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Annals of Parasitology 2021Leishmaniosis is one of the most important vectors borne disease that is endemic in tropical and subtropical areas. There are many approved treatment for different types...
Leishmaniosis is one of the most important vectors borne disease that is endemic in tropical and subtropical areas. There are many approved treatment for different types of leishmaniosis but all are with some adverse side effects that limited its uses. Here, we attempt to evaluate in vitro and ex vivo anti-leishmanial activities of Peganum harmala (P. harmala) and N. sativa (Nigella sativa) on promastigotes and amastigotes of L. major. The plants were extracted by maceration method and prepared in concentrations of 7.8, 3.9, 1.9, and 0.9 μg. L. major were cultured in RPMI-1640 medium alone and in J774 cell line separately. The extracts at different concentrations were assessed against promastigote (in vitro assay) and amastigotes (ex vivo assay) of L. major for 72 h at 22 and 37°C, respectively. In current work, N. sativa at highest concentration (7.8 μg/ml) showed 54.4 and 60% anti-leishmanial activity with IC50 of 5.3 and 3.278 μg/ml, respectively. Also, P. harmala at highest concentration (7.8 μg/ml) showed 68.9 and 58.6% antileishmanial activity with IC50 of 2.4 μg/ml for both of them, respectively. The SI value was 38.22 for N. sativa, 25.9 for P. harmala, 19.4 for Amphotericin B, and 16.33 for Glucantime. The results of our study indicated that N. sativa and P. harmala are effective against L. major promastigotes and amastigotes and could be consider as an alternative treatments for leishmaniosis. Therefore, it is recommended that further studies be performed to confirm the efficacy and evaluate the toxicity of the herbal extracts.
Topics: Antiprotozoal Agents; Leishmania major; Macrophages; Nigella sativa; Peganum
PubMed: 34598403
DOI: 10.17420/ap6702.344 -
Zeitschrift Fur Naturforschung. C,... Jul 2020Spontaneous lavender growing in uncultivated fields in Portugal have been used in traditional medicine for internal and external uses. The essential oils (EOs) of... (Review)
Review
Spontaneous lavender growing in uncultivated fields in Portugal have been used in traditional medicine for internal and external uses. The essential oils (EOs) of Lavandula stoechas subsp. luisieri are characterized by the presence of trans-α-necrodyl acetate and trans-necrodol. These EOs are able to prevent the generation and deposition of neurotoxic β-amyloid peptide in Alzheimer's disease. The EOs also present antibacterial, anti-fungal, anti-Leishmania, antioxidant, anti-inflammatory and antifeedant effects. In the case of hydrodistillation, the predominant compound of Lavandula viridis EO was 1,8-cineole, nevertheless in the case of supercritical fluid extraction, the main constituent was camphor. In in vitro shoots EOs, 1,8-cineole and α-pinene were the most important compounds. The EOs presented anti-fungal activity particularly against Cryptococcus neoformans and dermatophytes. The antioxidant and anti-protozoal activities of L. viridis EOs were lower than L. stoechas subsp. luisieri EOs, with hydrodistillation being the best method for obtaining samples with higher antioxidant and anti-acetylcholinesterase activities. The presence of fenchone, 1,8-cineole and camphor was a common trace of the Lavandula pedunculata subsp. pedunculata EOs and in in vitro axillary shoots EOs. Lavandula pedunculata subsp. lusitanica EOs were predominantly constituted of fenchone and camphor. The antioxidant activity of L. pedunculata subsp. lusitanica EOs was poorer than other Lavandula EOs from Portugal.
Topics: Amyloid beta-Peptides; Anti-Bacterial Agents; Antioxidants; Antiprotozoal Agents; Humans; Lavandula; Medicine, Traditional; Oils, Volatile; Plant Oils; Portugal
PubMed: 32452196
DOI: 10.1515/znc-2020-0044 -
Antimicrobial Agents and Chemotherapy May 2021Leishmaniasis and Chagas are among the most significant neglected tropical diseases. Due to several drawbacks with the current chemotherapy, developing new...
