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Infection and Immunity Mar 2021Today, more than a billion people-one-sixth of the world's population-are suffering from neglected tropical diseases. Human African trypanosomiasis, Chagas disease, and... (Review)
Review
Today, more than a billion people-one-sixth of the world's population-are suffering from neglected tropical diseases. Human African trypanosomiasis, Chagas disease, and leishmaniasis are neglected tropical diseases caused by protozoan parasites belonging to the genera and About half a million people living in tropical and subtropical regions of the world are at risk of contracting one of these three infections. Kinetoplastids have complex life cycles with different morphologies and unique physiological requirements at each life cycle stage. This review covers the latest findings on metabolic pathways impacting disease pathogenesis of kinetoplastids within the mammalian host. Nutrient availability is a key factor shaping parasite metabolism; thus, kinetoplastids display significant metabolic flexibility. Proteomic and transcriptomic profiles show that intracellular trypanosomatids are able to switch to an energy-efficient metabolism within the mammalian host system. Host metabolic changes can also favor parasite persistence, and contribute to symptom development, in a location-specific fashion. Ultimately, targeted and untargeted metabolomics studies have been a valuable approach to elucidate the specific biochemical pathways affected by infection within the host, leading to translational drug development and diagnostic insights.
Topics: Adaptation, Physiological; Animals; Antiprotozoal Agents; Disease Management; Disease Susceptibility; Energy Metabolism; Euglenozoa Infections; Host-Parasite Interactions; Humans; Leishmania; Metabolic Networks and Pathways; Trypanosoma
PubMed: 33526564
DOI: 10.1128/IAI.00644-20 -
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 -
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 -
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 -
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 -
Molecules (Basel, Switzerland) Feb 2021Betulinic acid (BA, 3β-hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpene acid present predominantly in ssp. (Betulaceae) and is also widely spread in many... (Review)
Review
Betulinic acid (BA, 3β-hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpene acid present predominantly in ssp. (Betulaceae) and is also widely spread in many species belonging to different plant families. BA presents a wide spectrum of remarkable pharmacological properties, such as cytotoxic, anti-HIV, anti-inflammatory, antidiabetic and antimicrobial activities, including antiprotozoal effects. The present review first describes the sources of BA and discusses the chemical strategies to produce this molecule starting from betulin, its natural precursor. Next, the antiprotozoal properties of BA are briefly discussed and the chemical strategies for the synthesis of analogues displaying antiplasmodial, antileishmanial and antitrypanosomal activities are systematically presented. The antiplasmodial activity described for BA was moderate, nevertheless, some C-3 position acylated analogues showed an improvement of this activity and the hybrid models-with artesunic acid-showed the most interesting properties. Some analogues also presented more intense antileishmanial activities compared with BA, and, in addition to these, heterocycles fused to C-2/C-3 positions and amide derivatives were the most promising analogues. Regarding the antitrypanosomal activity, some interesting antitrypanosomal derivatives were prepared by amide formation at the C-28 carboxylic group of the lupane skeleton. Considering that BA can be produced either by isolation of different plant extracts or by chemical transformation of betulin, easily obtained from ssp., it could be said that BA is a molecule of great interest as a starting material for the synthesis of novel antiprotozoal agents.
Topics: Antiprotozoal Agents; Models, Molecular; Pentacyclic Triterpenes; Triterpenes; Betulinic Acid
PubMed: 33670791
DOI: 10.3390/molecules26041081 -
Chirality Oct 2022Parasitic diseases, including malaria, leishmaniasis, and trypanosomiasis, affect billions of people and are responsible for almost 500,000 deaths/year. In particular,... (Review)
Review
Parasitic diseases, including malaria, leishmaniasis, and trypanosomiasis, affect billions of people and are responsible for almost 500,000 deaths/year. In particular, leishmaniasis, a neglected tropical disease, is considered a global public health problem because current drugs have several drawbacks including to toxicity, high cost, and drug resistance, which result in a lack of effective and readily available therapies. Therefore, the synthesis of new, safe, and effective molecules still requires the attention of the scientific community. Moreover, it is well known that chirality plays a crucial role in the antiparasitic activity of molecules, driving the design of their synthesis. Therefore, in this review we report a recent update on new chiral compounds with promising antileishmanial activity, focusing on synthetic approaches. Where reported, in most cases the enantiopure compound has shown better potency against the protozoa than its enantiomer or corresponding racemic mixture.
Topics: Antiprotozoal Agents; Humans; Leishmaniasis; Stereoisomerism
PubMed: 35947400
DOI: 10.1002/chir.23494 -
Molecules (Basel, Switzerland) Apr 2021Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole...
Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported. Herein, a series of 22 indazole derivatives was synthesized and studied as antiprotozoals. The 2-phenyl-2-indazole scaffold was accessed by a one-pot procedure, which includes a combination of ultrasound synthesis under neat conditions as well as Cadogan's cyclization. Moreover, some compounds were derivatized to have an appropriate set to provide structure-activity relationships (SAR) information. Whereas the antiprotozoal activity of six of these compounds against , , and had been previously reported, the activity of the additional 16 compounds was evaluated against these same protozoa. The biological assays revealed structural features that favor the antiprotozoal activity against the three protozoans tested, e.g., electron withdrawing groups at the 2-phenyl ring. It is important to mention that the indazole derivatives possess strong antiprotozoal activity and are also characterized by a continuous SAR.
Topics: Antiprotozoal Agents; Cheminformatics; Entamoeba histolytica; Giardia lamblia; Indazoles; Inhibitory Concentration 50; Parasitic Sensitivity Tests; Structure-Activity Relationship; Trichomonas vaginalis; Ultrasonics
PubMed: 33917871
DOI: 10.3390/molecules26082145 -
Expert Opinion on Drug Discovery Sep 2022is a prolific apicomplexan parasite that infects human and nonhuman animals worldwide and can cause severe brain and eye disease. Safer, more effective therapies for...
INTRODUCTION
is a prolific apicomplexan parasite that infects human and nonhuman animals worldwide and can cause severe brain and eye disease. Safer, more effective therapies for toxoplasmosis are needed. Cytochrome inhibitors are remarkably effective against toxoplasmosis and other apicomplexan-caused diseases.
AREAS COVERED
This work reviews cytochrome inhibitors. Emphasis is placed on the structure-activity relationships of these inhibitors with regard to efficacy, pharmacokinetics, selectivity of cytochrome over host, safety, and potential therapeutic strategies.
EXPERT OPINION
Cytochrome inhibitors are highly promising compounds for toxoplasmosis that have been effective in clinical and preclinical studies. Clinical experience with atovaquone previously validated cytochrome as a tractable drug target and, over the past decade, optimization of cytochrome inhibitors has resulted in improved bioavailability, metabolic stability, potency, blood-brain barrier penetration, and selectivity for the cytochrome over the mammalian . Recent studies have demonstrated preclinical safety, identified novel therapeutic strategies for toxoplasmosis using synergistic combinations or long-acting administration and provided insight into their role in chronic infection. This research has identified drug candidates that are more effective than clinically used drugs in preclinical measures of efficacy.
Topics: Animals; Antiprotozoal Agents; Atovaquone; Cytochromes; Humans; Structure-Activity Relationship; Toxoplasma; Toxoplasmosis
PubMed: 35772172
DOI: 10.1080/17460441.2022.2096588