-
Bioorganic & Medicinal Chemistry Feb 2021Three antifungal macrolides cyphomycin (1), caniferolide C (2) and GT-35 (3) were isolated from Streptomyces sp. ISID311, a bacterial symbiont associated with...
Three antifungal macrolides cyphomycin (1), caniferolide C (2) and GT-35 (3) were isolated from Streptomyces sp. ISID311, a bacterial symbiont associated with Cyphomyrmex fungus-growing ants. The planar structures of these compounds were established by 1 and 2D NMR data and MS analysis. The relative configurations of 1-3 were established using Kishi's universal NMR database method, NOE/ROE analysis and coupling constants analysis assisted by comparisons with NMR data of related compounds. Detailed bioinformatic analysis of cyphomycin biosynthetic gene cluster confirmed the stereochemical assignments. Compounds 1-3 displayed high antagonism against different strains of Escovopsis sp., pathogen fungi specialized to the fungus-growing ant system. Compounds 1-3 also exhibited potent antiprotozoal activity against intracellular amastigotes of the human parasite Leishmania donovani with IC values of 2.32, 0.091 and 0.073 µM, respectively, with high selectivity indexes.
Topics: Antiprotozoal Agents; Dose-Response Relationship, Drug; Leishmania donovani; Macrolides; Molecular Structure; Parasitic Sensitivity Tests; Streptomyces; Structure-Activity Relationship
PubMed: 33493972
DOI: 10.1016/j.bmc.2021.116016 -
Antimicrobial Agents and Chemotherapy Sep 2021This work reports the synthesis and characterization by Fourier transform infrared spectroscopy (FTIR), H, C, and Se nuclear magnetic resonance (NMR), mass spectrometry,...
This work reports the synthesis and characterization by Fourier transform infrared spectroscopy (FTIR), H, C, and Se nuclear magnetic resonance (NMR), mass spectrometry, and elemental analysis techniques as well as the evaluation of the leishmanicidal activity of 13 new selenophosphoramidate derivatives. Among the new compounds, four of them (compounds 1f, 1g, 2f, and 2g), which exhibited the best profiles, were tested against infected macrophages and were selected for further studies related to their leishmanicidal mechanism. In this regard, trypanothione redox system alteration was determined. Compound 1g, under similar conditions, was more effective than the corresponding references. In addition, theoretical calculations showed that this compound also presents most physicochemical and pharmacokinetic properties within the ranges expected for orally available drugs. It is believed that selenophosphoramidate functionalities may represent a scaffold to be explored toward the development of new agents for leishmania treatment.
Topics: Amides; Antiprotozoal Agents; Leishmania; Pharmaceutical Preparations; Phosphoric Acids; Selenium
PubMed: 34339279
DOI: 10.1128/AAC.00590-21 -
BMC Complementary Medicine and Therapies Dec 2023In the last few decades, the use of plant extracts and their phytochemicals as candidates for the management of parasitic diseases has increased tremendously. Irises are...
BACKGROUND
In the last few decades, the use of plant extracts and their phytochemicals as candidates for the management of parasitic diseases has increased tremendously. Irises are aromatic and medicinal plants that have long been employed in the treatment of different infectious diseases by traditional healers in many cultures. This study aims to explore the potential of three common Iris species (I. confusa Sealy, I. pseudacorus L. and I. germanica L.) against infectious diseases. Their in vitro antiprotozoal potency against Plasmodium falciparum, Trypanosoma brucei brucei, T. b. rhodesiense, T. cruzi and Leishmania infantum beside their cytotoxicity on MRC-5 fibroblasts and primary peritoneal murine macrophages were examined.
METHODS
The secondary metabolites of the tested extracts were characterized by UPLC-HRMS/MS and Pearsons correlation was used to correlate them with the antiprotozoal activity.
RESULTS
Overall, the non-polar fractions (NPF) showed a significant antiprotozoal activity (score: sc 2 to 5) in contrast to the polar fractions (PF). I. confusa NPF was the most active extract against P. falciparum [IC of 1.08 μg/mL, selectivity index (S.I. 26.11) and sc 5] and L. infantum (IC of 12.7 μg/mL, S.I. 2.22 and sc 2). I. pseudacorus NPF was the most potent fraction against T. b. rhodesiense (IC of 8.17 μg/mL, S.I. 3.67 and sc 3). Monogalactosyldiacylglycerol glycolipid (18:3/18:3), triaceylglycerol (18:2/18:2/18:3), oleic acid, and triterpenoid irridals (spirioiridoconfal C and iso-iridobelamal A) were the top positively correlated metabolites with antiplasmodium and antileishmanial activities of I. confusa NPF. Tumulosic acid, ceramide sphingolipids, corosolic, maslinic, moreollic acids, pheophytin a, triaceylglycerols, mono- and digalactosyldiacylglycerols, phosphatidylglycerol (22:6/18:3), phosphatidylcholines (18:1/18:2), and triterpenoid irridal iso-iridobelamal A, were highly correlated to I. pseudacorus NPF anti- T. b. rhodesiense activity. The ADME study revealed proper drug likeness properties for certain highly corelated secondary metabolites.
