Antiprotozoal Activity of Natural Products

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Plant-Derived Antibiotics".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 17332

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Guest Editor
Chemistry Interdisciplinary Project (CHIP), School of Pharmacy, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy
Interests: medicinal chemistry; small-molecules; essential oils; naturally-occurring compounds; NAD-dependent enzymes; plant secondary metabolites; bioactive-active fractionation; phytochemicals; ethnopharmacology; biological activity of natural compounds
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Special Issue Information

Dear Colleagues,

Neglected tropical diseases (NTDs), caused by protozoan parasites, are the leading cause of morbidity and mortality among the world’s low-income populations. They affect more than 1 billion people worldwide, causing around 500000 deaths each year and social discrimination and physical suffering. Of the 17 major NTDs, the life-threatening diseases Leishmaniasis, Malaria, Chagas disease, and human African Trypanosomiasis (HAT) are considered the most challenging due to their limited therapeutic options and high mortality rates. The absence of eagerly desired vaccines and the availability of limited chemotherapeutics, some with reduced efficacy and considerable drawbacks, hinder the efficient treatment of these diseases. Therefore, the discovery and development of novel effective, safe, and inexpensive antiprotozoal agents remain an urgent need. In this scenario, natural products can play an important role as potential lead compounds as they might have advantages over conventional chemical-based drugs (e.g., fewer drawbacks, better bioavailability, and less long-term toxicity). On this basis, this Special Issue is designed to gather review papers and original articles dealing with the potential antiprotozoal activities of plant secondary metabolites, including different classes such as terpenoids, alkaloids and phenolics. The Special Issue welcomes contributions on the following topics:

  • Phytochemical analysis and biological evaluation (in vitro and/or in vivo studies) of plant extracts/essential oils and isolated compounds.
  • Mode of action studies of natural products.
  • Structure-activity relationships studies including hemi-synthesized molecules.
  • Synergistic and antagonistic studies of mixtures of natural products
  • Development of new anti-protozoal agent formulations

Prof. Dr. Filippo Maggi
Prof. Dr.  Riccardo Petrelli
Guest Editors

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Keywords

  • Botanicals
  • Secondary metabolites
  • Isolation
  • Structural elucidation
  • Anti-protozoal activity

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Published Papers (8 papers)

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Editorial

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5 pages, 215 KiB  
Editorial
Editorial for the Special Issue “Antiprotozoal Activity of Natural Products”
by Cecilia Baldassarri, Eleonora Spinozzi, Marta Ferrati, Paolo Rossi, Filippo Maggi and Riccardo Petrelli
Antibiotics 2023, 12(12), 1650; https://doi.org/10.3390/antibiotics12121650 - 23 Nov 2023
Viewed by 733
Abstract
Neglected tropical diseases (NTDs), a diverse group of infectious diseases, represent the leading cause of morbidity and mortality among the world’s low-income populations [...] Full article
(This article belongs to the Special Issue Antiprotozoal Activity of Natural Products)

