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17 pages, 2506 KiB

Open AccessArticle

Phenotypic Evaluation of Nucleoside Analogues against Trypanosoma cruzi Infection: In Vitro and In Vivo Approaches

by Ludmila F. de A. Fiuza, Denise G. J. Batista, Roberson D. Girão, Fabian Hulpia, Paula Finamore-Araújo, Mustafa M. Aldfer, Ehab Kotb Elmahallawy, Harry P. De Koning, Otacílio Moreira, Serge Van Calenbergh and Maria de Nazaré C. Soeiro

Molecules 2022, 27(22), 8087; https://doi.org/10.3390/molecules27228087 - 21 Nov 2022

Cited by 6 | Viewed by 1662

Abstract

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is a serious public health problem. Current treatment is restricted to two drugs, benznidazole and nifurtimox, displaying serious efficacy and safety drawbacks. Nucleoside analogues represent a promising alternative as protozoans do not biosynthesize [...] Read more.

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is a serious public health problem. Current treatment is restricted to two drugs, benznidazole and nifurtimox, displaying serious efficacy and safety drawbacks. Nucleoside analogues represent a promising alternative as protozoans do not biosynthesize purines and rely on purine salvage from the hosts. Protozoan transporters often present different substrate specificities from mammalian transporters, justifying the exploration of nucleoside analogues as therapeutic agents. Previous reports identified nucleosides with potent trypanocidal activity; therefore, two 7-derivatized tubercidins (FH11706, FH10714) and a 3′-deoxytubercidin (FH8513) were assayed against T. cruzi. They were highly potent and selective, and the uptake of the tubercidin analogues appeared to be mediated by the nucleoside transporter TcrNT2. At 10 μM, the analogues reduced parasitemia >90% in 2D and 3D cardiac cultures. The washout assays showed that FH10714 sterilized the infected cultures. Given orally, the compounds did not induce noticeable mouse toxicity (50 mg/kg), suppressed the parasitemia of T. cruzi-infected Swiss mice (25 mg/kg, 5 days) and presented DNA amplification below the limit of detection. These findings justify further studies with longer treatment regimens, as well as evaluations in combination with nitro drugs, aiming to identify more effective and safer therapies for Chagas disease. Full article

(This article belongs to the Special Issue Medicinal Chemistry Studies of Neglected Diseases)

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24 pages, 6697 KiB

Open AccessArticle

The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2′-Deoxyuridine and Tubercidin Analogues

by Mustafa M. Aldfer, Ibrahim A. Alfayez, Hamza A. A. Elati, Nilanjana Gayen, Ehab Kotb Elmahallawy, Ana Milena Murillo, Sabrina Marsiccobetre, Serge Van Calenbergh, Ariel M. Silber and Harry P. de Koning

Molecules 2022, 27(22), 8045; https://doi.org/10.3390/molecules27228045 - 19 Nov 2022

Cited by 3 | Viewed by 1429

Abstract

Among the scarce validated drug targets against Chagas disease (CD), caused by Trypanosoma cruzi, the parasite’s nucleoside salvage system has recently attracted considerable attention. Although the trypanocidal activity of tubercidin (7-deazapurine) has long been known, the identification of a class of 7-substituted [...] Read more.

Among the scarce validated drug targets against Chagas disease (CD), caused by Trypanosoma cruzi, the parasite’s nucleoside salvage system has recently attracted considerable attention. Although the trypanocidal activity of tubercidin (7-deazapurine) has long been known, the identification of a class of 7-substituted tubercidin analogs with potent in vitro and in vivo activity and much-enhanced selectivity has made nucleoside analogs among the most promising lead compounds against CD. Here, we investigate the recently identified TcrNT2 nucleoside transporter and its potential role in antimetabolite chemotherapy. TcrNT2, expressed in a Leishmania mexicana cell line lacking the NT1 nucleoside transporter locus, displayed very high selectivity and affinity for thymidine with a K_m of 0.26 ± 0.05 µM. The selectivity was explained by interactions of 2-oxo, 4-oxo, 5-Me, 3′-hydroxy and 5′-hydroxy with the transporter binding pocket, whereas a hydroxy group at the 2′ position was deleterious to binding. This made 5-halogenated 2′-deoxyuridine analogues good substrates but 5-F-2′-deoxyuridine displayed disappointing activity against T. cruzi trypomastigotes. By comparing the EC₅₀ values of tubercidin and its 7-substituted analogues against L. mexicana Cas9, Cas9^ΔNT1 and Cas9^ΔNT1+TcrNT2 it was shown that TcrNT2 can take up tubercidin and, at a minimum, a subset of the analogs. Full article

