RESUMEN

INTRODUCTION: Toxicity and resistance to chemotherapy used to treat leishmaniasis are increasing. Research on natural plant compounds has revealed their antileishmanial effects on certain Leishmania organisms. This review aimed to estimate the pooled IC50 values of medicinal plants with promising antileishmanial activity in Ethiopia. METHODS: A systematic literature search was conducted using Science Direct, PubMed, Cochrane Library, and Google Scholar to locate potential studies. Studies published in peer-reviewed journals and gray literature in university repositories before April 1, 2022, which included a full-length study reporting the half-maximal inhibitory concentration (IC50) of Ethiopian medicinal plants that were written in English were included. Conference proceedings, review articles, letters to the editor, and correspondence were excluded. The quality of the included studies was assessed using the GIVIMP critical appraisal tools. Heterogeneity between studies was verified using Cochrane Q test statistics and I2 test statistics, and the effects were checked using Egger statistical test at a level of significance. A random-effects model was used to estimate the pooled IC50 of the medicinal plants. RESULTS: Six articles that were conducted in Ethiopia that fulfilled the inclusion criteria, with a total of 62 in vitro experiments, were reviewed. The aggregated mean IC50 for medicinal plants in Ethiopia was 16.80 (95% CI: 12.44, 21.16) and 13.81 (95% CI: 13.12, 14.50) µg/mL for antipromastigote and antiamastigote activity, respectively. Aqueous was the significant preparation with IC50 of 0.53 (0.34, 0.73) µg/mL against promastigote and 0.98 (0.20, 1.76) µg/mL against the amastigote stage. DISCUSSION: This review indicated that the pooled mean of IC50 for Ethiopian medicinal plants against promastigotes and amastigotes was relatively low and showed better efficacy. This strongly suggests the need to focus on antipromastigote and antiamastigote medicinal plants in Ethiopia for the development of antileishmanial drugs. It is necessary to identify their active components, and their potential toxic effects can lead to the production of well-tolerated and safe drugs for leishmaniasis. The high heterogeneity is the limitation of this study. REGISTRATION: The review has been registered at Prospero with identification number CRD42022343543.

Asunto(s)

Antiprotozoarios , Plantas Medicinales , Etiopía , Plantas Medicinales/química , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Humanos , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Concentración 50 Inhibidora , Leishmaniasis/tratamiento farmacológico , Leishmania/efectos de los fármacos

RESUMEN

A new polyketide, cladoic acid, was isolated from a fungus of the genus Cladosporium. The structure of the highly oxygenated trans-decalin ring with an all-E triene side chain was elucidated by extensive spectroscopic analysis. The unique chair/twist-boat conformation of the trans-decalin core and the flexibility of the B-ring were demonstrated by computer-aided conformational analysis. Cladoic acid was active against Trypanosoma cruzi and inhibited the proliferation of amastigotes and epimastigotes with IC50 values of 27 and 46 µM, respectively, but it did not show any appreciable activity against P388 murine leukemia cells, bacteria, or fungi, indicating it is a potential candidate for drug development against Chagas disease.

Asunto(s)

Cladosporium , Policétidos , Trypanosoma cruzi , Cladosporium/química , Trypanosoma cruzi/efectos de los fármacos , Animales , Policétidos/farmacología , Policétidos/química , Policétidos/aislamiento & purificación , Estructura Molecular , Ratones , Concentración 50 Inhibidora , Leucemia P388 , Enfermedad de Chagas/tratamiento farmacológico

RESUMEN

Novel antimalarials are urgently needed to combat rising resistance to available drugs. The imidazolopiperazine ganaplacide is a promising drug candidate, but decreased susceptibility of laboratory strains has been linked to polymorphisms in the Plasmodium falciparum cyclic amine resistance locus (PfCARL), acetyl-CoA transporter (PfACT), and UDP-galactose transporter (PfUGT). To characterize parasites causing disease in Africa, we assessed ex vivo drug susceptibilities to ganaplacide in 750 P. falciparum isolates collected in Uganda from 2017 to 2023. Drug susceptibilities were assessed using a 72-hour SYBR Green growth inhibition assay. The median IC50 for ganaplacide was 13.8 nM, but some isolates had up to 31-fold higher IC50s (31/750 with IC50 > 100 nM). To assess genotype-phenotype associations, we sequenced genes potentially mediating altered ganaplacide susceptibility in the isolates using molecular inversion probe and dideoxy sequencing methods. PfCARL was highly polymorphic, with eight mutations present in >5% of isolates. None of these eight mutations had previously been selected in laboratory strains with in vitro drug pressure and none were found to be significantly associated with decreased ganaplacide susceptibility. Mutations in PfACT and PfUGT were found in ≤5% of isolates, except for two frequent (>20%) mutations in PfACT; one mutation in PfACT (I140V) was associated with a modest decrease in susceptibility. Overall, Ugandan P. falciparum isolates were mostly highly susceptible to ganaplacide. Known resistance mediators were polymorphic, but mutations previously selected with in vitro drug pressure were not seen, and mutations identified in the Ugandan isolates were generally not associated with decreased ganaplacide susceptibility.