CONCLUSION
This study is the sole map correlating I. confusa and I. pseudacorus secondary metabolites to their newly explored antiprotozoal activity.
Topics: Mice; Animals; Iris Plant; Cell Line; Antiprotozoal Agents; Triterpenes; Communicable Diseases
PubMed: 38104072
DOI: 10.1186/s12906-023-04294-0 -
Journal of Enzyme Inhibition and... Dec 2020A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and...
Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives.
A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated against three protozoan parasites (, , and ). Biological results showed antiprotozoal activity with IC values in the µM range. In addition, the cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the CQ-sensitive strain 3D7. The quinazoline was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on strain. Moreover, as the telomeres of the parasites and are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the and telomeric G-quadruplexes by our best compounds through FRET melting assays.
Topics: Antiprotozoal Agents; Drug Design; Hep G2 Cells; Humans; Leishmania donovani; Plasmodium falciparum; Quinolines; Structure-Activity Relationship; Trypanosoma brucei brucei
PubMed: 31899980
DOI: 10.1080/14756366.2019.1706502 -
Frontiers in Cellular and Infection... 2023Leishmaniasis is a neglected tropical disease with a wide spectrum of clinical manifestations, ranging from visceral to cutaneous, with millions of new cases and... (Review)
Review
Leishmaniasis is a neglected tropical disease with a wide spectrum of clinical manifestations, ranging from visceral to cutaneous, with millions of new cases and thousands of deaths reported each year. The species of and the immune response of the host determine the severity of the disease. Leishmaniasis remains challenging to diagnose and treat, and there is no vaccine available. Several studies have been conducted on the use of herbal medicines for the treatment of leishmaniasis. Natural products can provide an inexhaustible source of chemical diversity with therapeutic potential. Terpenes are a class of natural products derived from a single isoprene unit, a five-carbon compound that forms the basic structure of isoprenoids. This review focuses on the most important and recent advances in the treatment of parasites of the genus with different subclasses of terpenes. Several mechanisms have been proposed in the literature, including increased oxidative stress, immunomodulatory role, and induction of different types of parasite cell death. However, this information needs to be brought together to provide an overview of how these compounds can be used as therapeutic tools for drug development and as a successful adjuvant strategy against sp.
Topics: Humans; Terpenes; Antiprotozoal Agents; Leishmania; Leishmaniasis; Cell Death; Biological Products
PubMed: 37799331
DOI: 10.3389/fcimb.2023.1260448 -
Journal of Biomedicine & Biotechnology 2010Visceral leishmaniasis remains a public health problem worldwide. This illness was included by the World Health Organization in the list of neglected tropical diseases... (Review)
Review
Visceral leishmaniasis remains a public health problem worldwide. This illness was included by the World Health Organization in the list of neglected tropical diseases targeted for elimination by 2015. The widespread emergence of resistance to pentavalent antimonials in India where half cases occur globally and the unavailability of a vaccine in clinical use constitute major obstacles in achieving of this goal. The last decade new antileishmanials became available, including the oral agent miltefosine. However, in poor endemic countries their wide use was curtailed because of the high costs, and also due to concerns of toxicity and emergence of resistance. Various mechanisms of antileishmanial resistance were identified recently in field isolates. Their elucidation will boost the design of new drugs and the molecular surveillance of resistance. Combination regimens should be evaluated in large trials. Overall, the development of antileishmanials has been generally slow; new drugs are needed. In order to control visceral leishmaniasis worldwide, treatment advances should become affordable in the poorest countries, where they are needed most.
