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Marine Drugs May 2023Among neglected tropical diseases, leishmaniasis is one of the leading causes, not only of deaths but also of disability-adjusted life years. This disease, caused by...
Among neglected tropical diseases, leishmaniasis is one of the leading causes, not only of deaths but also of disability-adjusted life years. This disease, caused by protozoan parasites of the genus triggers different clinical manifestations, with cutaneous, mucocutaneous, and visceral forms. As existing treatments for this parasitosis are not sufficiently effective or safe for the patient, in this work, different sesquiterpenes isolated from the red alga have been studied for this purpose. The different compounds were tested in vitro against the promastigote and amastigote forms of . Different assays were also performed, including the measurement of mitochondrial potential, determination of ROS accumulation, and chromatin condensation, among others, focused on the detection of the cell death process known in this type of organism as apoptosis-like. Five compounds were identified that displayed leishmanicidal activity: laurequinone, laurinterol, debromolaurinterol, isolaurinterol, and aplysin, showing IC values against promastigotes of 1.87, 34.45, 12.48, 10.09, and 54.13 µM, respectively. Laurequinone was the most potent compound tested and was shown to be more effective than the reference drug miltefosine against promastigotes. Different death mechanism studies carried out showed that laurequinone appears to induce programmed cell death or apoptosis in the parasite studied. The obtained results underline the potential of this sesquiterpene as a novel anti-kinetoplastid therapeutic agent.
Topics: Humans; Animals; Mice; Leishmania; Leishmaniasis; Leishmania mexicana; Skin; Plant Extracts; Antiprotozoal Agents; Mice, Inbred BALB C
PubMed: 37367658
DOI: 10.3390/md21060333 -
International Journal For Parasitology.... Aug 2021New drugs against visceral leishmaniasis with mechanisms of action differing from existing treatments and with adequate cost, stability, and properties are urgently...
New drugs against visceral leishmaniasis with mechanisms of action differing from existing treatments and with adequate cost, stability, and properties are urgently needed. No antitubulin drug is currently in the clinic against Leishmania infantum, the causative agent of visceral leishmaniasis in the Mediterranean area. We have designed and synthesized a focused library of 350 compounds against the Leishmania tubulin based on the structure-activity relationship (SAR) and sequence differences between host and parasite. The compounds synthesized are accessible, stable, and appropriately soluble in water. We assayed the library against Leishmania promastigotes, axenic, and intracellular amastigotes and found 0, 8, and 16 active compounds, respectively, with a high success rate against intracellular amastigotes of over 10%, not including the cytotoxic compounds. Five compounds have a similar or better potency than the clinically used miltefosine. 14 compounds showed a host-dependent mechanism of action that might be advantageous as it may render them less susceptible to the development of drug resistance. The active compounds cluster in five chemical classes that provide structure-activity relationships for further hit improvement and facilitate series development. Molecular docking is consistent with the proposed mechanism of action, supported by the observed structure-activity relationships, and suggests a potential extension to other Leishmania species due to sequence similarities. A new family of diarylsulfonamides designed against the parasite tubulins is active against Leishmania infantum and represents a new class of potential drugs with favorable cost, stability, and aqueous solubility for the treatment of visceral leishmaniasis (VL). These results could be extended to other clinically relevant species of Leishmania spp.