Asunto(s)

Antimaláricos , Resistencia a Medicamentos , Plasmodium falciparum , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/genética , Antimaláricos/farmacología , Uganda , Humanos , Resistencia a Medicamentos/genética , Malaria Falciparum/parasitología , Malaria Falciparum/tratamiento farmacológico , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Concentración 50 Inhibidora , Piperazinas/farmacología , Pruebas de Sensibilidad Parasitaria

RESUMEN

The treatment strategies for either human or animal babesiosis have been established and used for many years. With the rising indications of drug resistance and adverse side effects, finding effective and alternative therapies is urgently needed. Sitamaquine (SQ) is an 8-aminoquinoline that was first synthesized as a part of the collaborative anti-malarial program that led to primaquine. In this study, we evaluated the inhibitory effects of SQ on Babesia spp. in vitro and in vivo. The half-maximal inhibitory concentration (IC50) on in vitro cultured Babesia gibsoni was 8.04 ± 1.34 µM. Babesia gibsoni parasites showed degenerative morphological changes following SQ treatment. The in vivo growth inhibitory effects of SQ were evaluated in BALB/c mice infected with B. microti and atovaquone (ATV)-resistant B. microti strain. Oral administration of SQ at a dose of 20 mg/kg significantly inhibited the growth of B. microti and ATV-resistant B. microti. Meanwhile, SQ also showed inhibitory effects on the growth of B. rodhaini, a lethal rodent Babesia species. All mice infected with B. rodhaini treated with SQ survived, whereas the mice in the control group succumbed to the disease. The results obtained in this study indicate that SQ has potent inhibition effects against Babesia spp., which support SQ as a prospective alternative candidate for babesiosis treatment.

Asunto(s)

Aminoquinolinas , Babesia , Babesiosis , Ratones Endogámicos BALB C , Animales , Babesiosis/tratamiento farmacológico , Babesiosis/parasitología , Ratones , Babesia/efectos de los fármacos , Aminoquinolinas/farmacología , Aminoquinolinas/uso terapéutico , Aminoquinolinas/administración & dosificación , Antiprotozoarios/farmacología , Antiprotozoarios/administración & dosificación , Femenino , Concentración 50 Inhibidora , Atovacuona/farmacología , Atovacuona/uso terapéutico

RESUMEN

Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC50) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.

Asunto(s)

Adamantano , Antimaláricos , Antituberculosos , Plasmodium falciparum , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/farmacología , Antimaláricos/química , Humanos , Relación Estructura-Actividad , Antituberculosos/farmacología , Antituberculosos/química , Adamantano/farmacología , Adamantano/química , Adamantano/análogos & derivados , Animales , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Concentración 50 Inhibidora , Etilenodiaminas

RESUMEN

Many apicomplexan pathogens pose significant threats to humans and domestic animals, with the lack of effective drugs and drug resistance representing major challenges in disease management. To address this, the search for new and potent antimalarial drugs is crucial. Plant-based formulations offer a promising alternative for such drug development. Here, we evaluated the in vitro antiplasmodial activity of nine plant extracts, traditionally used to treat fever-like symptoms in Bangladesh. We assessed the antimalarial activity of plant extracts by using the Plasmodium falciparum 3D7 growth inhibition assay, an invasion assay, and a cytotoxicity assay. Of the nine plants studied, ethanolic and methanolic leaf extracts of Ficus hispida, Streblus asper, and Boerhavia repens exhibited high antiplasmodial activity, with IC50 values of 9.31, 4.13, 9.63 µg/ml (ethanolic) and 15.12, 6.63, 7.58 µg/ml (methanolic), respectively, and minimal toxicity (cell viability >80%). Clerodendrum viscosum displayed antiplasmodial effects with IC50 values of 28.90 µg/ml (ethanolic) and 30.57 µg/ml (methanolic). Adhatoda vasica, Mussaenda corymbosa, and Amaranthus spinosus ethanolic extracts showed antimalarial effects with IC50 values of 61.78 µg/ml, 66.31 µg/ml, and 64.14 µg/ml, respectively. However, methanolic extracts of A. vasica and A. spinosus had IC50 values >100 µg/ml. The ethanolic and methanolic extracts of A. vasica, A. spinosus, F. hispida, S. asper, and B. repens significantly reduced parasitemia by inhibiting invasion into erythrocytes. This study highlights the robust antimalarial activity and low cytotoxicity of leaf extracts of F. hispida, S. asper, and B. repens, indicating the presence of antimalarial compounds that warrant further investigation.

