoxic parameters with different degrees of efficiency. The compounds 4a, 4b, 4d, 4e, 4i, and 4j have pre-emergent inhibition behavior, while all the investigated compounds showed post emergent effect. Mechanism of action as clastogenic, aneugenic, and epigenetic were observed in the lettuce root meristematic cells, with alterations as stick chromosome, bridge, delay, c-metaphase, and loss. It is believed that glycerol-fluorinated triazole derivatives possess a scaffold that can be explored towards the development of new chemicals for the control of weed species.
Subject(s)
Alkaloids , Herbicides , Humans , Glycerol/toxicity , Triose Sugar Alcohols , Triazoles/toxicity , Meristem , Alkaloids/pharmacology , Herbicides/toxicity , Herbicides/chemistry , Plant Weeds , LactucaABSTRACT
The Zika virus (ZIKV) is an arbovirus and belongs to the Flaviviridae family and Flavivirus genus, with dissemination in the Americas. In Brazil, the predominant strain is the Asian, promoting outbreaks that started in 2015 and are directly related to microcephaly in newborns and Guillain-Barré syndrome in adults. Recently, researchers identified a new African strain circulating in Brazil at the mid-end of 2018 and the beginning of 2019, with the potential to originate a new epidemic. To date, there is no approved vaccine or drug for the treatment of Zika syndrome, and the development of therapeutic alternatives to treat it is of relevance. A critical approach is to use natural products when searching for new chemical agents to treat Zika syndrome. The present investigation describes the preparation of a series of 1,2,3-triazoles derived from the natural product vanillin and the evaluation of their virucide activity. A series of fourteen derivatives were prepared via alkylation of vanillin followed by CuAAC (the copper(I)-catalyzed azide-alkyne cycloaddition) reaction. The compounds were fully characterized by infrared (I.R.), nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HRMS) techniques. The cytotoxicity of Vero cells and the effect on the Zika Virus of the vanillin derivatives were evaluated. It was found that the most effective compound corresponded to 4-((1-(4-isopropylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxybenzaldehyde (8) (EC50 = 27.14 µM, IC50 = 334.9 µM). Subsequent assessments, namely pre and post-treatment assays, internalization and adsorption inhibition assays, kinetic, electronic microscopy analyses, and zeta potential determination, revealed that compound 8 blocks the Zika virus infection in vitro by acting on the viral particle. A molecular docking study was performed, and the results are also discussed.
Subject(s)
Zika Virus Infection , Zika Virus , Animals , Chlorocebus aethiops , Adult , Infant, Newborn , Humans , Zika Virus Infection/prevention & control , Vero Cells , Molecular Docking Simulation , Virus ReplicationABSTRACT
Few extracts of plant species from the Brazilian flora have been validated from a pharmacological and clinical point of view, and it is important to determine whether their traditional use is proven by pharmacological effects. Cenostigma pluviosum var. peltophoroides is one of those plants, which belongs to the Fabaceae family that is widely used in traditional medicine and is very rich in tannins. Due to the lack of effective drugs to treat severe cases of Covid-19, the main protease of SARS-CoV-2 (Mpro) becomes an attractive target in the research for new antivirals since this enzyme is crucial for virus replication and does not have homologs in humans. This study aimed to prospect inhibitor candidates among the compounds from C. pluviosum extract, by virtual screening simulations using SARS-CoV-2 Mpro as target. Experimental validation was made by inhibitory proteolytic assays of recombinant Mpro and by antiviral activity with infected Vero cells. Docking simulations identify four compounds with potential inhibitory activity of Mpro present in the extract. The compound pentagalloylglucose showed the best result in proteolytic kinetics experiments, with suppression of recombinant Mpro activity by approximately 60%. However, in experiments with infected cells ethyl acetate fraction and sub-fractions, F2 and F4 of C. pluviosum extract performed better than pentagalloylglucose, reaching close to 100% of antiviral activity. The prominent activity of the extract fractions in infected cells may be a result of a synergistic effect from the different hydrolyzable tannins present, performing simultaneous action on Mpro and other targets from SARS-CoV-2 and host.Communicated by Ramaswamy H. Sarma.
ABSTRACT
Inclusion complexes (ICs) of 2-hydroxypropyl-ß-cyclodextrin with the essential oil (EO) from Seculo XXI cultivar of Psidium guajava were prepared using kneading (KN) and freeze-drying (FD) methods. The resulting ICs clusters have a nanometric size, with a diameter of approximately 80 and 40 nm for KN and FD, respectively. Complexation efficiency was 80.3% and 50.8% for KN and FD methods, respectively. The larvicidal activity of the EO in DMSO on A. aegypti had LC50 and LC90 values of 51.49 and 64.51 µg mL-1, respectively. For the KN method, the toxicity corresponded to 77.54 and 107.29 µg mL-1 for LC50 and LC90, respectively. FD method demonstrated toxicity at concentrations above 600 µg mL-1. Thus, ICs enable the use of EO in breeding sites for A. aegypti, thus being potential products to be commercially exploited.