(This article belongs to the Special Issue Medicinal Chemistry Studies of Neglected Diseases)

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16 pages, 14690 KiB

Open AccessArticle

Efficient Oxidative Dearomatisations of Substituted Phenols Using Hypervalent Iodine (III) Reagents and Antiprotozoal Evaluation of the Resulting Cyclohexadienones against T. b. rhodesiense and P. falciparum Strain NF54

by Nina Scheiber, Gregor Blaser, Eva-Maria Pferschy-Wenzig, Marcel Kaiser, Pascal Mäser and Armin Presser

Molecules 2022, 27(19), 6559; https://doi.org/10.3390/molecules27196559 - 04 Oct 2022

Viewed by 1454

Abstract

Quinones and quinols are secondary metabolites of higher plants that are associated with many biological activities. The oxidative dearomatization of phenols induced by hypervalent iodine(III) reagents has proven to be a very useful synthetic approach for the preparation of these compounds, which are [...] Read more.

Quinones and quinols are secondary metabolites of higher plants that are associated with many biological activities. The oxidative dearomatization of phenols induced by hypervalent iodine(III) reagents has proven to be a very useful synthetic approach for the preparation of these compounds, which are also widely used in organic synthesis and medicinal chemistry. Starting from several substituted phenols and naphthols, a series of cyclohexadienone and naphthoquinone derivatives were synthesized using different hypervalent iodine(III) reagents and evaluated for their in vitro antiprotozoal activity. Antiprotozoal activity was assessed against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. We found that benzyl naphthoquinone 5c was the most active and selective molecule against T. brucei rhodesiense (IC₅₀ = 0.08 μM, SI = 275). Furthermore, the antiprotozoal assays revealed no specific effects. In addition, some key physicochemical parameters of the synthesised compounds were calculated. Full article

(This article belongs to the Special Issue Medicinal Chemistry Studies of Neglected Diseases)

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21 pages, 2820 KiB

Open AccessArticle

Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis

by Santo Previti, Roberta Ettari, Carla Di Chio, Rahul Ravichandran, Marta Bogacz, Ute A. Hellmich, Tanja Schirmeister, Sandro Cosconati and Maria Zappalà

Molecules 2022, 27(12), 3765; https://doi.org/10.3390/molecules27123765 - 11 Jun 2022

Cited by 8 | Viewed by 1864

Abstract

Human African Trypanosomiasis (HAT) is an endemic protozoan disease widespread in the sub-Saharan region that is caused by T. b. gambiense and T. b. rhodesiense. The development of molecules targeting rhodesain, the main cysteine protease of T. b. rhodesiense, has led [...] Read more.

Human African Trypanosomiasis (HAT) is an endemic protozoan disease widespread in the sub-Saharan region that is caused by T. b. gambiense and T. b. rhodesiense. The development of molecules targeting rhodesain, the main cysteine protease of T. b. rhodesiense, has led to a panel of inhibitors endowed with micro/sub-micromolar activity towards the protozoa. However, whilst impressive binding affinity against rhodesain has been observed, the limited selectivity towards the target still remains a hard challenge for the development of antitrypanosomal agents. In this paper, we report the synthesis, biological evaluation, as well as docking studies of a series of reduced peptide bond pseudopeptide Michael acceptors (SPR10–SPR19) as potential anti-HAT agents. The new molecules show K_i values in the low-micro/sub-micromolar range against rhodesain, coupled with k_2nd values between 1314 and 6950 M⁻¹ min⁻¹. With a few exceptions, an appreciable selectivity over human cathepsin L was observed. In in vitro assays against T. b. brucei cultures, SPR16 and SPR18 exhibited single-digit micromolar activity against the protozoa, comparable to those reported for very potent rhodesain inhibitors, while no significant cytotoxicity up to 70 µM towards mammalian cells was observed. The discrepancy between rhodesain inhibition and the antitrypanosomal effect could suggest additional mechanisms of action. The biological characterization of peptide inhibitor SPR34 highlights the essential role played by the reduced bond for the antitrypanosomal effect. Overall, this series of molecules could represent the starting point for further investigations of reduced peptide bond-containing analogs as potential anti-HAT agents Full article