Asunto(s)

Antimaláricos , Extractos Vegetales , Plantas Medicinales , Plasmodium falciparum , Plasmodium falciparum/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Plantas Medicinales/química , Antimaláricos/farmacología , Antimaláricos/química , Concentración 50 Inhibidora , Humanos , Hojas de la Planta/química , Animales , Bangladesh

RESUMEN

Fasciolosis is a food and waterborne disease caused by Fasciola spp., representing a global health burden to various hosts, including humans and other animals. This study investigates the in vitro activity of tellurium- and selenium-containing diaryl dichalcogenides: diacetal ditelluride (LQ07), diacetal diselenide (LQ62), and diacetyl diselenide (LQ68) alone and in combination with ivermectin (IVM) against eggs of Fasciola hepatica. The eggs were exposed for 12 h with each organochalcogen (OC) (0.1 - 2 mmol l-1) and IVM (0.01 - 2 mmol l-1) following an incubation of 15 days, allowing embryonation. The inhibitory concentration of 50 % (IC50) of each OC or IVM was tested with the IC10, IC30, and IC50 of IVM or each OC, respectively. LQ07, LQ62, and LQ68, as well as IVM, demonstrated a concentration-dependent ovicidal activity. The peak ovicidal activity of 99.74 % was achieved when IVM was tested at 2.0 mmol l-1. LQ62 and LQ68 demonstrated greater ovicidal activity, having an IC50 < 0.32 mmol l-1 being 6.25-fold more toxic than IVM alone. The percentage of dead eggs was significantly higher in the IVM group (early mortality), as Se-containing OCs led to the (miracidia) embryonation of the eggs with no hatching (late mortality). Blending Se-containing OCs and IVM showed an additive effect of up to 27 % against F. hepatica eggs. The present data contribute to the potential use of blending-based therapeutic strategies to combat F. hepatica infections in eradication programs worldwide. The combinations may also act against multidrug-resistant strains, reinstating drug-based parasite control.

Asunto(s)

Fasciola hepatica , Ivermectina , Animales , Fasciola hepatica/efectos de los fármacos , Ivermectina/farmacología , Antihelmínticos/farmacología , Concentración 50 Inhibidora , Óvulo/efectos de los fármacos , Calcógenos/farmacología , Calcógenos/química , Fascioliasis/tratamiento farmacológico , Fascioliasis/parasitología , Fascioliasis/veterinaria

RESUMEN

A new superior bacteria complementation model was achieved for testing antifolate compounds and investigating antifolate resistance in the dihydrofolate reductase (DHFR) enzyme of the malaria parasite. Earlier models depended on the addition of trimethoprim (TMP) to chemically suppress the host Escherichia coli (Ec) DHFR function. However, incomplete suppression of EcDHFR and potential interference of antibiotics needed to maintain plasmids for complementary gene expression can complicate the interpretations. To overcome such limitations, the folA (F) and thyA (T) genes were genetically knocked out (Δ) in E. coli BL21(DE3). The resulting EcΔFΔT cells were thymidine auxotroph where thymidine supplementation or functional complementation with heterologous DHFR-thymidylate synthase (TS) is needed to restore the loss of gene functions. When tested against pyrimethamine (PYR) and its analogs designed to target Plasmodium falciparum (Pf) DHFR-TS, the 50 % inhibitory concentration values obtained from EcΔFΔT surrogates expressing wildtype (PfTM4) or double mutant (PfK1) DHFR-TS showed strong correlations to the results obtained from the standard in vitro P. falciparum growth inhibition assay. Interestingly, while TMP had little effect on the susceptibility to PYR and analogs in EcΔFΔT expressing PfDHFR-TS, it hypersensitized the chemically knockdown E. coli BL21(DE3) expressing PfTM4 DHFR-TS but desensitized the one carrying PfK1 DHFR-TS. The low intrinsic expression level of PfTM4 in E. coli BL21(DE3) by western blot analysis may explain the hypersensitive to antifolates of chemical knockdown bacteria surrogate. These results demonstrated the usefulness of EcΔFΔT surrogate as a new tool for antifolate antimalarial screening with potential application for investigation of antifolate resistance mechanism.

