Research

21 pages, 9387 KiB

Open AccessArticle

Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines

by Dyhia Amrane, Armand Gellis, Sébastien Hutter, Marion Prieri, Pierre Verhaeghe, Nadine Azas, Patrice Vanelle and Nicolas Primas

Molecules 2020, 25(17), 3929; https://doi.org/10.3390/molecules25173929 - 27 Aug 2020

Cited by 14 | Viewed by 2832

Abstract

From three previously identified antiplasmodial hit compounds (A–C) and inactive series (D), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives [...] Read more.

From three previously identified antiplasmodial hit compounds (A–C) and inactive series (D), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 P. falciparum strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC₅₀ K1 P. falciparum ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (2, 9, 16, and 24) and two among 4-alkoxy derivatives (41 and 44). Regarding the two most potent molecules (16 and 41), five derivatives without a 2-CCl₃ group were prepared, evaluated, and appeared totally inactive (EC₅₀ > 50 µM), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity. Full article

(This article belongs to the Special Issue Purposing and Repurposing of Antimalarial Agents)

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39 pages, 1151 KiB

Open AccessArticle

4-Arylthieno[2,3-b]pyridine-2-carboxamides Are a New Class of Antiplasmodial Agents

by Sandra I. Schweda, Arne Alder, Tim Gilberger and Conrad Kunick

Molecules 2020, 25(14), 3187; https://doi.org/10.3390/molecules25143187 - 13 Jul 2020

Cited by 12 | Viewed by 4620

Abstract

Malaria causes hundreds of thousands of deaths every year, making it one of the most dangerous infectious diseases worldwide. Because the pathogens have developed resistance against most of the established anti-malarial drugs, new antiplasmodial agents are urgently needed. In analogy to similar antiplasmodial [...] Read more.

Malaria causes hundreds of thousands of deaths every year, making it one of the most dangerous infectious diseases worldwide. Because the pathogens have developed resistance against most of the established anti-malarial drugs, new antiplasmodial agents are urgently needed. In analogy to similar antiplasmodial ketones, 4-arylthieno[2,3-b]pyridine-2-carboxamides were synthesized by Thorpe-Ziegler reactions. In contrast to the related ketones, these carboxamides are only weak inhibitors of the plasmodial enzyme PfGSK-3 but the compounds nevertheless show strong antiparasitic activity. The most potent representatives inhibit the pathogens with IC₅₀ values in the two-digit nanomolar range and exhibit high selectivity indices (>100). Full article

(This article belongs to the Special Issue Purposing and Repurposing of Antimalarial Agents)

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10 pages, 610 KiB

Open AccessArticle

Palstimolide A: A Complex Polyhydroxy Macrolide with Antiparasitic Activity

by Lena Keller, Jair L. Siqueira-Neto, Julia M. Souza, Korina Eribez, Gregory M. LaMonte, Jennifer E. Smith and William H. Gerwick

Molecules 2020, 25(7), 1604; https://doi.org/10.3390/molecules25071604 - 31 Mar 2020

Cited by 16 | Viewed by 3349

Abstract

Marine Cyanobacteria (blue-green algae) have been shown to possess an enormous potential to produce structurally diverse natural products that exhibit a broad spectrum of potent biological activities, including cytotoxic, antifungal, antiparasitic, antiviral, and antibacterial activities. Here, we report the isolation and structure determination [...] Read more.

Marine Cyanobacteria (blue-green algae) have been shown to possess an enormous potential to produce structurally diverse natural products that exhibit a broad spectrum of potent biological activities, including cytotoxic, antifungal, antiparasitic, antiviral, and antibacterial activities. Here, we report the isolation and structure determination of palstimolide A, a complex polyhydroxy macrolide with a 40-membered ring that was isolated from a tropical marine cyanobacterium collected at Palmyra Atoll. NMR-guided fractionation in combination with MS²-based molecular networking and isolation via HPLC yielded 0.7 mg of the pure compound. The small quantity isolated along with the presence of significant signal degeneracy in both the ¹H and ¹³C-NMR spectra complicated the structure elucidation of palstimolide A. Various NMR experiments and solvent systems were employed, including the LR-HSQMBC experiment that allows the detection of long-range ¹H–¹³C correlation data across 4-, 5-, and even 6-bonds. This expanded NMR data set enabled the elucidation of the palstimolide’s planar structure, which is characterized by several 1,5-disposed hydroxy groups as well as a tert-butyl group. The compound showed potent antimalarial activity with an IC₅₀ of 223 nM as well as interesting anti-leishmanial activity with an IC₅₀ of 4.67 µM. Full article

(This article belongs to the Special Issue Purposing and Repurposing of Antimalarial Agents)

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15 pages, 3524 KiB

Open AccessArticle

Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites

by Ana Carolina C. de Sousa, Keletso Maepa, Jill M. Combrinck and Timothy J. Egan

Molecules 2020, 25(7), 1571; https://doi.org/10.3390/molecules25071571 - 29 Mar 2020

Cited by 9 | Viewed by 3161

Abstract

With the continued loss of antimalarials to resistance, drug repositioning may have a role in maximising efficiency and accelerating the discovery of new antimalarial drugs. Bayesian statistics was previously used as a tool to virtually screen USFDA approved drugs for predicted β-haematin (synthetic [...] Read more.

