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Fitoterapia Mar 2021Five known compounds (1-5) were isolated from the extract of Mundulea sericea leaves. Similar investigation of the roots of this plant afforded an additional three known...
Five known compounds (1-5) were isolated from the extract of Mundulea sericea leaves. Similar investigation of the roots of this plant afforded an additional three known compounds (6-8). The structures were elucidated using NMR spectroscopic and mass spectrometric analyses. The absolute configuration of 1 was established using ECD spectroscopy. In an antiplasmodial activity assay, compound 1 showed good activity with an IC of 2.0 μM against chloroquine-resistant W2, and 6.6 μM against the chloroquine-sensitive 3D7 strains of Plasmodium falciparum. Some of the compounds were also tested for antileishmanial activity. Dehydrolupinifolinol (2) and sericetin (5) were active against drug-sensitive Leishmania donovani (MHOM/IN/83/AG83) with IC values of 9.0 and 5.0 μM, respectively. In a cytotoxicity assay, lupinifolin (3) showed significant activity on BEAS-2B (IC 4.9 μM) and HePG2 (IC 10.8 μM) human cell lines. All the other compounds showed low cytotoxicity (IC > 30 μM) against human lung adenocarcinoma cells (A549), human liver cancer cells (HepG2), lung/bronchus cells (epithelial virus transformed) (BEAS-2B) and immortal human hepatocytes (LO2).
Topics: Antimalarials; Antineoplastic Agents, Phytogenic; Antiprotozoal Agents; Cell Line, Tumor; Fabaceae; Flavonoids; Humans; Kenya; Molecular Structure; Nitric Oxide; Phytochemicals; Plant Leaves; Plant Roots; Plasmodium falciparum
PubMed: 33271256
DOI: 10.1016/j.fitote.2020.104796 -
PloS One 2022Investigating the chemical diversity of natural products from tropical environments is an inspiring approach to developing new drug candidates for neglected tropical...
Investigating the chemical diversity of natural products from tropical environments is an inspiring approach to developing new drug candidates for neglected tropical diseases (NTDs). In the present study, phenotypic screenings for antiprotozoal activity and a combination of computational and biological approaches enabled the identification and characterization of four cytochalasins, which are fungal metabolites from Brazilian biodiversity sources. Cytochalasins A-D exhibited IC50 values ranging from 2 to 20 μM against intracellular Trypanosoma cruzi and Leishmania infantum amastigotes, values comparable to those of the standard drugs benznidazole and miltefosine for Chagas disease and leishmaniasis, respectively. Furthermore, cytochalasins A-D reduced L. infantum infections by more than 80% in THP-1 cells, most likely due to the inhibition of phagocytosis by interactions with actin. Molecular modelling studies have provided useful insights into the mechanism of action of this class of compounds. Furthermore, cytochalasins A-D showed moderate cytotoxicity against normal cell lines (HFF-1, THP-1, and HepG2) and a good overall profile for oral bioavailability assessed in vitro. The results of this study support the use of natural products from Brazilian biodiversity sources to find potential drug candidates for two of the most important NTDs.
Topics: Actins; Antiprotozoal Agents; Biological Products; Cytochalasins; Drug Discovery; Humans; Neglected Diseases; Trypanosoma cruzi
PubMed: 36190979
DOI: 10.1371/journal.pone.0275002 -
Biomolecules Nov 2020Plants have been used as drugs to treat human disease for centuries. Ursonic acid (UNA) is a naturally occurring pentacyclic triterpenoid extracted from certain... (Comparative Study)
Comparative Study Review
Plants have been used as drugs to treat human disease for centuries. Ursonic acid (UNA) is a naturally occurring pentacyclic triterpenoid extracted from certain medicinal herbs such as . Since the pharmacological effects and associated mechanisms of UNA are not well-known, in this work, we attempt to introduce the therapeutic potential of UNA with a comparison to ursolic acid (ULA), a well-known secondary metabolite, for beneficial effects. UNA has a keto group at the C-3 position, which may provide a critical difference for the varied biological activities between UNA and ULA. Several studies previously showed that UNA exerts pharmaceutical effects similar to, or stronger than, ULA, with UNA significantly decreasing the survival and proliferation of various types of cancer cells. UNA has potential to exert inhibitory effects in parasitic protozoa that cause several tropical diseases. UNA also exerts other potential effects, including antihyperglycemic, anti-inflammatory, antiviral, and antioxidant activities. Of note, a recent study highlighted the suppressive potential of UNA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molecular modifications of UNA may enhance bioavailability, which is crucial for in vivo and clinical studies. In conclusion, UNA has promising potential to be developed in anticancer and antiprotozoan pharmaceuticals. In-depth investigations may increase the possibility of UNA being developed as a novel reagent for chemotherapy.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Antioxidants; Antiprotozoal Agents; Antiviral Agents; Betacoronavirus; Humans; Hypoglycemic Agents; Plants; SARS-CoV-2; Triterpenes; Ursolic Acid
PubMed: 33147723
DOI: 10.3390/biom10111505 -
Brazilian Journal of Medical and... 2023Leishmaniasis is a neglected disease that affects millions of people worldwide, and special attention should be given to treatment because the available drugs have...