Asunto(s)

Escherichia coli , Antagonistas del Ácido Fólico , Técnicas de Inactivación de Genes , Plasmodium falciparum , Pirimetamina , Tetrahidrofolato Deshidrogenasa , Timidilato Sintasa , Escherichia coli/genética , Escherichia coli/efectos de los fármacos , Antagonistas del Ácido Fólico/farmacología , Tetrahidrofolato Deshidrogenasa/genética , Tetrahidrofolato Deshidrogenasa/metabolismo , Timidilato Sintasa/genética , Timidilato Sintasa/metabolismo , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/genética , Pirimetamina/farmacología , Antimaláricos/farmacología , Concentración 50 Inhibidora , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Resistencia a Medicamentos/genética , Prueba de Complementación Genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Complejos Multienzimáticos

RESUMEN

Moringa oleifera (M. oleifera) is a plant widely used for its beneficial properties both in medical and non-medical fields. Because they produce bioactive metabolites, plants are a major resource for drug discovery. In this study, two different cultivars of leaves of M. oleifera (Salento and Barletta) were obtained by maceration or microwave-assisted extraction (MAE). We demonstrated that extracts obtained by MAE exhibited a lower cytotoxic profile compared to those obtained by maceration at concentrations ranged from 25 to 400 µg/mL, on both Vero CCL-81 and Vero/SLAM cells. We examined their antiviral properties against two viruses, i.e., the human coronavirus 229E (HCoV-229E) and measles virus (MeV), which are both responsible for respiratory infections. The extracts were able to inhibit the infection of both viruses and strongly prevented their attack and entry into the cells in a range of concentrations from 50 to 12 µg/mL. Particularly active was the variety of Salento that registered a 50% inhibitory concentration (IC50) at 21 µg/mL for HCoV-229E and at 6 µg/mL for MeV. We identified the presence of several compounds through high performance liquid chromatography (HPLC); in particular, chlorogenic and neochlorogenic acids, quercetin 3-O-ß-d-glucopyranoside (QGP), and glucomoringin (GM) were mainly observed. In the end, M. oleifera can be considered a promising candidate for combating viral infections with a very strong action in the early stages of viral life cycle, probably by destructuring the viral particles blocking the virus-cell fusion.

Asunto(s)

Antivirales , Moringa oleifera , Extractos Vegetales , Hojas de la Planta , Moringa oleifera/química , Antivirales/farmacología , Antivirales/química , Antivirales/aislamiento & purificación , Extractos Vegetales/farmacología , Extractos Vegetales/química , Hojas de la Planta/química , Chlorocebus aethiops , Células Vero , Animales , Virus del Sarampión/efectos de los fármacos , Coronavirus Humano 229E/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Supervivencia Celular/efectos de los fármacos

RESUMEN

Temsavir binds directly to the HIV-1 envelope glycoprotein gp120 and selectively inhibits interactions between HIV-1 and CD4 receptors. Previous studies identified gp120 amino acid positions where substitutions are associated with reduced susceptibility to temsavir. The mechanism by which temsavir susceptibility is altered in these envelope glycoproteins was evaluated. Pseudoviruses encoding gp120 substitutions alone (S375H/I/M/N, M426L, M434I, M475I) or in combination (S375H + M475I) were engineered on a wild-type JRFL background. Temsavir-gp120 and CD4-gp120 binding kinetics and ability of temsavir to block CD4-gp120 binding were evaluated using the purified polymorphic gp120 proteins and a Creoptix® WAVE Delta grating-coupled interferometry system. Fold-change in half-maximal inhibitory concentration (IC50) in JRFL-based pseudoviruses containing the aforementioned polymorphisms relative to that of wild-type ranged from 4-fold to 29,726-fold, while temsavir binding affinity for the polymorphic gp120 proteins varied from 0.7-fold to 73.7-fold relative to wild-type gp120. Strong correlations between temsavir IC50 and temsavir binding affinity (r = 0.7332; P = 0.0246) as well as temsavir binding on-rate (r = -0.8940; P = 0.0011) were observed. Binding affinity of gp120 proteins for CD4 varied between 0.4-fold and 3.1-fold compared with wild-type gp120; no correlations between temsavir IC50 and CD4 binding kinetic parameters were observed. For all polymorphic gp120 proteins, temsavir was able to fully block CD4 binding; 3 polymorphs required higher temsavir concentrations. Loss of susceptibility to temsavir observed for gp120 polymorphisms strongly correlated with reductions in temsavir binding on-rate. Nonetheless, temsavir retained the ability to fully block CD4-gp120 engagement given sufficiently high concentrations.