With the continued loss of antimalarials to resistance, drug repositioning may have a role in maximising efficiency and accelerating the discovery of new antimalarial drugs. Bayesian statistics was previously used as a tool to virtually screen USFDA approved drugs for predicted β-haematin (synthetic haemozoin) inhibition and in vitro antimalarial activity. Here, we report the experimental evaluation of nine of the highest ranked drugs, confirming the accuracy of the model by showing an overall 93% hit rate. Lapatinib, nilotinib, and lomitapide showed the best activity for inhibition of β-haematin formation and parasite growth and were found to inhibit haemozoin formation in the parasite, providing mechanistic insights into their mode of antimalarial action. We then screened the USFDA approved drugs for binding to the β-haematin crystal, applying a docking method in order to evaluate its performance. The docking method correctly identified imatinib, lapatinib, nilotinib, and lomitapide. Experimental evaluation of 22 of the highest ranked purchasable drugs showed a 24% hit rate. Lapatinib and nilotinib were chosen as templates for shape and electrostatic similarity screening for lead hopping using the in-stock ChemDiv compound catalogue. The actives were novel structures worthy of future investigation. This study presents a comparison of different in silico methods to identify new haemozoin-inhibiting chemotherapeutic alternatives for malaria that proved to be useful in different ways when taking into consideration their strengths and limitations. Full article

(This article belongs to the Special Issue Purposing and Repurposing of Antimalarial Agents)

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8 pages, 1115 KiB

Open AccessCommunication

Antiplasmodial Activity of p-Substituted Benzyl Thiazinoquinone Derivatives and Their Potential against Parasitic Infections

by Marcello Casertano, Marialuisa Menna, Caterina Fattorusso, Nicoletta Basilico, Silvia Parapini, Marco Persico and Concetta Imperatore

Molecules 2020, 25(7), 1530; https://doi.org/10.3390/molecules25071530 - 27 Mar 2020

Cited by 3 | Viewed by 2070

Abstract

Malaria is a life-threatening disease and, what is more, the resistance to available antimalarial drugs is a recurring problem. The resistance of Plasmodium falciparum malaria parasites to previous generations of medicines has undermined malaria control efforts and reversed gains in child survival. This [...] Read more.

Malaria is a life-threatening disease and, what is more, the resistance to available antimalarial drugs is a recurring problem. The resistance of Plasmodium falciparum malaria parasites to previous generations of medicines has undermined malaria control efforts and reversed gains in child survival. This paper describes a continuation of our ongoing efforts to investigate the effects against Plasmodium falciparum strains and human microvascular endothelial cells (HMEC-1) of a series of methoxy p-benzyl-substituted thiazinoquinones designed starting from a pointed antimalarial lead candidate. The data obtained from the newly tested compounds expanded the structure–activity relationships (SARs) of the thiazinoquinone scaffold, indicating that antiplasmodial activity is not affected by the inductive effect but rather by the resonance effect of the introduced group at the para position of the benzyl substituent. Indeed, the current survey was based on the evaluation of antiparasitic usefulness as well as the selectivity on mammalian cells of the tested p-benzyl-substituted thiazinoquinones, upgrading the knowledge about the active thiazinoquinone scaffold. Full article

(This article belongs to the Special Issue Purposing and Repurposing of Antimalarial Agents)

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14 pages, 8961 KiB

Open AccessArticle

In Vitro Activities of MMV Malaria Box Compounds against the Apicomplexan Parasite Neospora caninum, the Causative Agent of Neosporosis in Animals

by Joachim Müller, Pablo A. Winzer, Kirandeep Samby and Andrew Hemphill

Molecules 2020, 25(6), 1460; https://doi.org/10.3390/molecules25061460 - 24 Mar 2020

Cited by 5 | Viewed by 3007

Abstract

(1) Background: Neospora caninum is a major cause of abortion in cattle and represents a veterinary health problem of great economic significance. In order to identify novel chemotherapeutic agents for the treatment of neosporosis, the Medicines for Malaria Venture (MMV) Malaria Box, a [...] Read more.