Research

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17 pages, 2211 KiB  
Article
Kaurane-Type Diterpenoids as Potential Inhibitors of Dihydrofolate Reductase-Thymidylate Synthase in New World Leishmania Species
by Chonny Herrera-Acevedo, Renata Priscila Barros de Menezes, Natália Ferreira de Sousa, Luciana Scotti, Marcus Tullius Scotti and Ericsson Coy-Barrera
Antibiotics 2023, 12(4), 663; https://doi.org/10.3390/antibiotics12040663 - 28 Mar 2023
Cited by 3 | Viewed by 1266
Abstract
The bifunctional enzyme Dihydrofolate reductase-thymidylate synthase (DHFR-TS) plays a crucial role in the survival of the Leishmania parasite, as folates are essential cofactors for purine and pyrimidine nucleotide biosynthesis. However, DHFR inhibitors are largely ineffective in controlling trypanosomatid infections, largely due to the [...] Read more.
The bifunctional enzyme Dihydrofolate reductase-thymidylate synthase (DHFR-TS) plays a crucial role in the survival of the Leishmania parasite, as folates are essential cofactors for purine and pyrimidine nucleotide biosynthesis. However, DHFR inhibitors are largely ineffective in controlling trypanosomatid infections, largely due to the presence of Pteridine reductase 1 (PTR1). Therefore, the search for structures with dual inhibitory activity against PTR1/DHFR-TS is crucial in the development of new anti-Leishmania chemotherapies. In this research, using the Leishmania major DHFR-TS recombinant protein, enzymatic inhibitory assays were performed on four kauranes and two derivatives that had been previously tested against LmPTR1. The structure 302 (6.3 µM) and its derivative 302a (4.5 µM) showed the lowest IC50 values among the evaluated molecules. To evaluate the mechanism of action of these structures, molecular docking calculations and molecular dynamics simulations were performed using a DHFR-TS hybrid model. Results showed that hydrogen bond interactions are critical for the inhibitory activity against LmDHFR-TS, as well as the presence of the p-hydroxyl group of the phenylpropanoid moiety of 302a. Finally, additional computational studies were performed on DHFR-TS structures from Leishmania species that cause cutaneous and mucocutaneous leishmaniasis in the New World (L. braziliensis, L. panamensis, and L. amazonensis) to explore the targeting potential of these kauranes in these species. It was demonstrated that structures 302 and 302a are multi-Leishmania species compounds with dual DHFR-TS/PTR1 inhibitory activity. Full article
(This article belongs to the Special Issue Antiprotozoal Activity of Natural Products)
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17 pages, 3013 KiB  
Article
Chemical Composition and In Vitro and In Silico Antileishmanial Evaluation of the Essential Oil from Croton linearis Jacq. Stems
by Jesús García-Díaz, Julio César Escalona-Arranz, Ania Ochoa-Pacheco, Sócrates Golzio Dos Santos, Rosalia González-Fernández, Julio Alberto Rojas-Vargas, Lianet Monzote and William N. Setzer
Antibiotics 2022, 11(12), 1712; https://doi.org/10.3390/antibiotics11121712 - 28 Nov 2022
Cited by 2 | Viewed by 1579
Abstract
Croton linearis Jacq. is an aromatic shrub that has been utilized in traditional medicine in the Bahamas, Jamaica, and Cuba. Recent studies have revealed the antiprotozoal potential of its leaves. The present work is aimed to identify the volatile constituents of essential oil [...] Read more.
Croton linearis Jacq. is an aromatic shrub that has been utilized in traditional medicine in the Bahamas, Jamaica, and Cuba. Recent studies have revealed the antiprotozoal potential of its leaves. The present work is aimed to identify the volatile constituents of essential oil from the stems of C. linearis (CLS-EO) and evaluate its in vitro antileishmanial activity. In addition, an in silico study of the molecular interactions was performed using molecular docking. A gas chromatographic–mass spectrometric analysis of CLS-EO identified 1,8-cineole (27.8%), α-pinene (11.1%), cis-sabinene (8.1%), p-cymene (5.7%), α-terpineol (4.4%), epi-γ-eudesmol (4.2%), linalool (3.9%), and terpinen-4-ol (2.6%) as major constituents. The evaluation of antileishmanial activity showed that CLS-EO has good activity on both parasite forms (IC50Promastigote = 21.4 ± 0.1 μg/mL; IC50Amastigote = 18.9 ± 0.3 μg/mL), with a CC50 of 49.0 ± 5.0 μg/mL on peritoneal macrophages from BALB/c mice (selectivity index = 2 and 3 using the promastigote and amastigote results). Molecular docking showed good binding of epi-γ-eudesmol with different target enzymes of Leishmania. This study is the first report of the chemical composition and anti-Leishmania evaluation of CLS-EO. These findings provide support for further studies of the antileishmanial effect of this product. Full article
(This article belongs to the Special Issue Antiprotozoal Activity of Natural Products)
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15 pages, 6626 KiB  
