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21 pages, 1626 KiB

Open AccessArticle

Synthesis and Evaluation of Biological Activities of Bis(spiropyrazolone)cyclopropanes: A Potential Application against Leishmaniasis

by Olalla Barreiro-Costa, Gabriela Morales-Noboa, Patricio Rojas-Silva, Eliana Lara-Barba, Javier Santamaría-Aguirre, Natalia Bailón-Moscoso, Juan Carlos Romero-Benavides, Ana Herrera, Cristina Cueva, Lenin Ron-Garrido, Ana Poveda and Jorge Heredia-Moya

Molecules 2021, 26(16), 4960; https://doi.org/10.3390/molecules26164960 - 17 Aug 2021

Cited by 5 | Viewed by 6658

Abstract

This work focuses on the search and development of drugs that may become new alternatives to the commercial drugs currently available for treatment of leishmaniasis. We have designed and synthesized 12 derivatives of bis(spiropyrazolone)cyclopropanes. We then characterized their potential application in therapeutic use. [...] Read more.

This work focuses on the search and development of drugs that may become new alternatives to the commercial drugs currently available for treatment of leishmaniasis. We have designed and synthesized 12 derivatives of bis(spiropyrazolone)cyclopropanes. We then characterized their potential application in therapeutic use. For this, the in vitro biological activities against three eukaryotic models—S. cerevisiae, five cancer cell lines, and the parasite L. mexicana—were evaluated. In addition, cytotoxicity against non-cancerous mammalian cells has been evaluated and other properties of interest have been characterized, such as genotoxicity, antioxidant properties and, in silico predictive adsorption, distribution, metabolism, and excretion (ADME). The results that we present here represent a first screening, indicating two derivatives of bis(spiropyrazolone)cyclopropanes as good candidates for the treatment of leishmaniasis. They have good specificity against parasites with respect to mammalian cells. Full article

(This article belongs to the Special Issue Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology)

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37 pages, 7798 KiB

Open AccessArticle

Design, Synthesis and Antiparasitic Evaluation of Click Phospholipids

by George E. Magoulas, Pantelis Afroudakis, Kalliopi Georgikopoulou, Marina Roussaki, Chiara Borsari, Theano Fotopoulou, Nuno Santarem, Emile Barrias, Paloma Tejera Nevado, Julia Hachenberg, Eugenia Bifeld, Bernhard Ellinger, Maria Kuzikov, Irini Fragiadaki, Effie Scoulica, Joachim Clos, Sheraz Gul, Maria Paola Costi, Wanderley de Souza, Kyriakos C. Prousis, Anabela Cordeiro da Silva and Theodora Calogeropoulou Show full author list Hide full author list

Molecules 2021, 26(14), 4204; https://doi.org/10.3390/molecules26144204 - 10 Jul 2021

Cited by 3 | Viewed by 3094

Abstract

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania [...] Read more.

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure–activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative 27 substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC₅₀) against THP-1 macrophages ranged between 50 and 100 μM. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases. Full article

(This article belongs to the Special Issue Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology)

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12 pages, 1048 KiB

Open AccessArticle

Synthesis and In Vitro Antiprotozoan Evaluation of 4-/8-Aminoquinoline-based Lactams and Tetrazoles

by Matshawandile Tukulula, Stefan Louw, Mathew Njoroge and Kelly Chibale

Molecules 2020, 25(24), 5941; https://doi.org/10.3390/molecules25245941 - 15 Dec 2020

Cited by 3 | Viewed by 1761

Abstract

A second generation of 4-aminoquinoline- and 8-aminoquinoline-based tetrazoles and lactams were synthesized via the Staudinger and Ugi multicomponent reactions. These compounds were subsequently evaluated in vitro for their potential antiplasmodium activity against a multidrug-resistant K1 strain and for their antitrypanosomal activity against a [...] Read more.

A second generation of 4-aminoquinoline- and 8-aminoquinoline-based tetrazoles and lactams were synthesized via the Staudinger and Ugi multicomponent reactions. These compounds were subsequently evaluated in vitro for their potential antiplasmodium activity against a multidrug-resistant K1 strain and for their antitrypanosomal activity against a cultured T. b. rhodesiense STIB900 strain. Several of these compounds (4a–g) displayed good antiplasmodium activities (IC₅₀ = 0.20–0.62 µM) that were comparable to the reference drugs, while their antitrypanosomal activity was moderate (<20 µM). Compound 4e was 2-fold more active than primaquine and was also the most active (IC₅₀ = 7.01 µM) against T. b. rhodesiense and also exhibited excellent aqueous solubility (>200 µM) at pH 7. Full article

(This article belongs to the Special Issue Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology)

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18 pages, 1434 KiB

Open AccessArticle

Nucleotides and AHCC Enhance Th1 Responses In Vitro in Leishmania-Stimulated/Infected Murine Cells

by María Auxiliadora Dea-Ayuela, Sergi Segarra, Dolores R. Serrano and Francisco Bolás-Fernández

Molecules 2020, 25(17), 3918; https://doi.org/10.3390/molecules25173918 - 27 Aug 2020

Cited by 3 | Viewed by 3257

Abstract

A stronger Th1 (cellular) immune response in canine leishmaniosis (CanL) leads to a better prognosis. Dietary nucleotides plus AHCC^® have shown beneficial effects in dogs with clinical leishmaniosis and in clinically healthy Leishmania-infected dogs. The potential leishmanicidal activity of nucleotides and [...] Read more.