Topics: Antiprotozoal Agents; Drug Resistance; Humans; Leishmania infantum; Leishmaniasis, Visceral; Molecular Docking Simulation
PubMed: 34015753
DOI: 10.1016/j.ijpddr.2021.02.006 -
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 -
The Indian Journal of Medical Research Jan 2011Visceral leishmaniasis (VL) or kala-azar is a chronic protozoan infection in humans associated with significant global morbidity and mortality. The causative agent is a... (Review)
Review
Visceral leishmaniasis (VL) or kala-azar is a chronic protozoan infection in humans associated with significant global morbidity and mortality. The causative agent is a haemoflagellate protozoan Leishmania donovani, an obligate intracellular parasite that resides and multiplies within macrophages of the reticulo-endothelial system. Most of the existing anti-leishmanial drugs have serious side effects that limit their clinical application. As an alternate strategy, vaccination is also under experimental and clinical trials. The in vitro evaluation designed to facilitate rapid testing of a large number of drugs has been focussed on the promastigotes milt little attention on the clinically relevant parasite stage, amastigotes. Screening designed to closely reflect the situation in vivo is currently time consuming, laborious, and expensive, since it requires intracellular amastigotes and animal model. The ability to select transgenic Leishmania expressing reporter proteins, such as the green fluorescent proteins (GFP) or the luciferase opened up new possibilities for the development of drug screening models. Many experimental animal models like rodents, dogs and monkeys have been developed, each with specific features, but none accurately reproduces what happens in humans. Available in vitro and in vivo methodologies for antileishmanial drug screening and their respective advantages and disadvantages are reviewed.
Topics: Animals; Animals, Genetically Modified; Antiprotozoal Agents; Clinical Trials as Topic; Drug Discovery; Drug Evaluation, Preclinical; Genes, Reporter; High-Throughput Screening Assays; Humans; Leishmania donovani; Leishmaniasis, Visceral; Protozoan Proteins
PubMed: 21321417
DOI: No ID Found -
Marine Drugs Oct 2017Leishmaniasis is a vector-borne neglected tropical disease caused by protozoan parasites of the genus and transmitted by the female and sand flies. The currently... (Review)
Review
Leishmaniasis is a vector-borne neglected tropical disease caused by protozoan parasites of the genus and transmitted by the female and sand flies. The currently prescribed therapies still rely on pentavalent antimonials, pentamidine, paromomycin, liposomal amphotericin B, and miltefosine. However, their low efficacy, long-course treatment regimen, high toxicity, adverse side effects, induction of parasite resistance and high cost require the need for better drugs given that antileishmanial vaccines may not be available in the near future. Although most drugs are still derived from terrestrial sources, the interest in marine organisms as a potential source of promising novel bioactive natural agents has increased in recent years. About 28,000 compounds of marine origin have been isolated with hundreds of new chemical entities. Recent trends in drug research from natural resources indicated the high interest of aquatic eukaryotic photosynthetic organisms, marine algae in the search for new chemical entities given their broad spectrum and high bioactivities including antileishmanial potential. This current review describes prepared extracts and compounds from marine macroalgae along with their antileishmanial activity and provides prospective insights for antileishmanial drug discovery.
Topics: Animals; Antiprotozoal Agents; Aquatic Organisms; Humans; Leishmaniasis; Seaweed
PubMed: 29109372
DOI: 10.3390/md15110323 -
Journal of Postgraduate Medicine 2003Leishmaniasis, a parasitic disease transmitted by the bite of some species of sandflies affects various age groups depending on the infecting Leishmania species,... (Review)
Review
Leishmaniasis, a parasitic disease transmitted by the bite of some species of sandflies affects various age groups depending on the infecting Leishmania species, geographic location, disease reservoir, and host immunocompetence. Visceral leishmaniasis is the most severe form of the disease affecting children. The extent and presentation of the disease depend on several factors, including the humoral and cell-mediated immune response of the host, the virulence of the infecting species, and the parasite burden. Children are at greater risk than adults in endemic areas. Malnutrition contributes to the development of disease, and incomplete therapy of initial disease is a risk factor for recurrence of leishmaniasis. Children usually present with intermittent fever, paleness, refusal to feed or anorexia, weight loss, and abdominal distension. Splenomegaly, hepatomegaly, lymph node enlargement, thrombocytopaenia, anaemia, leukopaenia and hypergammaglobulinemia are the most common findings in Paediatric leishmaniasis. Molecular methods appear to offer the promise of accurate non-invasive tools for the diagnosis of Leishmaniasis. Till these methods are evaluated, definite diagnosis will rely on the demonstration of the infecting parasite in various tissues. World-wide, with the notable exception of India, pentavalent antimonial compounds remain the most effective and the most affordable therapy for this disease. Lipid formulations of amphotericin B were assessed as short duration treatment and were proved to be effective. However, their cost precludes their wide use in developing countries. Miltefosine, a new oral agent, might prove effective, safe, and affordable. Strategies aimed at control of the micro-population of sandflies, eradication of canine leishmaniasis, and offering personal protection against sandfly bites, together with health education programs in developing countries, can help control the disease. Development of an effective vaccine remains a priority.