Asunto(s)

Fármacos Anti-VIH , Antígenos CD4 , Proteína gp120 de Envoltorio del VIH , VIH-1 , Unión Proteica , Proteína gp120 de Envoltorio del VIH/metabolismo , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/química , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Fármacos Anti-VIH/farmacología , Antígenos CD4/metabolismo , Antígenos CD4/genética , Sustitución de Aminoácidos , Polimorfismo Genético , Farmacorresistencia Viral , Concentración 50 Inhibidora , Cinética

RESUMEN

Avian influenza outbreaks, including ones caused by highly pathogenic A(H5N1) clade 2.3.4.4b viruses, have devastated animal populations and remain a threat to humans. Risk elements assessed for emerging influenza viruses include their susceptibility to approved antivirals. Here, we screened >20,000 neuraminidase (NA) or polymerase acidic (PA) protein sequences of potentially pandemic A(H5Nx), A(H7Nx), and A(H9N2) viruses that circulated globally in 2010-2023. The frequencies of NA or PA substitutions associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NA inhibitors (NAIs) (oseltamivir, zanamivir) or a cap-dependent endonuclease inhibitor (baloxavir) were low: 0.60% (137/22,713) and 0.62% (126/20,347), respectively. All tested subtypes were susceptible to NAIs and baloxavir at sub-nanomolar concentrations. A(H9N2) viruses were the most susceptible to oseltamivir, with IC50s 3- to 4-fold lower than for other subtypes (median IC50: 0.18 nM; n = 22). NA-I222M conferred RI of A(H5N1) viruses by oseltamivir (with a 26-fold IC50 increase), but NA-S246N did not reduce inhibition. PA-E23G, PA-K34R, PA-I38M/T, and the previously unreported PA-A36T caused RI by baloxavir in all subtypes tested. Avian A(H9N2) viruses endemic in Egyptian poultry predominantly acquired PA-I38V, which causes only a <3-fold decrease in the baloxavir EC50 and fails to meet the RI criteria. PA-E199A/D in A(H7Nx) and A(H9N2) viruses caused a 2- to 4-fold decrease in EC50 (close to the borderline for RI) and should be closely monitored. Our data indicate antiviral susceptibility is high among avian influenza A viruses with pandemic potential and present novel markers of resistance to existing antiviral interventions.

Asunto(s)

Antivirales , Aves , Dibenzotiepinas , Farmacorresistencia Viral , Inhibidores Enzimáticos , Genotipo , Virus de la Influenza A , Gripe Aviar , Neuraminidasa , Oseltamivir , Piridonas , Triazinas , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/genética , Antivirales/farmacología , Gripe Aviar/virología , Animales , Inhibidores Enzimáticos/farmacología , Dibenzotiepinas/farmacología , Farmacorresistencia Viral/genética , Piridonas/farmacología , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/genética , Virus de la Influenza A/enzimología , Triazinas/farmacología , Oseltamivir/farmacología , Aves/virología , Morfolinas/farmacología , Endonucleasas/antagonistas & inhibidores , Endonucleasas/genética , Endonucleasas/metabolismo , Subtipo H9N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H9N2 del Virus de la Influenza A/genética , Proteínas Virales/genética , Proteínas Virales/antagonistas & inhibidores , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/genética , Subtipo H5N1 del Virus de la Influenza A/enzimología , Zanamivir/farmacología , Fenotipo , Humanos , Concentración 50 Inhibidora

RESUMEN

Senolytics are drugs that specifically target senescent cells. Flavonoids such as quercetin and fisetin possess selective senolytic activities. This study aims to investigate if chalcones exhibit anti-senescence activities. Anti-senescence effect of 11 chalcone derivatives on the replicative senescence human aortic endothelial cells (HAEC) and human fetal lung fibroblasts (IMR90) was evaluated. Compound 2 (4-methoxychalcone) and compound 4 (4-bromo-4'-methoxychalcone) demonstrated increased cytotoxicity in senescent HAEC compared to young HAEC, with significant differences on IC50 values. Their anti-senescence effects on HAEC exceeded fisetin. Higher selectivity of compound 4 toward HAEC over IMR90 could be attributed to 4-methoxy (4-OMe) substitution at ring A (R1). Chalcone derivatives have potentials as senolytics in mitigating replicative senescence, warranting further research and development on chalcones as anti-senescent agent.