Leishmaniasis and Chagas are among the most significant neglected tropical diseases. Due to several drawbacks with the current chemotherapy, developing new antikinetoplastid drugs has become an urgent issue. In the present work, a bioassay-guided investigation of the root bark of on and led to the identification of two -friedo-nor-oleanane triterpenoids (celastroloids), 20β-hydroxy-tingenone (celastroloid 5) and 3--methyl-6-oxo-tingenol (celastroloid 8), as promising antikinetoplastid leads. They displayed higher potency on promastigotes (50% inhibitory concentrations [ICs], 0.44 and 1.12 μM, respectively), intracellular amastigotes (ICs, 0.83 and 1.91 μM, respectively), and epimastigote stage (ICs, 2.61 and 3.41 μM, respectively) than reference drugs miltefosine and benznidazole. This potency was coupled with an excellent selectivity index on murine macrophages. Mechanism of action studies, including mitochondrial membrane potential (Δψm) and ATP-level analysis, revealed that celastroloids could induce apoptotic cell death in triggered by the mitochondria. In addition, the structure-activity relationship is discussed. These findings strongly underline the potential of celastroloids as lead compounds to develop novel antikinetoplastid drugs.
Topics: Animals; Antiprotozoal Agents; Leishmania mexicana; Leishmaniasis; Maytenus; Mice; Trypanosoma cruzi
PubMed: 33753334
DOI: 10.1128/AAC.02236-20 -
Molecules (Basel, Switzerland) Apr 2024Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current...
Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current antiprotozoal treatments and the lack of approved vaccines. Considering the demand for novel therapeutic drugs, a series of BODIPY derivatives with several functionalizations at the , 2 and/or 6 positions of the core were synthesized and characterized. The in vitro activity against and parasites was carried out alongside a human healthy cell line (MRC-5) to establish selectivity indices (SIs). Notably, the -substituted BODIPY, with 1-dimethylaminonaphthalene () and anthracene moiety (), were the most active against , displaying IC = 4.84 and 5.41 μM, with a 16 and 18-fold selectivity over MRC-5 cells, respectively. In contrast, the mono-formylated analogues and exhibited the highest toxicity (IC = 2.84 and 6.17 μM, respectively) and selectivity (SI = 24 and 11, respectively) against . Further insights on the activity of these compounds were gathered from molecular docking studies. The results suggest that these BODIPYs act as competitive inhibitors targeting the NADPH/NADP linkage site of the pteridine reductase (PR) enzyme. Additionally, these findings unveil a range of quasi-degenerate binding complexes formed between the PRs and the investigated BODIPY derivatives. These results suggest a potential correlation between the anti-parasitic activity and the presence of multiple configurations that block the same site of the enzyme.
Topics: Boron Compounds; Trypanosoma brucei brucei; Humans; Molecular Docking Simulation; Antiprotozoal Agents; Leishmania major; Drug Design; Structure-Activity Relationship; Cell Line; Molecular Structure; Trypanocidal Agents; Oxidoreductases
PubMed: 38731562
DOI: 10.3390/molecules29092072 -
International Journal of Molecular... Aug 2022Leishmaniasis is a neglected tropical disease that kills more than 20,000 people each year. The chemotherapy available for the treatment of the disease is limited, and...
Leishmaniasis is a neglected tropical disease that kills more than 20,000 people each year. The chemotherapy available for the treatment of the disease is limited, and novel approaches to discover novel drugs are urgently needed. Herein, 2D- and 4D-quantitative structure-activity relationship (QSAR) models were developed for a series of oxazole and oxadiazole derivatives that are active against , the causative agent of visceral leishmaniasis. A clustering strategy based on structural similarity was applied with molecular fingerprints to divide the complete set of compounds into two groups. Hierarchical clustering was followed by the development of 2D- ( = 0.90, pred = 0.82) and 4D-QSAR models ( = 0.80, pred = 0.64), which showed improved statistical robustness and predictive ability.