Leishmaniasis is a neglected disease that affects millions of people worldwide, and special attention should be given to treatment because the available drugs have limitations, which can lead to low therapeutic adherence and parasitic resistance. This study evaluated the activity of the bioactive naphthoquinones, lapachol and β-lapachone, against Leishmania amazonensis. The cell alterations were evaluated in vitro on promastigote and amastigote forms. The lethal dose (LD50) at 24, 48, and 72 h on the promastigote's forms using lapachol was 75.60, 72.82, and 58.85 μg/mL and for β-lapachone was 0.65, 1.24, and 0.71 μg/mL, respectively. The naphthoquinones significantly inhibited the survival rate of L. amazonensis amastigotes at 83.11, 57.59, and 34.95% for lapachol (82.28, 41.14, and 20.57 µg/mL), and 78.49, 83.25, and 80.22% for β-lapachone (3.26, 1.63, and 0.815 µg/mL). The compounds on the promastigote's forms led to the loss of mitochondrial membrane potential, induced changes in the integrity of the membrane, caused damage to cells suggestive of the apoptotic process, and showed inhibition of tumor necrosis factor (TNF)-α and interleukin (IL)-6 production. The results showed that these naphthoquinones are promising candidates for research on new drugs with anti-Leishmania activity derived from natural products.
Topics: Humans; Animals; Mice; Antiprotozoal Agents; Mice, Inbred BALB C; Leishmania mexicana; Naphthoquinones
PubMed: 37255095
DOI: 10.1590/1414-431X2023e12693 -
ChemMedChem Dec 2021Structures of several dozen of known antibacterial, antifungal or antiprotozoal agents are based on the amino acid scaffold. In most of them, the amino acid skeleton is... (Review)
Review
Structures of several dozen of known antibacterial, antifungal or antiprotozoal agents are based on the amino acid scaffold. In most of them, the amino acid skeleton is of a crucial importance for their antimicrobial activity, since very often they are structural analogs of amino acid intermediates of different microbial biosynthetic pathways. Particularly, some aminophosphonate or aminoboronate analogs of protein amino acids are effective enzyme inhibitors, as structural mimics of tetrahedral transition state intermediates. Synthesis of amino acid antimicrobials is a particular challenge, especially in terms of the need for enantioselective methods, including the asymmetric synthesis. All these issues are addressed in this review, summing up the current state-of-the-art and presenting perspectives fur further progress.
Topics: Amino Acids; Animals; Anti-Bacterial Agents; Antifungal Agents; Antiprotozoal Agents; Bacteria; Enzyme Inhibitors; Fungi; Microbial Sensitivity Tests; Plasmodium; Stereoisomerism; Trypanosoma
PubMed: 34596961
DOI: 10.1002/cmdc.202100503 -
Antimicrobial Agents and Chemotherapy Jan 2022Infection with spp. can cause severe diarrhea, leading to long-term adverse impacts and even death in malnourished children and immunocompromised patients. The only...
