Exploring heteroaromatic rings as a replacement for the labile amide of antiplasmodial pantothenamides

ABSTRACTThe Plasmodium parasites that cause malaria are adept at developing resistance to antimalarial drugs, necessitating the search for new antiplasmodials. Although several amide analogs of pantothenate (pantothenamides) show potent antiplasmodial activity, hydrolysis by pantetheinases (or vanins) present in blood rapidly inactivates them. We report herein the facile synthesis and biological activity of a small library of pantothenamide analogs in which the labile amide group is replaced with a variety of heteroaromatic rings. Several of the new analogs display antiplasmodial activity in the nanomolar range against P. falciparum and/or P. knowlesi in the presence of pantetheinase. A previously reported triazole and an isoxazole derivative presented here were further characterized and found to possess high selectivity indices, medium or high Caco-2 permeability, and medium or low microsomal clearance in vitro. Although we show here that the two compounds fail to suppress proliferation of P. berghei in vivo, pharmacokinetic and contact time data presented provide a benchmark for the compound profile required to achieve antiplasmodial activity in mice and should facilitate lead optimization.

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Naphthoquinones and derivatives for chemotherapy: perspectives and limitations of their anti-trypanosomatids activities

Current Pharmaceutical Design ◽

10.2174/1381612826666201109111802 ◽

2020 ◽

Vol 26 ◽

Author(s):

Luíza Dantas-Pereira ◽

Edézio F. Cunha-Junior ◽

Valter V. Andrade-Neto ◽

John F. Bower ◽

Guilherme A. M. Jardim ◽

...

Keyword(s):

Large Scale ◽

Neglected Tropical Diseases ◽

Folk Medicine ◽

Leishmania Species ◽

Parasitic Infections ◽

Mechanistic Analysis ◽

Leishmania Spp ◽

Nanomolar Range

: Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo are essential for the development of a novel, specific and safe derivative, minimizing adverse effects.

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In vitro and in vivo antiplasmodial activity of novel quinoline derivative compounds by molecular hybridization

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2021.113271 ◽

2021 ◽

Vol 215 ◽

pp. 113271

Author(s):

Juliane Aparecida Marinho ◽

Daniel Silqueira Martins Guimarães ◽

Nícolas Glanzmann ◽

Giovana de Almeida Pimentel ◽

Izabelle Karine da Costa Nunes ◽

...

Keyword(s):

Quinoline Derivative ◽

Antiplasmodial Activity ◽

Molecular Hybridization

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In vitro and in vivo Antiplasmodial Activity of Momordica balsamina Alone or in a Traditional Mixture

Chemotherapy ◽

10.1159/000095960 ◽

2006 ◽

Vol 52 (6) ◽

pp. 288-292 ◽

Cited By ~ 16

Author(s):

F. Benoit-Vical ◽

P. Grellier ◽

A. Abdoulaye ◽

I. Moussa ◽

A. Ousmane ◽

...

Keyword(s):

Antiplasmodial Activity

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Antiparasitary Activity Of The Juglone Compound: A Narrative Review

Research Journal of Pharmacology and Pharmacy ◽

10.28933/rjpp-2021-06-1805 ◽

2021 ◽

pp. 13

Author(s):

◽

Keyword(s):

Mortality Rate ◽

Leishmania Donovani ◽

Inhibitory Concentration ◽

Narrative Review ◽

Hymenolepis Nana ◽

Compound A ◽

Living Organisms ◽

Nanomolar Range

Objective: To report, based on the literature, the action of the compound 5-hydroxy-1,4-naphthoquinone against parasites (protozoa and helminths) that affect humans. Methods: This is a narrative review that used Pubmed and Google Scholar as a data tool. This work included articles published until September 2020 that were directly related to the use of the compound juglone in antiparasitic trials. Results: The compound juglone demonstrated promising effects as a human and animal antiparasitic substance. In protozoa, the Apicomplexo Toxoplasma gondii parasite showed a high mortality rate in concentrations of juglone in the nanomolar range. The juglone showed an average inhibitory concentration (IC50) of 1.62 µM, >100 µM, and 2.02 µM µM for Trypanosoma cruzi, T. brucei rhodesiense, and Leishmania donovani, respectively. Also, the juglone showed antihelmintic activity on Hymenolepis nana in mice, and on adult worms of Schistosoma mansoni (LE strain) with IC50 34.16 µM, 32.14 µM, and 25 µM in the 24h, 48h, and 72 h, respectively. Conclusion: The results published so far show the in vitro antiparasitic potential of juglone, and the need for further studies on the specific mode of action that interacts with parasites. Besides, the literature is still limited to studies that evaluate in vivo the compound juglone, requiring better information on its interaction with living organisms.