Asunto(s)

Senescencia Celular , Chalconas , Células Endoteliales , Fibroblastos , Humanos , Senescencia Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Chalconas/farmacología , Fibroblastos/efectos de los fármacos , Células Cultivadas , Senoterapéuticos/farmacología , Concentración 50 Inhibidora , Aorta/efectos de los fármacos , Aorta/citología , Relación Estructura-Actividad , Línea Celular

RESUMEN

Phytocompounds possess the potential to treat a broad spectrum of disorders due to their remarkable bioactivity. Naturally occurring compounds possess lower toxicity profiles, which making them attractive targets for drug development. Hydnocarpus wightianus seeds were extracted using ethanol, acetone, and hexane solvents. The extracts were evaluated for phytochemicals screening and other therapeutic characteristics, such as free radicals scavenging, anti α-amylase, anti α-glucosidase, and anti-bacterial activities. The ethanolic extract exhibited noteworthy antibacterial characteristics and demonstrated considerable antioxidant, and anti-diabetic effects. The IC50 value of the ethanolic extract for Dpph, α-amylase, and α-glucosidase were found to be 77.299 ± 3.381 µg/mL, 165.56 2.56 µg/mL, and 136.58 ± 5.82 µg/mL, respectively. The ethanolic extract was effective against Methicillin resistant Staphylococcus aureus (26 mm zone of inhibition at 100 µL concentration). Molecular docking investigations revealed the phytoconstituent's inhibitory mechanisms against diabetic, free radicals, and bacterial activity. Docking score for phytocompounds against targeted protein varies from -7.2 to -5.1 kcal/mol. The bioactive compounds present in the ethanolic extract were identified by Gas chromatography/Mass spectrometry analysis, followed by molecular docking and molecular dynamic simulation studies to further explore the phytoconstituent's inhibitory mechanism of α-glucosidase, ∝-amylase, radical scavenging, and bacterial activity. The electronic structure and possible pharmacological actions of the phytocompound were revealed through the use of Density Functional Theory (DFT) analysis. Computational and in vitro studies revealed that these identified compounds have anti-diabetic, anti-oxidant, and anti-bacterial activities against antibiotic-resistant strain of Staphylococcus aureus.

Asunto(s)

Antibacterianos , Antioxidantes , Simulación del Acoplamiento Molecular , Fitoquímicos , Extractos Vegetales , Semillas , alfa-Amilasas , Extractos Vegetales/farmacología , Extractos Vegetales/química , Semillas/química , Antibacterianos/farmacología , Antibacterianos/química , Antioxidantes/farmacología , Antioxidantes/química , alfa-Amilasas/antagonistas & inhibidores , Fitoquímicos/farmacología , Fitoquímicos/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , alfa-Glucosidasas/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Simulación por Computador , Concentración 50 Inhibidora

RESUMEN

Leishmaniasis is a disease of public health relevance that demands new therapeutic alternatives due to the toxicity of conventional treatments. In this study, 27 plants of interest to the Unified Health System (SUS) were evaluated for cytotoxicity in macrophages, leishmanicidal activity and production of nitric oxide (NO). None of the species demonstrated cytotoxicity to macrophages (CC50 >100 µg/mL). Extracts from Chenopodium ambrosioides, Equisetum arvense, Maytenus ilicifolia showed greater efficacy in inducing the death of Leishmania amazonensis amastigotes with IC50 of 68.4, 82.3, 75.7 µg/mL, respectively. The species Cynara scolymus, Punica granatum and Passiflora alata were the most effective in inducing an increase in the indirect concentration of NO (41.31, 29.30 and 28.86 µM, respectively) in cultures of macrophages infected with L. amazonensis. Furthermore, Punica granatum was also the most effective species in inducing an increase in NO in macrophages infected by Leishmania chagasi (19.90 µM). The results obtained so far support the continuation of studies, with the possibility of developing safer and more effective treatments for leishmaniasis, using natural products. The identification of plants that stimulate the production of NO in macrophages infected by Leishmania opens doors for more detailed investigations of the mechanism of action of these natural products.

Asunto(s)

Macrófagos , Extractos Vegetales , Plantas Medicinales , Extractos Vegetales/farmacología , Plantas Medicinales/química , Plantas Medicinales/clasificación , Animales , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Óxido Nítrico/metabolismo , Ratones , Leishmania mexicana/efectos de los fármacos , Leishmania/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Antiprotozoarios/farmacología , Concentración 50 Inhibidora

RESUMEN

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.