(1) Background: Neospora caninum is a major cause of abortion in cattle and represents a veterinary health problem of great economic significance. In order to identify novel chemotherapeutic agents for the treatment of neosporosis, the Medicines for Malaria Venture (MMV) Malaria Box, a unique collection of anti-malarial compounds, were screened against N. caninum tachyzoites, and the most efficient compounds were characterized in more detail. (2) Methods: A N. caninum beta-galactosidase reporter strain grown in human foreskin fibroblasts was treated with 390 compounds from the MMV Malaria Box. The IC₅₀s of nine compounds were determined, all of which had been previously been shown to be active against another apicomplexan parasite, Theileria annulata. The effects of three of these compounds on the ultrastructure of N. caninum tachyzoites were further investigated by transmission electron microscopy at different timepoints after initiation of drug treatment. (3) Results: Five MMV Malaria Box compounds exhibited promising IC₅₀s below 0.2 µM. The compound with the lowest IC₅₀, namely 25 nM, was MMV665941. This compound and two others, MMV665807 and MMV009085, specifically induced distinct alterations in the tachyzoites. More specifically, aberrant structural changes were first observed in the parasite mitochondrion, and subsequently progressed to other cytoplasmic compartments of the tachyzoites. The pharmacokinetic (PK) data obtained in mice suggest that treatment with MMV665941 could be potentially useful for further in vivo studies. (4) Conclusions: We have identified five novel compounds with promising activities against N. caninum, the effects of three of these compounds were studies by transmission electron microscopy (TEM). Their modes of action are unknown and require further investigation. Full article

(This article belongs to the Special Issue Purposing and Repurposing of Antimalarial Agents)

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15 pages, 5447 KiB

Open AccessFeature PaperArticle

Primaquine and Chloroquine Fumardiamides as Promising Antiplasmodial Agents

by Maja Beus, Diana Fontinha, Jana Held, Zrinka Rajić, Lidija Uzelac, Marijeta Kralj, Miguel Prudêncio and Branka Zorc

Molecules 2019, 24(15), 2812; https://doi.org/10.3390/molecules24152812 - 01 Aug 2019

Cited by 7 | Viewed by 4431

Abstract

This paper describes a continuation of our efforts in the pursuit of novel antiplasmodial agents with optimized properties. Following our previous discovery of biologically potent asymmetric primaquine (PQ) and halogenaniline fumardiamides (1–6), we now report their significant in vitro [...] Read more.

This paper describes a continuation of our efforts in the pursuit of novel antiplasmodial agents with optimized properties. Following our previous discovery of biologically potent asymmetric primaquine (PQ) and halogenaniline fumardiamides (1–6), we now report their significant in vitro activity against the hepatic stages of Plasmodium parasites. Furthermore, we successfully prepared chloroquine (CQ) analogue derivatives (11–16) and evaluated their activity against both the hepatic and erythrocytic stages of Plasmodium. Our results have shown that PQ fumardiamides (1–6) exert both higher activity against P. berghei hepatic stages and lower toxicity against human hepatoma cells than the parent drug and CQ derivatives (11–16). The favourable cytotoxicity profile of the most active compounds, 5 and 6, was corroborated by assays performed on human cells (human breast adenocarcinoma (MCF-7) and non-tumour embryonic kidney cells (HEK293T)), even when glucose-6-phosphate dehydrogenase (G6PD) was inhibited. The activity of CQ fumardiamides on P. falciparum erythrocytic stages was higher than that of PQ derivatives, comparable to CQ against CQ-resistant strain PfDd2, but lower than CQ when tested on the CQ-sensitive strain Pf3D7. In addition, both sets of compounds showed favourable drug-like properties. Hence, quinoline fumardiamides could serve as a starting point towards the development of safer and more effective antiplasmodial agents. Full article

(This article belongs to the Special Issue Purposing and Repurposing of Antimalarial Agents)

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Review

Jump to: Research, Other

19 pages, 1033 KiB

Open AccessReview

Drug Repurposing: A Review of Old and New Antibiotics for the Treatment of Malaria: Identifying Antibiotics with a Fast Onset of Antiplasmodial Action

by Lais Pessanha de Carvalho, Andrea Kreidenweiss and Jana Held

Molecules 2021, 26(8), 2304; https://doi.org/10.3390/molecules26082304 - 15 Apr 2021

Cited by 15 | Viewed by 5698

Abstract

Malaria is one of the most life-threatening infectious diseases and constitutes a major health problem, especially in Africa. Although artemisinin combination therapies remain efficacious to treat malaria, the emergence of resistant parasites emphasizes the urgent need of new alternative chemotherapies. One strategy is [...] Read more.