(This article belongs to the Special Issue Medicinal Chemistry Studies of Neglected Diseases)

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17 pages, 5837 KiB

Open AccessArticle

Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in P. falciparum

by Aiyada Aroonsri, Chayaphat Wongsombat, Philip Shaw, Siegrid Franke, Jude Przyborski and Annette Kaiser

Molecules 2022, 27(8), 2463; https://doi.org/10.3390/molecules27082463 - 11 Apr 2022

Viewed by 2140

Abstract

The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases [...] Read more.

The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites’ genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (dhs) and deoxyhypusine hydroxylase (DOHH) enzymes. dhs from Plasmodium has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human dhs inhibitors led to 6-bromo-N-(1H-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC₅₀ value of 0.062 µM. We investigated this allosteric dhs inhibitor in Plasmodium. In vitro P. falciparum growth assays showed weak inhibition activity, with IC₅₀ values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the Pfdhs gene, as shown by chemogenomic profiling with transgenically modified P. falciparum lines. Moreover, in dose-dependent enzymatic assays with purified recombinant P. falciparum dhs protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled Pfdhs, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in P. falciparum dhs, which might foster the development of parasite-specific inhibitors. Full article

(This article belongs to the Special Issue Medicinal Chemistry Studies of Neglected Diseases)

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20 pages, 10568 KiB

Open AccessArticle

Exploring the Antiparasitic Activity of Tris-1,3,4-Thiadiazoles against Toxoplasma gondii-Infected Mice

by Tahani M. Almutairi, Nadjet Rezki, Mohamed Reda Aouad, Mohamed Hagar, Basant A. Bakr, Moaaz T. Hamed, Maha Khairy Hassen, Bassma H. Elwakil and Esraa Abdelhamid Moneer

Molecules 2022, 27(7), 2246; https://doi.org/10.3390/molecules27072246 - 30 Mar 2022

Cited by 8 | Viewed by 1889

Abstract

Nitrogen-containing atoms in their core structures have been exclusive building blocks in drug discovery and development. One of the most significant and well-known heterocycles is the 1,3,4-thidiazole nucleus, which is found in a wide range of natural products and therapeutic agents. In the [...] Read more.

Nitrogen-containing atoms in their core structures have been exclusive building blocks in drug discovery and development. One of the most significant and well-known heterocycles is the 1,3,4-thidiazole nucleus, which is found in a wide range of natural products and therapeutic agents. In the present work, certain tris-1,3,4-thiadiazole derivatives (6, 7) were synthesized through a multi-step synthesis approach. All synthesized compounds were characterized using different spectroscopic tools. Previously, thiadiazole compounds as anti-Toxoplasma gondii agents have been conducted and reported in vitro. However, this is the first study to test the anti-Toxoplasma gondii activity of manufactured molecular hybrids thiadiazole in an infected mouse model with the acute RH strain of T. gondii. All the observed results demonstrated compound (7)’s powerful activity, with a considerable reduction in the parasite count reaching 82.6% in brain tissues, followed by liver and spleen tissues (65.35 and 64.81%, respectively). Inflammatory and anti-inflammatory cytokines assessments proved that Compound 7 possesses potent antiparasitic effect. Furthermore, docking tests against TgCDPK1 and ROP18 kinase (two major enzymes involved in parasite invasion and egression) demonstrated compound 7’s higher potency compared to compound 6 and megazol. According to the mentioned results, tris-1,3,4-thiadiazole derivatives under test can be employed as potent antiparasitic agents against the acute RH strain of T. gondii. Full article