Infection with spp. can cause severe diarrhea, leading to long-term adverse impacts and even death in malnourished children and immunocompromised patients. The only FDA-approved drug for treating cryptosporidiosis, nitazoxanide, has limited efficacy in the populations impacted the most by the diarrheal disease, and safe, effective treatment options are urgently needed. Initially identified by a large-scale phenotypic screening campaign, the antimycobacterial therapeutic clofazimine demonstrated great promise in both and preclinical models of infection. Unfortunately, a phase 2a clinical trial in HIV-infected adults with cryptosporidiosis did not identify any clofazimine treatment effect on infection burden or clinical outcomes. To explore whether clofazimine's lack of efficacy in the phase 2a trial may have been due to subtherapeutic clofazimine concentrations, a pharmacokinetic/pharmacodynamic modeling approach was undertaken to determine the relationship between clofazimine concentrations and treatment effects in multiple preclinical infection models. Exposure-response relationships were characterized using and logistic models, which allowed predictions of efficacious clofazimine concentrations for the control and reduction of disease burden. After establishing exposure-response relationships for clofazimine treatment of infection in our preclinical model studies, it was unmistakable that the clofazimine levels observed in the phase 2a study participants were well below concentrations associated with anti- efficacy. Thus, despite a dosing regimen above the highest doses recommended for mycobacterial therapy, it is very likely the lack of treatment effect in the phase 2a trial was at least partially due to clofazimine concentrations below those required for efficacy against cryptosporidiosis. It is unlikely that clofazimine will provide a remedy for the large number of cryptosporidiosis patients currently without a viable treatment option unless alternative, safe clofazimine formulations with improved oral absorption are developed. (This study has been registered in ClinicalTrials.gov under identifier NCT03341767.).
Topics: Adult; Antiprotozoal Agents; Child; Clofazimine; Cryptosporidiosis; Cryptosporidium; Diarrhea; Humans
PubMed: 34748385
DOI: 10.1128/AAC.01560-21 -
Frontiers in Immunology 2022New therapeutic strategies for visceral leishmaniasis (VL) have been studied, and the development of an immunotherapeutic agent that modulates the host's immune response...
New therapeutic strategies for visceral leishmaniasis (VL) have been studied, and the development of an immunotherapeutic agent that modulates the host's immune response is necessary. The aim of this study was to evaluate the bioactive extracts of photosynthetic microorganisms (PMs) for their leishmanicidal/leishmanistatic and immunomodulatory potentials. Bioactive extracts from PMs ( and ) were obtained by sonication. Reference drugs, miltefosine (MTF) and N-methylglucamine antimoniate (Sb), were also evaluated. The selectivity index (SI) of treatments was determined by assays of inhibitory concentration (IC) in cells and cytotoxic concentrations (CC) in human peripheral blood mononuclear cells by the MTT method. The immune response was evaluated in healthy human cells by the production of cytokines and nitric oxide (NO) and the gene expression of , , , and , using four concentrations (CC, ½ CC, ¼ CC, and IC) for stimulation. Based on the data obtained, we observed that the extracts of (SI = 4.7) and (SI = 3.8) presented better results when compared to Sb (SI = 2.1). When analyzing the immune response results, we identified that the extracts of PMs stimulated the production of cytokines of the Th1 profile more than the reference drugs. The extracts also demonstrated the ability to stimulate NO synthesis. Regarding gene expression, in all concentrations of extracts, we found a balance between the Th1/Th2 profile, with the average expression of the gene more than the in the highest concentration (CC). Regarding the extract of , we can observe that, in the lowest concentrations, a balance between all the genes was present, with the average expression of the gene being lower than the others. The best result was found in the ½ CC concentration, stimulating a balanced positive expression between the Th1×Th17×Treg profiles, with a negative expression of . Thus, PM extracts showed promising results, presenting low toxicity, leishmanicidal/leishmanistatic activity, and induction of the immune response, which could be potential therapeutic candidates for VL.
Topics: Animals; Antiprotozoal Agents; Cytokines; Humans; Leishmaniasis, Visceral; Leukocytes, Mononuclear; Mice; Mice, Inbred BALB C
PubMed: 35844611
DOI: 10.3389/fimmu.2022.891495 -
European Journal of Medicinal Chemistry Dec 2020Malaria and tuberculosis are still among the leading causes of death in low-income countries. The 1,4-naphthoquinone (NQ) scaffold can be found in a variety of...