A stronger Th1 (cellular) immune response in canine leishmaniosis (CanL) leads to a better prognosis. Dietary nucleotides plus AHCC^® have shown beneficial effects in dogs with clinical leishmaniosis and in clinically healthy Leishmania-infected dogs. The potential leishmanicidal activity of nucleotides and AHCC was assessed by quantifying nitric oxide (NO) production and replication of parasites. Their effects on lymphocyte proliferation were studied with and without soluble Leishmania infantum antigen (SLA) stimulation. Cytokine level variations were assessed using naïve and L. infantum-infected macrophages/lymphocytes cocultures. Promastigotes and amastigotes proliferation and NO macrophage production were not directly affected. Lymphocyte proliferation was significantly enhanced by nucleotides, AHCC, and their combinations only after SLA stimulation. Nucleotides and AHCC significantly increased the production of IL-1β, IL-2, IL-5, IL-9, IL-10, and IL-12 by naïve immune cells. In naïve and L. infantum-infected macrophage/lymphocyte cocultures, nucleotides with or without AHCC led to significant increases in IFN-γ and TNF-α. Given that these cytokines are involved in the effective Th1 immune response against Leishmania parasites, these mechanisms of action could explain the previously reported in vivo clinical efficacy of such combination and further support the use of nucleotides with or without AHCC in the management of CanL patients. Full article

(This article belongs to the Special Issue Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology)

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16 pages, 1421 KiB

Open AccessArticle

Synthesis, Structure and In Vitro Anti-Trypanosomal Activity of Non-Toxic Arylpyrrole-Based Chalcone Derivatives

by Ayanda I. Zulu, Ogunyemi O. Oderinlo, Cuan Kruger, Michelle Isaacs, Heinrich C. Hoppe, Vincent J. Smith, Clinton G. L. Veale and Setshaba D. Khanye

Molecules 2020, 25(7), 1668; https://doi.org/10.3390/molecules25071668 - 04 Apr 2020

Cited by 14 | Viewed by 3578

Abstract

With an intention of identifying chalcone derivatives exhibiting anti-protozoal activity, a cohort of relatively unexplored arylpyrrole-based chalcone derivatives were synthesized in moderate to good yields. The resultant compounds were evaluated in vitro for their potential activity against a cultured Trypanosoma brucei brucei 427 [...] Read more.

With an intention of identifying chalcone derivatives exhibiting anti-protozoal activity, a cohort of relatively unexplored arylpyrrole-based chalcone derivatives were synthesized in moderate to good yields. The resultant compounds were evaluated in vitro for their potential activity against a cultured Trypanosoma brucei brucei 427 strain. Several compounds displayed mostly modest in vitro anti-trypanosomal activity with compounds 10e and 10h emerging as active candidates with IC₅₀ values of 4.09 and 5.11 µM, respectively. More importantly, a concomitant assessment of their activity against a human cervix adenocarcinoma (HeLa) cell line revealed that these compounds are non-toxic. Full article

(This article belongs to the Special Issue Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology)

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22 pages, 3313 KiB

Open AccessArticle

Synthesis and Evaluation of Antileishmanial and Cytotoxic Activity of Benzothiopyrane Derivatives

by Cristian Ortiz, Fernando Echeverri, Sara Robledo, Daniela Lanari, Massimo Curini, Wiston Quiñones and Esteban Vargas

Molecules 2020, 25(4), 800; https://doi.org/10.3390/molecules25040800 - 12 Feb 2020

Cited by 8 | Viewed by 3773

Abstract

In continuation of our efforts to identify promising antileishmanial agents based on the chroman scaffold, we synthesized several substituted 2H-thiochroman derivatives, including thiochromenes, thichromanones and hydrazones substituted in C-2 or C-3 with carbonyl or carboxyl groups. Thirty-two compounds were thus obtained, characterized, [...] Read more.