Asunto(s)

Enfermedad de Chagas , Triazoles , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Animales , Triazoles/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Tripanocidas/farmacología , Ratones , Concentración 50 Inhibidora , Pruebas de Sensibilidad Parasitaria , Tiazoles

RESUMEN

Previous data suggest a lack of cross-resistance between the gp120-directed attachment inhibitor temsavir (active moiety of fostemsavir) and the CD4-directed post-attachment inhibitor ibalizumab. Recently, analysis of HIV-1 envelopes with reduced sensitivity to both inhibitors was undertaken to determine whether they shared genotypic correlates of resistance. Sequences from 2 envelopes with reduced susceptibility to both agents were mapped onto a temsavir-bound gp120 structure. Residues within 5.0 Å of the temsavir binding site were evaluated using reverse genetics. Broader applicability and contextual determinants of key substitutions were further assessed using envelopes from participants in the phase 3 BRIGHTE study. Temsavir sensitivity was measured by half-maximal inhibitory concentration (IC50) and ibalizumab sensitivity by IC50 and maximum percent inhibition (MPI). One envelope required substitutions of E113D and T434M for full restoration of temsavir susceptibility. Neither substitution nor their combination affected ibalizumab sensitivity. However, in the second envelope, an E202 substitution (HXB2, T202) was sufficient for observed loss of susceptibility to both inhibitors. One BRIGHTE participant with no ibalizumab exposure had an emergent K202E substitution at protocol-defined virologic failure, with reduced sensitivity to both inhibitors. Introducing T202E into previously susceptible clinical isolates reduced temsavir potency by ≥ 40-fold and ibalizumab MPI from >99% to ∼80%. Interestingly, introduction of the gp120 V5 region from a highly ibalizumab-susceptible envelope mitigated the E202 effect on ibalizumab but not temsavir. A rare HIV-1 gp120 E202 mutation reduced temsavir susceptibility, and depending on sequence context, could result in reduced susceptibility to ibalizumab.

Asunto(s)

Fármacos Anti-VIH , Farmacorresistencia Viral , Proteína gp120 de Envoltorio del VIH , Infecciones por VIH , VIH-1 , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/metabolismo , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Fármacos Anti-VIH/farmacología , Organofosfatos/farmacología , Sitios de Unión , Concentración 50 Inhibidora , Anticuerpos Monoclonales , Piperazinas

RESUMEN

Leishmania major is responsible for zoonotic cutaneous leishmaniasis. Therapy is mainly based on the use of antimony-based drugs; however, treatment failures and illness relapses were reported. Although studies were developed to understand mechanisms of drug resistance, the interactions of resistant parasites with their reservoir hosts and vectors remain poorly understood. Here we compared the development of two L. major MON-25 trivalent antimony-resistant lines, selected by a stepwise in vitro Sb(III)-drug pressure, to their wild-type parent line in the natural vector Phlebotomus papatasi. The intensity of infection, parasite location and morphological forms were compared by microscopy. Parasite growth curves and IC50 values have been determined before and after the passage in Ph. papatasi. qPCR was used to assess the amplification rates of some antimony-resistance gene markers. In the digestive tract of sand flies, Sb(III)-resistant lines developed similar infection rates as the wild-type lines during the early-stage infections, but significant differences were observed during the late-stage of the infections. Thus, on day 7 p. i., resistant lines showed lower representation of heavy infections with colonization of the stomodeal valve and lower percentage of metacyclic promastigote forms in comparison to wild-type strains. Observed differences between both resistant lines suggest that the level of Sb(III)-resistance negatively correlates with the quality of the development in the vector. Nevertheless, both resistant lines developed mature infections with the presence of infective metacyclic forms in almost half of infected sandflies. The passage of parasites through the sand fly guts does not significantly influence their capacity to multiply in vitro. The IC50 values and molecular analysis of antimony-resistance genes showed that the resistant phenotype of Sb(III)-resistant parasites is maintained after passage through the sand fly. Sb(III)-resistant lines of L. major MON-25 were able to produce mature infections in Ph. papatasi suggesting a possible circulation in the field using this vector.

Asunto(s)

Antimonio , Resistencia a Medicamentos , Leishmania major , Leishmaniasis Cutánea , Phlebotomus , Phlebotomus/parasitología , Phlebotomus/efectos de los fármacos , Leishmania major/efectos de los fármacos , Leishmania major/genética , Animales , Antimonio/farmacología , Resistencia a Medicamentos/genética , Leishmaniasis Cutánea/parasitología , Leishmaniasis Cutánea/transmisión , Insectos Vectores/parasitología , Insectos Vectores/efectos de los fármacos , Fenotipo , Antiprotozoarios/farmacología , Concentración 50 Inhibidora , Femenino