Malaria and tuberculosis are still among the leading causes of death in low-income countries. The 1,4-naphthoquinone (NQ) scaffold can be found in a variety of anti-infective agents. Herein, we report an optimised, high yield process for the preparation of various 2-arylnaphthoquinones by a palladium-catalysed Suzuki reaction. All synthesised compounds were evaluated for their in-vitro antiprotozoal and antimycobacterial activity. Antiprotozoal activity was assessed against Plasmodium falciparum (P.f.) NF54 and Trypanosoma brucei rhodesiense (T.b.r.) STIB900, and antimycobacterial activity against Mycobacterium smegmatis (M.s.) mc 155. Substitution with pyridine and pyrimidine rings significantly increased antiplasmodial potency of our compounds. The 2-aryl-NQs exhibited trypanocidal activity in the nM range with a very favourable selectivity profile. (Pseudo)halogenated aryl-NQs were found to have a pronounced effect indicating inhibition of mycobacterial efflux pumps. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. In addition, the physicochemical parameters of the synthesised compounds were discussed.
Topics: Anti-Bacterial Agents; Antiprotozoal Agents; Catalysis; Chemistry Techniques, Synthetic; Mycobacterium smegmatis; Palladium; Plasmodium falciparum; Quinones; Trypanosoma brucei rhodesiense
PubMed: 33002847
DOI: 10.1016/j.ejmech.2020.112837 -
Scientific Reports May 2022This study evaluated the morphological changes caused by fractions and subfractions, obtained from barks of Aspidosperna nitidum, against L. (L.) amazonensis...
This study evaluated the morphological changes caused by fractions and subfractions, obtained from barks of Aspidosperna nitidum, against L. (L.) amazonensis promastigotes. The ethanolic extract (EE) obtained through the maceration of trunk barks was subjected to an acid-base partition, resulting the neutral (FN) and the alkaloid (FA) fractions, and fractionation under reflux, yielded hexane (FrHEX), dichloromethane (FrDCL), ethyl acetate (FrACoET), and methanol (FrMEOH) fractions. The FA was fractionated and three subfractions (SF5-6, SF8, and SF9) were obtained and analyzed by HPLC-DAD and H NMR. The antipromastigote activity of all samples was evaluated by MTT, after that, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) for the active fractions were performed. Chromatographic analyzes suggest the presence of alkaloids in EE, FN, FA, and FrDCL. The fractionation of FA led to the isolation of the indole alkaloid dihydrocorynantheol (SF8 fractions). The SF5-6, dihydrocorynantheol and SF-9 samples were active against promastigotes, while FrDCL was moderately active. The SEM analysis revealed cell rounding and changes in the flagellum of the parasites. In the TEM analysis, the treated promastigotes showed changes in flagellar pocket and kinetoplast, and presence of lipid inclusions. These results suggest that alkaloids isolated from A. nitidum are promising as leishmanicidal.
Topics: Alkaloids; Antiprotozoal Agents; Aspidosperma; Indole Alkaloids; Leishmania; Plant Extracts
PubMed: 35606396
DOI: 10.1038/s41598-022-12396-x -
BMC Microbiology Feb 2022Leishmaniasis is a vector-borne disease that is endemic in the tropical and sub-tropical areas of the world. Low efficacy and high cytotoxicity of the current treatment...
BACKGROUND
Leishmaniasis is a vector-borne disease that is endemic in the tropical and sub-tropical areas of the world. Low efficacy and high cytotoxicity of the current treatment regimens for leishmaniasis is one of the most important health problems. In this experimental study, anti-leishmanial effects of different concentrations of resveratrol and resveratrol nano-emulsion (RNE) were assessed.
METHODS
RNE was prepared using the probe ultra-sonication method. The cytotoxicity was evaluated using the MTT technique on the L929 cell line. The anti-leishmanial activities on promastigotes of leishmania were assessed using vital staining and infected BALB/c mice were used to assess the in vivo anti-leishmanial effects.
RESULTS
In vitro and in vivo assays revealed that all concentrations of resveratrol and RNE had valuable inhibitory effects against Leishmania major in comparison to the control group (P < 0.05). The half maximal inhibitory concentration (IC) values were calculated as 16.23 and 35.71 µg/mL for resveratrol and RNE, respectively. Resveratrol and RNE showed no cytotoxicity against the L929 cell line.
CONCLUSIONS
According to the potent in vitro and in vivo anti-leishmanial activity of RNE at low concentration against L. major, we suggest that it could be a promising anti-leishmanial therapeutic against L. major in the future.
Topics: Animals; Antiprotozoal Agents; Cell Line; Emulsions; Female; Leishmania major; Leishmaniasis, Cutaneous; Macrophages; Mice; Mice, Inbred BALB C; Nanoparticles; Resveratrol
PubMed: 35168553
DOI: 10.1186/s12866-022-02455-8