(This article belongs to the Special Issue Medicinal Chemistry Studies of Neglected Diseases)

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Review

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16 pages, 4561 KiB

Open AccessReview

An Undefined Interaction between Polyamines and Heat Shock Proteins Leads to Cellular Protection in Plasmodium falciparum and Proliferating Cells in Various Organisms

by Xolani H. Makhoba, Rino Ragno, Annette Kaiser and Enzo Agostinelli

Molecules 2023, 28(4), 1686; https://doi.org/10.3390/molecules28041686 - 10 Feb 2023

Cited by 1 | Viewed by 1733

Abstract

Environmental stimuli can distress the internal reaction of cells and their normal function. To react promptly to sudden environmental changes, a cascade of heat shock proteins (Hsps) functions to protect and act as housekeepers inside the cells. In parallel to the heat shock [...] Read more.

Environmental stimuli can distress the internal reaction of cells and their normal function. To react promptly to sudden environmental changes, a cascade of heat shock proteins (Hsps) functions to protect and act as housekeepers inside the cells. In parallel to the heat shock response, the metabolic polyamine (PA) status changes. Here, we discuss possible ways of putative interactions between Hsps and polyamines in a wide lineage of eukaryotic model organisms with a particular focus on parasitic protozoa such as Plasmodium falciparum (P. falciparum). The supposed interaction between polyamines and Hsps may protect the parasite from the sudden change in temperature during transmission from the female Anopheles mosquito to a human host. Recent experiments performed with the spermidine mimetic inhibitor 15-deoxyspergualine in Plasmodium in vitro cultures show that the drug binds to the C-terminal EEVD motif of Hsp70. This leads to inhibition of protein biosynthesis caused by prevention of eIF5A2 phosphorylation and eukaryotic initiation factor 5A (eIF5A) modification. These observations provide further evidence that PAs are involved in the regulation of protein biosynthesis of Hsps to achieve a protective effect for the parasite during transmission. Full article

(This article belongs to the Special Issue Medicinal Chemistry Studies of Neglected Diseases)

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13 pages, 1399 KiB

Open AccessReview

Drug Repurposing and De Novo Drug Discovery of Protein Kinase Inhibitors as New Drugs against Schistosomiasis

by Bernardo Pereira Moreira, Michael H. W. Weber, Simone Haeberlein, Annika S. Mokosch, Bernhard Spengler, Christoph G. Grevelding and Franco H. Falcone

Molecules 2022, 27(4), 1414; https://doi.org/10.3390/molecules27041414 - 19 Feb 2022

Cited by 11 | Viewed by 3206

Abstract

Schistosomiasis is a neglected tropical disease affecting more than 200 million people worldwide. Chemotherapy relies on one single drug, praziquantel, which is safe but ineffective at killing larval stages of this parasite. Furthermore, concerns have been expressed about the rise in resistance against [...] Read more.

Schistosomiasis is a neglected tropical disease affecting more than 200 million people worldwide. Chemotherapy relies on one single drug, praziquantel, which is safe but ineffective at killing larval stages of this parasite. Furthermore, concerns have been expressed about the rise in resistance against this drug. In the absence of an antischistosomal vaccine, it is, therefore, necessary to develop new drugs against the different species of schistosomes. Protein kinases are important molecules involved in key cellular processes such as signaling, growth, and differentiation. The kinome of schistosomes has been studied and the suitability of schistosomal protein kinases as targets demonstrated by RNA interference studies. Although protein kinase inhibitors are mostly used in cancer therapy, e.g., for the treatment of chronic myeloid leukemia or melanoma, they are now being increasingly explored for the treatment of non-oncological conditions, including schistosomiasis. Here, we discuss the various approaches including screening of natural and synthetic compounds, de novo drug development, and drug repurposing in the context of the search for protein kinase inhibitors against schistosomiasis. We discuss the status quo of the development of kinase inhibitors against schistosomal serine/threonine kinases such as polo-like kinases (PLKs) and mitogen-activated protein kinases (MAP kinases), as well as protein tyrosine kinases (PTKs). Full article

(This article belongs to the Special Issue Medicinal Chemistry Studies of Neglected Diseases)

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