RESUMEN

Toxoplasma gondii and Neospora caninum are major worldwide morbidity-causing pathogens. Bumped kinase inhibitors (BKIs) are a compound class that has been optimized to target the apicomplexan calcium-dependent protein kinase 1 (CDPK1) - and several members of this class have proven to be safe and highly active in vitro and in vivo. BKI-1708 is based on a 5-aminopyrazole-4-carboxamide scaffold, and exhibited in vitro IC50 values of 120 nM for T. gondii and 480 nM for N. caninum ß-galactosidase expressing strains, and did not affect human foreskin fibroblast (HFF) viability at concentrations up to 25 µM. Electron microscopy established that exposure of tachyzoite-infected fibroblasts to 2.5 µM BKI-1708 in vitro induced the formation of multinucleated schizont-like complexes (MNCs), characterized by continued nuclear division and harboring newly formed intracellular zoites that lack the outer plasma membrane. These zoites were unable to finalize cytokinesis to form infective tachyzoites. BKI-1708 did not affect zebrafish (Danio rerio) embryo development during the first 96 h following egg hatching at concentrations up to 2 µM. Treatments of mice with BKI-1708 at 20 mg/kg/day during five consecutive days resulted in drug plasma levels ranging from 0.14 to 4.95 µM. In vivo efficacy of BKI-1708 was evaluated by oral application of 20 mg/kg/day from day 9-13 of pregnancy in mice experimentally infected with N. caninum (NcSpain-7) tachyzoites or T. gondii (TgShSp1) oocysts. This resulted in significantly decreased cerebral parasite loads and reduced vertical transmission in both models without drug-induced pregnancy interference.

Asunto(s)

Coccidiosis , Fibroblastos , Neospora , Pirazoles , Toxoplasma , Animales , Neospora/efectos de los fármacos , Toxoplasma/efectos de los fármacos , Ratones , Coccidiosis/tratamiento farmacológico , Coccidiosis/parasitología , Pirazoles/farmacología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/parasitología , Humanos , Antiprotozoarios/farmacología , Concentración 50 Inhibidora , Toxoplasmosis/tratamiento farmacológico , Toxoplasmosis/parasitología , Modelos Animales de Enfermedad , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas

RESUMEN

Herein we report the design and the synthesis of a library of new and more hydrophilic bisindole analogues based on our previously identified antileishmanial compound URB1483 that failed the preliminary in vivo test. The novel bisindoles were phenotypically screened for efficacy against Leishmania infantum promastigotes and simultaneously for toxicity on human macrophage-like THP-1 cells. Among the less toxic compounds, eight bisindoles showed IC50 below 10 µM. The most selective compound 1h (selectivity index = 10.1, comparable to miltefosine) and the most potent compound 2c (IC50 = 2.7 µM) were tested for their efficacy on L. infantum intracellular amastigotes. The compounds also demonstrated their efficacy in the in vitro infection model, showing IC50 of 11.1 and 6.8 µM for 1h and 2c, respectively. Moreover, 1h showed a better toxicity profile than the commercial drug miltefosine. For all these reasons, 1h could be a possible new starting point for hydrophilic antileishmanial agents with low cytotoxicity on human macrophage-like cells.

Asunto(s)

Antiprotozoarios , Leishmania infantum , Leishmania infantum/efectos de los fármacos , Humanos , Antiprotozoarios/farmacología , Antiprotozoarios/química , Células THP-1 , Indoles/farmacología , Indoles/química , Interacciones Hidrofóbicas e Hidrofílicas , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacología , Fosforilcolina/química , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Concentración 50 Inhibidora

RESUMEN

Two new meroterpenoids, aspergienynes O and P (1 and 2), one new natural compound, aspergienyne Q (3), and a new α-pyrone derivative named 3-(4-methoxy-2-oxo-2H-pyran-6-yl)butanoic acid (4) were isolated from the mangrove endophytic fungal strain Aspergillus sp. GXNU-Y85, along with five known compounds (5-9). The absolute configurations of those new isolates were confirmed through extensive analysis using spectroscopic data (HRESIMS, NMR, and ECD). The pharmacological study of the anti-proliferation activity indicated that isolates 5 and 9 displayed moderate inhibitory effects against HeLa and A549 cells, with the IC50 values ranging from 16.6 to 45.4 µM.

Asunto(s)

Aspergillus , Pironas , Terpenos , Aspergillus/química , Humanos , Pironas/farmacología , Pironas/química , Pironas/aislamiento & purificación , Terpenos/farmacología , Terpenos/química , Terpenos/aislamiento & purificación , Células A549 , Células HeLa , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Estructura Molecular , Endófitos/química , Concentración 50 Inhibidora , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Espectroscopía de Resonancia Magnética