Malaria is one of the most life-threatening infectious diseases and constitutes a major health problem, especially in Africa. Although artemisinin combination therapies remain efficacious to treat malaria, the emergence of resistant parasites emphasizes the urgent need of new alternative chemotherapies. One strategy is the repurposing of existing drugs. Herein, we reviewed the antimalarial effects of marketed antibiotics, and described in detail the fast-acting antibiotics that showed activity in nanomolar concentrations. Antibiotics have been used for prophylaxis and treatment of malaria for many years and are of particular interest because they might exert a different mode of action than current antimalarials, and can be used simultaneously to treat concomitant bacterial infections. Full article

(This article belongs to the Special Issue Purposing and Repurposing of Antimalarial Agents)

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29 pages, 1237 KiB

Open AccessReview

Repurposing Drugs to Fight Hepatic Malaria Parasites

by Diana Fontinha, Isabel Moules and Miguel Prudêncio

Molecules 2020, 25(15), 3409; https://doi.org/10.3390/molecules25153409 - 28 Jul 2020

Cited by 12 | Viewed by 3957

Abstract

Malaria remains one of the most prevalent infectious diseases worldwide, primarily affecting some of the most vulnerable populations around the globe. Despite achievements in the treatment of this devastating disease, there is still an urgent need for the discovery of new drugs that [...] Read more.

Malaria remains one of the most prevalent infectious diseases worldwide, primarily affecting some of the most vulnerable populations around the globe. Despite achievements in the treatment of this devastating disease, there is still an urgent need for the discovery of new drugs that tackle infection by Plasmodium parasites. However, de novo drug development is a costly and time-consuming process. An alternative strategy is to evaluate the anti-plasmodial activity of compounds that are already approved for other purposes, an approach known as drug repurposing. Here, we will review efforts to assess the anti-plasmodial activity of existing drugs, with an emphasis on the obligatory and clinically silent liver stage of infection. We will also review the current knowledge on the classes of compounds that might be therapeutically relevant against Plasmodium in the context of other communicable diseases that are prevalent in regions where malaria is endemic. Repositioning existing compounds may constitute a faster solution to the current gap of prophylactic and therapeutic drugs that act on Plasmodium parasites, overall contributing to the global effort of malaria eradication. Full article

(This article belongs to the Special Issue Purposing and Repurposing of Antimalarial Agents)

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16 pages, 1425 KiB

Open AccessReview

Antimalarial Agents as Therapeutic Tools Against Toxoplasmosis—A Short Bridge between Two Distant Illnesses

by Alina Secrieru, Inês C. C. Costa, Paul M. O'Neill and Maria L. S. Cristiano

Molecules 2020, 25(7), 1574; https://doi.org/10.3390/molecules25071574 - 30 Mar 2020

Cited by 19 | Viewed by 4804

Abstract

Toxoplasmosis is an infectious disease with paramount impact worldwide, affecting many vulnerable populations and representing a significant matter of concern. Current therapies used against toxoplasmosis are based essentially on old chemotypes, which fail in providing a definitive cure for the disease, placing the [...] Read more.

Toxoplasmosis is an infectious disease with paramount impact worldwide, affecting many vulnerable populations and representing a significant matter of concern. Current therapies used against toxoplasmosis are based essentially on old chemotypes, which fail in providing a definitive cure for the disease, placing the most sensitive populations at risk for irreversible damage in vital organs, culminating in death in the most serious cases. Antimalarial drugs have been shown to possess key features for drug repurposing, finding application in the treatment of other parasite-borne illnesses, including toxoplasmosis. Antimalarials provide the most effective therapeutic solutions against toxoplasmosis and make up for the majority of currently available antitoxoplasmic drugs. Additionally, other antiplasmodial drugs have been scrutinized and many promising candidates have emanated in recent developments. Available data demonstrate that it is worthwhile to explore the activity of classical and most recent antimalarial chemotypes, such as quinolines, endoperoxides, pyrazolo[1,5-a]pyrimidines, and nature-derived peptide-based parasiticidal agents, in the context of toxoplasmosis chemotherapy, in the quest for encountering more effective and safer tools for toxoplasmosis control or eradication. Full article

(This article belongs to the Special Issue Purposing and Repurposing of Antimalarial Agents)

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Other

Jump to: Research, Review

8 pages, 2074 KiB

Open AccessLetter

Synthesis and Antileishmanial Activity of 1,2,4,5-Tetraoxanes against Leishmania donovani

by Lília I. L. Cabral, Sébastien Pomel, Sandrine Cojean, Patrícia S. M. Amado, Philippe M. Loiseau and Maria L. S. Cristiano

Molecules 2020, 25(3), 465; https://doi.org/10.3390/molecules25030465 - 22 Jan 2020

Cited by 25 | Viewed by 3653

Abstract

A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC₅₀ values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, [...] Read more.

A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC₅₀ values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC₅₀ value of 2.52 ± 0.65 µm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis. Full article

(This article belongs to the Special Issue Purposing and Repurposing of Antimalarial Agents)

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