Editorial

5 pages, 215 KiB

Open AccessEditorial

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://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics12121650 - 23 Nov 2023

Viewed by 738

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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics12040663 - 28 Mar 2023

Cited by 3 | Viewed by 1275

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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11121712 - 28 Nov 2022

Cited by 2 | Viewed by 1588

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 (IC_{50Promastigote} = 21.4 ± 0.1 μg/mL; IC_50Amastigote = 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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11091206 - 06 Sep 2022

Cited by 6 | Viewed by 1569

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

Open AccessArticle

Novel Formula of Antiprotozoal Mixtures

by Hubert Iwiński, Jacek Łyczko, Henryk Różański and Antoni Szumny

Antibiotics 2022, 11(7), 913; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11070913 - 07 Jul 2022

Cited by 2 | Viewed by 1607

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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10111413 - 18 Nov 2021

Cited by 5 | Viewed by 1763

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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10060696 - 10 Jun 2021

Cited by 8 | Viewed by 2165

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

Open AccessReview

Next-Generation Human Liver Models for Antimalarial Drug Assays

by Kasem Kulkeaw

Antibiotics 2021, 10(6), 642; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10060642 - 27 May 2021

Cited by 7 | Viewed by 5132

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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