Topics: Antiprotozoal Agents; Cluster Analysis; Humans; Leishmaniasis, Visceral; Oxadiazoles; Oxazoles; Quantitative Structure-Activity Relationship
PubMed: 36012163
DOI: 10.3390/ijms23168898 -
Molecules (Basel, Switzerland) Apr 2022There is a need for new, cost-effective drugs to treat leishmaniasis. A strategy based on traditional medicine practiced in Bolivia led to the discovery of the... (Review)
Review
There is a need for new, cost-effective drugs to treat leishmaniasis. A strategy based on traditional medicine practiced in Bolivia led to the discovery of the 2-substituted quinoline series as a source of molecules with antileishmanial activity and low toxicity. This review documents the development of the series from the first isolated natural compounds through several hundred synthetized molecules to an optimized compound exhibiting an in vitro IC value of 0.2 µM against , and a selectivity index value of 187, together with in vivo activity on the /hamster model. Attempts to establish structure-activity relationships are described, as well as studies that have attempted to determine the mechanism of action. For the latter, it appears that molecules of this series act on multiple targets, possibly including the immune system, which could explain the observed lack of drug resistance after in vitro drug pressure. We also show how nanotechnology strategies could valorize these drugs through adapted formulations and how a mechanistic targeting approach could generate new compounds with increased activity.
Topics: Animals; Antiprotozoal Agents; Cricetinae; Leishmania donovani; Leishmaniasis; Quinolines; Structure-Activity Relationship
PubMed: 35408712
DOI: 10.3390/molecules27072313 -
The Brazilian Journal of Infectious... 2023Leishmaniasis is transmitted by sandfly which carries the intracellular protozoa in their midgut. Among visceral, cutaneous and mucocutaneous leishmaniasis, visceral... (Review)
Review
Leishmaniasis is transmitted by sandfly which carries the intracellular protozoa in their midgut. Among visceral, cutaneous and mucocutaneous leishmaniasis, visceral type that is caused by Leishmania donovani is the most lethal one. Findings of leishmanial structure and species took place in 19 century and was initiated by Donovan. Leishmaniasis is still a major concern of health issues in many endemic countries in Asia, Africa, the Americas, and the Mediterranean region. Worldwide1.5-2 million new cases of cutaneous leishmaniasis and 500,000 cases of visceral leishmaniasis are reported each year. Leishmaniasis is endemic in nearly 90 countries worldwide and close to 12 million new cases of leishmaniasis are reported worldwide annually. Studies on antileishmanial drug development is of major concern as leishmaniasis are the second largest parasitic killer in the world and the available drugs are either toxic or costly. The major surface GP63 protease, also known as Zinc- metalloproteases present on the surface of leishmanial promastigotes, can be targeted for drug development. Protease inhibitors targeting such surface proteases show promising results. Different protease inhibitors have been isolated from marine actinobacteria against many infectious diseases. Metabolites produced by these actinobacteria may have greater importance for the discovery and development of new antileishmanial drugs. Hence, this review discusses the background, current situation, treatment, and protease inhibitors from marine actinobacteria for drug development against GP63 molecules.
Topics: Humans; Leishmaniasis, Visceral; Protease Inhibitors; Leishmania donovani; Leishmaniasis, Cutaneous; Antiprotozoal Agents
PubMed: 36603827
DOI: 10.1016/j.bjid.2022.102739 -
Scientific Reports Oct 2023In this study, six analogs of 2-arylquinoline were synthesized and evaluated for their in vitro and in vivo antiplasmodial and leishmanicidal activity. At a later stage,...
In this study, six analogs of 2-arylquinoline were synthesized and evaluated for their in vitro and in vivo antiplasmodial and leishmanicidal activity. At a later stage, hemolytic activity and druggability were tested in vitro and in silico, respectively, observing as a result: firstly, compounds showed half-maximal effective concentration (EC) values between 3.6 and 19.3 µM. Likewise, a treatment using the compounds 4a-f caused improvement in most of the treated hamsters and cured some of them. Regarding the antiplasmodial activity, the compounds showed moderate to high activity, although they did not show hemolytic activity. Furthermore, 4e and 4f compounds were not able to control P. berghei infection when administered to animal models. Molecular dynamic simulations, molecular docking and ligand binding affinity indicate good characteristics of the studied compounds, which are expected to be active. And lastly, the compounds are absorbable at the hematoencephalic barrier but not in the gastrointestinal tract. In summary, ADMET properties suggest that these molecules may be used as a safe treatment against Leishmania.