Article
Antiprotozoal Activity of Thymoquinone (2-Isopropyl-5-methyl-1,4-benzoquinone) for the Treatment of Leishmania major-Induced Leishmaniasis: In Silico and In Vitro Studies
by Kamal A. Qureshi, Mahrukh Imtiaz, Ibrahim Al Nasr, Waleed S. Koko, Tariq A. Khan, Mariusz Jaremko, Syed Mahmood and M. Qaiser Fatmi
Antibiotics 2022, 11(9), 1206; https://doi.org/10.3390/antibiotics11091206 - 06 Sep 2022
Cited by 6 | Viewed by 1562
Abstract
Leishmaniasis, a neglected tropical parasitic disease (NTPD), is caused by various Leishmania species. It transmits through the bites of the sandfly. The parasite is evolving resistance to commonly prescribed antileishmanial drugs; thus, there is an urgent need to discover novel antileishmanial drugs to [...] Read more.
Leishmaniasis, a neglected tropical parasitic disease (NTPD), is caused by various Leishmania species. It transmits through the bites of the sandfly. The parasite is evolving resistance to commonly prescribed antileishmanial drugs; thus, there is an urgent need to discover novel antileishmanial drugs to combat drug-resistant leishmaniasis. Thymoquinone (2-isopropyl-5-methyl-1,4-benzoquinone; TQ), a primary pharmacologically active ingredient of Nigella sativa (black seed) essential oil, has been reported to possess significant antiparasitic activity. Therefore, the present study was designed to investigate the in vitro and in silico antileishmanial activity of TQ against various infectious stages of Leishmania major (L. major), i.e., promastigotes and amastigotes, and its cytotoxicity against mice macrophages. In silico molecular dockings of TQ were also performed with multiple selected target proteins of L. major, and the most preferred antileishmanial drug target protein was subjected to in silico molecular dynamics (MD) simulation. The in vitro antileishmanial activity of TQ revealed that the half-maximal effective concentration (EC50), half-maximal cytotoxic concentration (CC50), and selectivity index (SI) values for promastigotes are 2.62 ± 0.12 μM, 29.54 ± 0.07 μM, and 11.27, while for the amastigotes, they are 17.52 ± 0.15 μM, 29.54 ± 0.07 μM, and 1.69, respectively. The molecular docking studies revealed that squalene monooxygenase is the most preferred antileishmanial drug target protein for TQ, whereas triosephosphate isomerase is the least preferred. The MD simulation revealed that TQ remained stable in the binding pocket throughout the simulation. Additionally, the binding energy calculations using Molecular Mechanics Generalized-Born Surface Area (MMGBSA) indicated that TQ is a moderate binder. Thus, the current study shows that TQ is a promising antileishmanial drug candidate that could be used to treat existing drug-resistant leishmaniasis. Full article
(This article belongs to the Special Issue Antiprotozoal Activity of Natural Products)
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17 pages, 349 KiB  
Article
Novel Formula of Antiprotozoal Mixtures
by Hubert Iwiński, Jacek Łyczko, Henryk Różański and Antoni Szumny
Antibiotics 2022, 11(7), 913; https://doi.org/10.3390/antibiotics11070913 - 07 Jul 2022
Cited by 2 | Viewed by 1596
Abstract
Antimicrobial resistance (AMR) is becoming more common in both bacteria and pathogenic protozoa. Therefore, new solutions are being sought as alternatives to currently used agents. There are many new ideas and solutions, especially compounds of natural origin, including essential oils. In the present [...] Read more.
Antimicrobial resistance (AMR) is becoming more common in both bacteria and pathogenic protozoa. Therefore, new solutions are being sought as alternatives to currently used agents. There are many new ideas and solutions, especially compounds of natural origin, including essential oils. In the present study, the antiprotozoal activity of a mixture of essential oils (eucalyptus, lavender, cedar and tea tree), organic acids (acetic acid, propionic acid and lactic acid) and metal ions (Cu, Zn, Mn) were tested. As a model, protozoans were selected: Euglena gracilis, Gregarina blattarum, Amoeba proteus, Paramecium caudatum, Pentatrichomonas hominis. The tested concentrations of mixtures were in the range of 0.001–1.5%. The analyses show unexpected, very strong protozoicidal activity of combinations, presenting the synergy of compounds via determination of LD50 and LD100 values. Obtained mixtures showed significantly higher activity against protozoans, compared to chloramphenicol and metronidazole. Most of the analyzed samples show high antiprotozoal activity at very low concentration, in the range of 0.001–0.009%. The most effective combinations for all analyzed protozoans were the cedar essential oil and tea tree essential oil with a mixture of acids and manganese or zinc ions. Innovative combinations of essential oils, organic acids and metal ions are characterized by very high antiprotozoal activity at low doses, which, after further investigation, can be applicable for control of protozoan pathogens. Full article