Topics: Animals; Antiprotozoal Agents; Child; Developing Countries; Humans; Leishmania donovani; Leishmaniasis, Visceral; Protozoan Vaccines; Risk Factors
PubMed: 12865569
DOI: 10.4103/0022-3859.930 -
International Journal of Molecular... Jan 2018Natural products from plants have been used since ancestral times to treat a wide variety of diseases worldwide. Plants of the genus (Sage) have been reported to be... (Review)
Review
Natural products from plants have been used since ancestral times to treat a wide variety of diseases worldwide. Plants of the genus (Sage) have been reported to be used for the prevention and treatment of various diseases and ailments. In particular, some species have been used in traditional medicine to treat diseases caused by protozoan parasites of the genera , and and scientific studies have demonstrated the activity of various isolated constituents from these plants against these pathogens. The current review attempts to give a critical overview of published information about the antiprotozoal activity of species of the genus and their chemical constituents. It is meant to give a unified overview of these results in order to avoid repetitions caused, e.g., by limited access to some primary reports, and to stimulate further research to possibly facilitate the development of new molecular leads against protozoal neglected tropical diseases (NTDs) based on constituents.
Topics: Antiprotozoal Agents; Biological Products; Oils, Volatile; Plant Extracts; Salvia
PubMed: 29337909
DOI: 10.3390/ijms19010264 -
Expert Opinion on Drug Discovery Dec 2013Endemic in Latin America, Chagas disease is now becoming a serious global health problem, and yet has no financial viability for the pharmaceutical industry and remains... (Review)
Review
INTRODUCTION
Endemic in Latin America, Chagas disease is now becoming a serious global health problem, and yet has no financial viability for the pharmaceutical industry and remains incurable. In 2012, two antimycotic drugs inhibitors of fungal sterol 14α-demethylase (CYP51) - posaconazole and ravuconazole - entered clinical trials. Availability of the X-ray structure of the orthologous enzyme from the causative agent of the disease, protozoan parasite Trypanosoma cruzi, determined in complexes with posaconazole as well as with several experimental protozoa-specific CYP51 inhibitors opens an excellent opportunity to improve the situation.
AREAS COVERED
This article summarizes the information available in PubMed and Google on the outcomes of treatment of the chronic Chagas disease. It also outlines the major features of the T. cruzi CYP51 structure and the possible structure-based strategies for rational design of novel T. cruzi specific drugs.
EXPERT OPINION
There is no doubt that screenings for alternative drug-like molecules as well as mining the T. cruzi genome for novel drug targets are of great value and might eventually lead to groundbreaking discoveries. However, all newly identified molecules must proceed through the long, expensive and low-yielding drug optimization process, and all novel potential drug targets must be validated in terms of their essentiality and druggability. CYP51 is already a well-validated and highly successful target for clinical and agricultural antifungals. With minimal investments into the final stages of their development/trials, T. cruzi-specific CYP51 inhibitors can provide an immediate treatment for Chagas disease, either on their own or in combination with the currently available drugs.
Topics: 14-alpha Demethylase Inhibitors; Animals; Antifungal Agents; Antiprotozoal Agents; Chagas Disease; Drug Design; Humans; Trypanosoma cruzi
PubMed: 24079515
DOI: 10.1517/17460441.2013.845554 -
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 -
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