Subject(s)
Aedes , Insecticides , Oils, Volatile , Psidium , Animals , Oils, Volatile/pharmacology , 2-Hydroxypropyl-beta-cyclodextrin , Larva , Insecticides/pharmacologyABSTRACT
Leishmaniasis is a parasitic disease found in tropical and subtropical regions around the world, caused by parasites of the genus Leishmania. The disease is a public health concern and presents clinical manifestations that can cause death, disability, and mutilation. The parasite has promastigote (vector) and amastigote (vertebrate host) forms and kinase enzymes are involved in this differentiation process. In the present investigation, we show, for the first time, evidence of a serine/arginine protein kinase in Leshmania braziliensis (LbSRPK). Our results show that amastigotes express more LbSRPK than promastigotes. Analogues of SRPIN340 (a known inhibitor of SRPK) were evaluated for their leishmanicidal activity and two of them, namely SRVIC22 and SRVIC32 showed important leishmanicidal activity in vitro. SRVIC22 and SRVIC32 were able to reduce the infection rate in macrophages and the number of intracellular amastigotes by 55 and 60%, respectively. Bioinformatics analysis revealed the existence of two different amino acid residues in the active site of LbSRPK compared to their human homologue (Tyr/Leu-and Ser/Tyr), which could explain the absence of leishmanicidal activity of SRPIN340 on infected macrophages. In order to enhance leishmanicidal activity of the analogues, optimizations were proposed in the structures of the ligands, suggesting strong interactions with the catalytic site of LbSRPK. Although the evidence on the action of inhibitors upon LbSRPK is only indirect, our studies not only reveal, for the first time, evidence of a SRPK in Leishmania, but also shed light on a new therapeutic target for drug development.
Subject(s)
Arginine Kinase , Leishmania braziliensis , Leishmania , Humans , Animals , Mice , Protein Kinases , Protein Serine-Threonine Kinases , Arginine , Serine , Mice, Inbred BALB CABSTRACT
Biomass valorization is essential, particularly in emerging countries. Here, hydrochar from arabica coffee straw was functionalized with a triazole group (HD-TRz) for use as a support of palladium nanoparticles (PdNPs-HD-TRz) applied in the Ullmann coupling reaction for the first time. It provided remarkably excellent selectivities, conversions at a temperature as low as 45 °C and catalyst recyclability, surpassing previous literature performances. Hydrochar was obtained by one-pot reaction via hydrothermal synthesis, using NaOH solution as activating agent and functionalized with a 1,3-triazole group by CuAAC "click" reaction. The PdNPs were prepared via reduction of hydrochar-bound Pd(II) using NaBH4. Hydrochar functionalization was monitored by infrared spectroscopy, and X-ray diffraction (XRD) allowed to observe carbon and palladium planes in hydrochar and PdNPs HD-TRz structures. The PdNPs presented a spherical shape with 2.1 ± 0.1 nm size, homogeneously distributed in the carbon coverslips. The HD-TRz-supported PdNPs were used as a catalyst in the Ullmann reaction of iodobenzene, using ethanol as solvent with 100% of conversion and 91% selectivity at 45 °C. The material was reused, presenting 100% of conversion and selectivities of 92, 84 and 73% for the 1st, 2nd and 3rd cycle, respectively. The scope of the reaction was expanded to other molecules showing the potential of this and other triazole-hydrochar-supported nanocatalysts.
Subject(s)
Iodobenzenes , Metal Nanoparticles , Carbon , Coffee , Ethanol , Metal Nanoparticles/chemistry , Palladium/chemistry , Sodium Hydroxide , Solvents , TriazolesABSTRACT
The serine/arginine-rich protein kinases (SRPK) specifically phosphorylate their substrates at RS-rich dipeptides, which are abundantly found in SR splicing factors. SRPK are classically known for their ability to affect the splicing and expression of gene isoforms commonly implicated in cancer and diseases associated with infectious processes. Non-splicing functions have also been attributed to SRPK, which highlight their functional plasticity and relevance as therapeutic targets for pharmacological intervention. In this sense, different SRPK inhibitors have been developed, such as the well-known SRPIN340 and its derivatives, with anticancer and antiviral activities. Here we evaluated the potential immunomodulatory activity of SRPIN340 and three trifluoromethyl arylamide derivatives. In in vitro analysis with RAW 264.7 macrophages and primary splenocytes, all the compounds modulated the expression of immune response mediators and antigen-presentation molecules related to a tendency for M2 macrophage polarization. Immunization experiments were carried out in mice to evaluate their potential as vaccine immunostimulants. When administrated alone, the compounds altered the expression of immune factors at the injection site and did not produce macroscopic or microscopic local reactions. In addition, when prepared as an adjuvant with inactivated EHV-1 antigens, all the compounds increased the anti-EHV-1 neutralizing antibody titers, a change that is consistent with an increased Th2 response. These findings demonstrate that SRPIN340 and its derivatives exhibit a noticeable capacity to modulate innate and adaptative immune cells, disclosing their potential to be used as vaccine adjuvants or in immunotherapies.