(This article belongs to the Special Issue Antiprotozoal Activity of Natural Products)
16 pages, 1625 KiB  
Article
Antitrypanosomal Activity of Anthriscus Nemorosa Essential Oils and Combinations of Their Main Constituents
by Cecilia Baldassarri, Giulia Falappa, Eugenia Mazzara, Laura Acquaticci, Elena Ossoli, Diego Romano Perinelli, Giulia Bonacucina, Stefano Dall’Acqua, Loredana Cappellacci, Filippo Maggi, Farahnaz Ranjbarian, Anders Hofer and Riccardo Petrelli
Antibiotics 2021, 10(11), 1413; https://doi.org/10.3390/antibiotics10111413 - 18 Nov 2021
Cited by 5 | Viewed by 1755
Abstract
This study aimed to investigate the susceptibility of Trypanosoma brucei to the Anthriscus nemorosa essential oils (EOs), isolated compounds from these oils, and artificial mixtures of the isolated compounds in their conventional and nanoencapsulated forms. The chemical composition of the essential oils from [...] Read more.
This study aimed to investigate the susceptibility of Trypanosoma brucei to the Anthriscus nemorosa essential oils (EOs), isolated compounds from these oils, and artificial mixtures of the isolated compounds in their conventional and nanoencapsulated forms. The chemical composition of the essential oils from the aerial parts and roots of Anthriscus nemorosa, obtained from a wild population growing in central Italy, were analyzed by gas chromatography/mass spectrometry (GC/MS). In both cases, the predominant class of compounds was monoterpene hydrocarbons, which were more abundant in the EOs from the roots (81.5%) than the aerial parts (74.0%). The overall results of this work have shed light on the biological properties of A. nemorosa EO from aerial parts (EC50 = 1.17 μg/mL), farnesene (EC50 = 0.84 μg/mL), and artificial mixtures (Mix 3–5, EC50 in the range of 1.27 to 1.58 μg/mL) as relevant sources of antiprotozoal substances. Furthermore, the pool measurements of ADP (adenosine diphosphate) and NTPs (nucleoside triphosphates) in the cultivated bloodstream form of trypanosomes exposed to different concentrations of EOs showed a disturbed energy metabolism, as indicated by increased pools of ADP in comparison to ATP (adenosine triphosphate) and other NTPs. Ultimately, this study highlights the significant efficacy of A. nemorosa EO to develop long-lasting and effective antiprotozoal formulations, including nanoemulsions. Full article
(This article belongs to the Special Issue Antiprotozoal Activity of Natural Products)
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21 pages, 1036 KiB  
Article
Antiprotozoal Nor-Triterpene Alkaloids from Buxus sempervirens L.
by Lara U. Szabó, Marcel Kaiser, Pascal Mäser and Thomas J. Schmidt
Antibiotics 2021, 10(6), 696; https://doi.org/10.3390/antibiotics10060696 - 10 Jun 2021
Cited by 8 | Viewed by 2155
Abstract
Malaria and human African trypanosomiasis (HAT; sleeping sickness) are life-threatening tropical diseases caused by protozoan parasites. Due to limited therapeutic options, there is a compelling need for new antiprotozoal agents. In a previous study, O-tigloylcyclovirobuxeine-B was recovered from a B. sempervirens L. [...] Read more.
Malaria and human African trypanosomiasis (HAT; sleeping sickness) are life-threatening tropical diseases caused by protozoan parasites. Due to limited therapeutic options, there is a compelling need for new antiprotozoal agents. In a previous study, O-tigloylcyclovirobuxeine-B was recovered from a B. sempervirens L. (common box; Buxaceae) leaf extract by bioactivity-guided isolation. This nor-cycloartane alkaloid was identified as possessing strong and selective in vitro activity against the causative agent of malaria tropica, Plasmodium falciparum (Pf). The purpose of this study is the isolation of additional alkaloids from B. sempervirens L. to search for further related compounds with strong antiprotozoal activity. In conclusion, 25 alkaloids were obtained from B. sempervirens L., including eight new natural products and one compound first described for this plant. The structure elucidation was accomplished by UHPLC/+ESI-QqTOF-MS/MS and NMR spectroscopy. The isolated alkaloids were tested against Pf and Trypanosoma brucei rhodesiense (Tbr), the causative agent of East African sleeping sickness. To assess their selectivity, cytotoxicity against mammalian cells (L6 cell line) was tested as well. Several of the compounds displayed promising in vitro activity against the pathogens in a sub-micromolar range with concurrent high selectivity indices (SI). Consequently, various alkaloids from B. sempervirens L. have the potential to serve as a novel antiprotozoal lead structure. Full article
(This article belongs to the Special Issue Antiprotozoal Activity of Natural Products)
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Review