Topics: Antiprotozoal Agents; Drug Resistance; Drug Therapy, Combination; Humans; Leishmaniasis, Visceral
PubMed: 19888437
DOI: 10.1155/2010/617521 -
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 -
Frontiers in Cellular and Infection... 2022Leishmaniasis is one of the major public health concerns in Latin America, Africa, Asia, and Europe. The absence of vaccines for human use and the lack of effective... (Review)
Review
Leishmaniasis is one of the major public health concerns in Latin America, Africa, Asia, and Europe. The absence of vaccines for human use and the lack of effective vector control programs make chemotherapy the main strategy to control all forms of the disease. However, the high toxicity of available drugs, limited choice of therapeutic agents, and occurrence of drug-resistant parasite strains are the main challenges related to chemotherapy. Currently, only a small number of drugs are available for leishmaniasis treatment, including pentavalent antimonials (Sb), amphotericin B and its formulations, miltefosine, paromomycin sulphate, and pentamidine isethionate. In addition to drug toxicity, therapeutic failure of leishmaniasis is a serious concern. The occurrence of drug-resistant parasites is one of the causes of therapeutic failure and is closely related to the diversity of parasites in this genus. Owing to the enormous plasticity of the genome, resistance can occur by altering different metabolic pathways, demonstrating that resistance mechanisms are multifactorial and extremely complex. Genetic variability and genome plasticity cause not only the available drugs to have limitations, but also make the search for new drugs challenging. Here, we examined the biological characteristics of parasites that hinder drug discovery.
Topics: Amphotericin B; Antiprotozoal Agents; Genetic Variation; Humans; Leishmania; Leishmaniasis
PubMed: 35141175
DOI: 10.3389/fcimb.2022.826287 -
PLoS Neglected Tropical Diseases Mar 2016Leishmania aethiopica is the etiological agent of cutaneous leishmaniasis (CL) in Ethiopia and can cause severe and complicated cases such as diffuse CL (DCL),... (Review)
Review
Leishmania aethiopica is the etiological agent of cutaneous leishmaniasis (CL) in Ethiopia and can cause severe and complicated cases such as diffuse CL (DCL), mucocutaneous leishmaniasis or extensive CL, requiring systemic treatment. Despite the substantial burden, evidence-based treatment guidelines are lacking. We conducted a systematic review of clinical studies reporting on treatment outcomes of CL due to L aethiopica in order to help identify potentially efficacious medications on CL that can be taken forward for clinical trials. We identified a total of 24 records reporting on 506 treatment episodes of CL presumably due to L aethiopica. The most commonly used drugs were antimonials (n = 201), pentamidine (n = 150) and cryotherapy (n = 103). There were 20 case reports/series, with an overall poor study quality. We only identified two small and/or poor quality randomized controlled trials conducted a long time ago. There were two prospective non-randomized studies reporting on cryotherapy, antimonials and pentamidine. With cryotherapy, cure rates were 60-80%, and 69-85% with antimonials. Pentamidine appeared effective against complicated CL, also in cases non-responsive to antimonials. However, all studies suffered from methodological limitations. Data on miltefosine, paromomycin and liposomal amphotericin B are extremely scarce. Only a few studies are available on DCL. The only potentially effective treatment options for DCL seem to be antimonials with paromomycin in combination or pentamidine, but none have been properly evaluated. In conclusion, the evidence-base for treatment of complicated CL due to L aethiopica is extremely limited. While antimonials remain the most available CL treatment in Ethiopia, their efficacy and safety in CL should be better defined. Most importantly, alternative first line treatments (such as miltefosine or paromomycin) should be explored. High quality trials on CL due to L aethiopica are urgently needed, exploring group sequential methods to evaluate several options in parallel.
Topics: Adolescent; Adult; Aged; Antiprotozoal Agents; Child; Child, Preschool; Cryotherapy; Ethiopia; Female; Humans; Leishmania; Leishmaniasis, Cutaneous; Male; Middle Aged; Prospective Studies; Treatment Outcome; Young Adult
PubMed: 26938448
DOI: 10.1371/journal.pntd.0004495 -
Frontiers in Cellular and Infection... 2021Current treatments for giardiasis include drugs with undesirable side effects, which increase the levels of therapeutic desertion and promote drug resistance in the...
Current treatments for giardiasis include drugs with undesirable side effects, which increase the levels of therapeutic desertion and promote drug resistance in the parasites. Herein, we describe the antigiardiasic evaluation on Giardia lamblia trophozoites of a structurally diverse collection of 74 molecules. Among these scaffolds, we discovered a benzopyrrolizidine derivative with higher antigiardiasic activity (IC = 11 µM) and lower cytotoxicity in human cell cultures (IC = 130 µM) than those displayed by the current gold-standard drugs (metronidazole and tinidazole). Furthermore, this compound produced morphologic modifications of trophozoites, with occasional loss of one of the nuclei, among other changes not observed with standard giardicidal drugs, suggesting that it might act through a novel mechanism of action.
Topics: Animals; Antiprotozoal Agents; Giardia lamblia; Giardiasis; Humans; Metronidazole; Trophozoites
PubMed: 35096662
DOI: 10.3389/fcimb.2021.828100