In continuation of our efforts to identify promising antileishmanial agents based on the chroman scaffold, we synthesized several substituted 2H-thiochroman derivatives, including thiochromenes, thichromanones and hydrazones substituted in C-2 or C-3 with carbonyl or carboxyl groups. Thirty-two compounds were thus obtained, characterized, and evaluated against intracellular amastigotes of Leishmania (V) panamensis. Twelve compounds were active, with EC₅₀ values lower than 40 µM, but only four compounds displayed the highest antileishmanial activity, with EC₅₀ values below 10 µM; these all compounds possess a good Selectivity Index > 2.6. Although two active compounds were thiochromenes, a clear structure-activity relationship was not detected since each active compound has a different substitution pattern. Full article

(This article belongs to the Special Issue Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology)

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16 pages, 1319 KiB

Open AccessArticle

Trypanocidal Activity of Flavanone Derivatives

by Gabriela Maciel Diogo, Josimara Souza Andrade, Policarpo Ademar Sales Junior, Silvane Maria Fonseca Murta, Viviane Martins Rebello Dos Santos and Jason Guy Taylor

Molecules 2020, 25(2), 397; https://doi.org/10.3390/molecules25020397 - 17 Jan 2020

Cited by 16 | Viewed by 2949

Abstract

Chagas disease, also known as American trypanosomiasis, is classified as a neglected disease by the World Health Organization. For clinical treatment, only two drugs have been on the market, Benznidazole and Nifurtimox, both of which are recommended for use in the acute phase [...] Read more.

Chagas disease, also known as American trypanosomiasis, is classified as a neglected disease by the World Health Organization. For clinical treatment, only two drugs have been on the market, Benznidazole and Nifurtimox, both of which are recommended for use in the acute phase but present low cure rates in the chronic phase. Furthermore, strong side effects may result in discontinuation of this treatment. Faced with this situation, we report the synthesis and trypanocidal activity of 3-benzoyl-flavanones. Novel 3-benzoyl-flavanone derivatives were prepared in satisfactory yields in the 3-step synthetic procedure. According to recommended guidelines, the whole cell-based screening methodology was utilized that allowed for the simultaneous use of both parasite forms responsible for human infection. The majority of the tested compounds displayed promising anti-Trypanosoma cruzi activity and the most potent flavanone bearing a nitrofuran moiety was more potent than the reference drug, Benznidazole. Full article

(This article belongs to the Special Issue Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology)

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Review

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41 pages, 14641 KiB

Open AccessReview

An Overview on Target-Based Drug Design against Kinetoplastid Protozoan Infections: Human African Trypanosomiasis, Chagas Disease and Leishmaniases

by Violeta Kourbeli, Eleni Chontzopoulou, Kalliopi Moschovou, Dimitrios Pavlos, Thomas Mavromoustakos and Ioannis P. Papanastasiou

Molecules 2021, 26(15), 4629; https://doi.org/10.3390/molecules26154629 - 30 Jul 2021

Cited by 46 | Viewed by 4504

Abstract

The protozoan diseases Human African Trypanosomiasis (HAT), Chagas disease (CD), and leishmaniases span worldwide and therefore their impact is a universal concern. The present regimen against kinetoplastid protozoan infections is poor and insufficient. Target-based design expands the horizon of drug design and development [...] Read more.

The protozoan diseases Human African Trypanosomiasis (HAT), Chagas disease (CD), and leishmaniases span worldwide and therefore their impact is a universal concern. The present regimen against kinetoplastid protozoan infections is poor and insufficient. Target-based design expands the horizon of drug design and development and offers novel chemical entities and potential drug candidates to the therapeutic arsenal against the aforementioned neglected diseases. In this review, we report the most promising targets of the main kinetoplastid parasites, as well as their corresponding inhibitors. This overview is part of the Special Issue, entitled “Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology”. Full article

(This article belongs to the Special Issue Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology)

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14 pages, 1887 KiB

Open AccessReview

Challenges in Chagas Disease Drug Development

by Amanda F. Francisco, Shiromani Jayawardhana, Francisco Olmo, Michael D. Lewis, Shane R. Wilkinson, Martin C. Taylor and John M. Kelly

Molecules 2020, 25(12), 2799; https://doi.org/10.3390/molecules25122799 - 17 Jun 2020

Cited by 29 | Viewed by 4686

Abstract

The protozoan parasite Trypanosoma cruzi causes Chagas disease, an important public health problem throughout Latin America. Current therapeutic options are characterised by limited efficacy, long treatment regimens and frequent toxic side-effects. Advances in this area have been compromised by gaps in our knowledge [...] Read more.

The protozoan parasite Trypanosoma cruzi causes Chagas disease, an important public health problem throughout Latin America. Current therapeutic options are characterised by limited efficacy, long treatment regimens and frequent toxic side-effects. Advances in this area have been compromised by gaps in our knowledge of disease pathogenesis, parasite biology and drug activity. Nevertheless, several factors have come together to create a more optimistic scenario. Drug-based research has become more systematic, with increased collaborations between the academic and commercial sectors, often within the framework of not-for-profit consortia. High-throughput screening of compound libraries is being widely applied, and new technical advances are helping to streamline the drug development pipeline. In addition, drug repurposing and optimisation of current treatment regimens, informed by laboratory research, are providing a basis for new clinical trials. Here, we will provide an overview of the current status of Chagas disease drug development, highlight those areas where progress can be expected, and describe how fundamental research is helping to underpin the process. Full article

(This article belongs to the Special Issue Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology)

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