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16 pages, 1671 KiB  
Review
Next-Generation Human Liver Models for Antimalarial Drug Assays
by Kasem Kulkeaw
Antibiotics 2021, 10(6), 642; https://doi.org/10.3390/antibiotics10060642 - 27 May 2021
Cited by 7 | Viewed by 5124
Abstract
Advances in malaria prevention and treatment have significantly reduced the related morbidity and mortality worldwide, however, malaria continues to be a major threat to global public health. Because Plasmodium parasites reside in the liver prior to the appearance of clinical manifestations caused by [...] Read more.
Advances in malaria prevention and treatment have significantly reduced the related morbidity and mortality worldwide, however, malaria continues to be a major threat to global public health. Because Plasmodium parasites reside in the liver prior to the appearance of clinical manifestations caused by intraerythrocytic development, the Plasmodium liver stage represents a vulnerable therapeutic target to prevent progression. Currently, a small number of drugs targeting liver-stage parasites are available, but all cause lethal side effects in glucose-6-phosphate dehydrogenase-deficient individuals, emphasizing the necessity for new drug development. Nevertheless, a longstanding hurdle to developing new drugs is the availability of appropriate in vitro cultures, the crucial conventional platform for evaluating the efficacy and toxicity of drugs in the preclinical phase. Most current cell culture systems rely primarily on growing immortalized or cancerous cells in the form of a two-dimensional monolayer, which is not very physiologically relevant to the complex cellular architecture of the human body. Although primary human cells are more relevant to human physiology, they are mainly hindered by batch-to-batch variation, limited supplies, and ethical issues. Advances in stem cell technologies and multidimensional culture have allowed the modelling of human infectious diseases. Here, current in vitro hepatic models and toolboxes for assaying the antimalarial drug activity are summarized. Given the physiological potential of pluripotent and adult stem cells to model liver-stage malaria, the opportunities and challenges in drug development against liver-stage malaria is highlighted, paving the way to assess the efficacy of hepatic plasmodicidal activity. Full article
(This article belongs to the Special Issue Antiprotozoal Activity of Natural Products)
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