Topics: Animals; Antimalarials; Molecular Docking Simulation; Antiprotozoal Agents; Leishmania; Structure-Activity Relationship
PubMed: 37845281
DOI: 10.1038/s41598-023-43805-4 -
Antimicrobial Agents and Chemotherapy Aug 2022Chemotherapy is the key intervention to control visceral leishmaniasis (VL), a neglected tropical disease. Current regimens include not only a few drugs but also present...
Chemotherapy is the key intervention to control visceral leishmaniasis (VL), a neglected tropical disease. Current regimens include not only a few drugs but also present several drawbacks, including moderate to severe toxicity, cost, long-term administration, patient compliance, and growing drug resistance. Thus, the need for better treatment options against VL is a priority. In an endeavor to find an orally active and affordable antileishmanial agent, we evaluated the therapeutic potential of compounds belonging to the (2,2')-3,3'-(ethane-1,2-diylbis(azanediyl))bis(1-(4-halophenyl)-6-hydroxyhex-2-en-1-ones) series, identified as inhibitor(s) of Leishmania donovani dipeptidylcarboxypeptidase, a novel drug target. Among them, compound 3c exhibited best antileishmanial efficacy via both intraperitoneal and oral routes. Therefore, the present study led to the identification of compound 3c as the lead candidate for treating VL.
Topics: Administration, Oral; Antiprotozoal Agents; Drug Resistance; Humans; Leishmania donovani; Leishmaniasis, Visceral
PubMed: 35852367
DOI: 10.1128/aac.02361-21 -
Marine Drugs Mar 2020Neglected Tropical Diseases (NTD) represent a serious threat to humans, especially for those living in poor or developing countries. Almost one-sixth of the world... (Review)
Review
Neglected Tropical Diseases (NTD) represent a serious threat to humans, especially for those living in poor or developing countries. Almost one-sixth of the world population is at risk of suffering from these diseases and many thousands die because of NTDs, to which we should add the sanitary, labor and social issues that hinder the economic development of these countries. Protozoan-borne diseases are responsible for more than one million deaths every year. Visceral leishmaniasis, Chagas disease or sleeping sickness are among the most lethal NTDs. Despite not being considered an NTD by the World Health Organization (WHO), malaria must be added to this sinister group. Malaria, caused by the apicomplexan parasite , is responsible for thousands of deaths each year. The treatment of this disease has been losing effectiveness year after year. Many of the medicines currently in use are obsolete due to their gradual loss of efficacy, their intrinsic toxicity and the emergence of drug resistance or a lack of adherence to treatment. Therefore, there is an urgent and global need for new drugs. Despite this, the scant interest shown by most of the stakeholders involved in the pharmaceutical industry makes our present therapeutic arsenal scarce, and until recently, the search for new drugs has not been seriously addressed. The sources of new drugs for these and other pathologies include natural products, synthetic molecules or repurposing drugs. The most frequent sources of natural products are microorganisms, e.g., bacteria, fungi, yeasts, algae and plants, which are able to synthesize many drugs that are currently in use (e.g. antimicrobials, antitumor, immunosuppressants, etc.). The marine environment is another well-established source of bioactive natural products, with recent applications against parasites, bacteria and other pathogens which affect humans and animals. Drug discovery techniques have rapidly advanced since the beginning of the millennium. The combination of novel techniques that include the genetic modification of pathogens, bioimaging and robotics has given rise to the standardization of High-Performance Screening platforms in the discovery of drugs. These advancements have accelerated the discovery of new chemical entities with antiparasitic effects. This review presents critical updates regarding the use of High-Throughput Screening (HTS) in the discovery of drugs for NTDs transmitted by protozoa, including malaria, and its application in the discovery of new drugs of marine origin.
Topics: Animals; Antiprotozoal Agents; Aquatic Organisms; Biological Products; Drug Discovery; Drug Resistance; Euglenozoa Infections; High-Throughput Screening Assays; Humans; Malaria, Falciparum; Neglected Diseases; Plasmodium falciparum; Plasmodium malariae; Trypanosomatina
PubMed: 32244488
DOI: 10.3390/md18040187