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In Vitro and In Vivo Antiplasmodial Activity of Kenyan Medicinal Plants

Aspects of African Biodiversity ◽

10.1039/9781847559647-00020 ◽

2009 ◽

pp. 20-28

Keyword(s):

Medicinal Plants ◽

Antiplasmodial Activity

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Antiplasmodial and Cytotoxic Activities of Extracts of Selected Medicinal Plants Used to Treat Malaria in Embu County, Kenya

Journal of Parasitology Research ◽

10.1155/2020/8871375 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Bibianne Waiganjo ◽

Gervason Moriasi ◽

Jared Onyancha ◽

Nelson Elias ◽

Francis Muregi

Keyword(s):

Side Effects ◽

Medicinal Plants ◽

Stem Bark ◽

Antiplasmodial Activity ◽

Chloroquine Resistance ◽

Cytotoxic Activities ◽

Aqueous Extracts ◽

Methanolic Extracts

Malaria is a deadly disease caused by a protozoan parasite whose mode of transmission is through a female Anopheles mosquito. It affects persons of all ages; however, pregnant mothers, young children, and the elderly suffer the most due to their dwindled immune state. The currently prescribed antimalarial drugs have been associated with adverse side effects ranging from intolerance to toxicity. Furthermore, the costs associated with conventional approach of managing malaria are arguably high especially for persons living in low-income countries, hence the need for alternative and complementary approaches. Medicinal plants offer a viable alternative because of their few associated side effects, are arguably cheaper, and are easily accessible. Based on the fact that studies involving antimalarial medicinal plants as potential sources of efficacious and cost-effective pharmacotherapies are far between, this research was designed to investigate antiplasmodial and cytotoxic activities of organic and aqueous extracts of selected plants used by Embu traditional medicine practitioners to treat malaria. The studied plants included Erythrina abyssinica (stem bark), Schkuhria pinnata (whole plant), Sterculia africana (stem bark), Terminalia brownii (leaves), Zanthoxylum chalybeum (leaves), Leonotis mollissima (leaves), Carissa edulis (leaves), Tithonia diversifolia (leaves and flowers), and Senna didymobotrya (leaves and pods). In vitro antiplasmodial activity studies of organic and water extracts were carried out against chloroquine-sensitive (D6) and chloroquine-resistance (W2) strains of Plasmodium falciparum. In vivo antiplasmodial studies were done by Peter’s four-day suppression test to test for their in vivo antimalarial activity against P. berghei. Finally, cytotoxic effects and safety of the studied plant extracts were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) rapid calorimetric assay technique. The water and methanolic extracts of T. brownii and S. africana and dichloromethane extracts of E. abyssinica, S. pinnata, and T. diversifolia leaves revealed high in vitro antiplasmodial activities (IC50≤10 μg/ml). Further, moderate in vivo antimalarial activities were observed for water and methanolic extracts of L. mollissima and S. africana and for dichloromethane extracts of E. abyssinica and T. diversifolia leaves. In this study, aqueous extracts of T. brownii and S. africana demonstrated high antiplasmodial activity and high selectivity indices values (SI≥10) and were found to be safe. It was concluded that T. brownii and S. africana aqueous extracts were potent antiplasmodial agents. Further focused studies geared towards isolation of active constituents and determination of in vivo toxicities to ascertain their safety are warranted.

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In vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of novel semisynthetic analogues

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01995-20 ◽

2020 ◽

Author(s):

Fidelia Ijeoma Uche ◽

Xiaozhen Guo ◽

Jude Okokon ◽

Imran Ullah ◽

Paul Horrocks ◽

...

Keyword(s):

Metabolic Pathways ◽

High Performance ◽

Antimalarial Activity ◽

Biological Activities ◽

Antiplasmodial Activity ◽

Survival Times ◽

Antiproliferative Effects ◽

Future Evaluation

Bisbenzylisoquinoline (BBIQ) alkaloids are a diverse group of natural products that demonstrate a range of biological activities. In this study, the in vitro antiplasmodial activity of three BBIQ alkaloids (cycleanine (1), isochondodendrine (2) and 2′-norcocsuline (3)) isolated from the Triclisia subcordata Oliv. medicinal plant traditionally used for the treatment of malaria in Nigeria are studied alongside two semi-synthetic analogues (4 and 5) of cycleanine. The antiproliferative effects against a chloroquine-resistant Plasmodium falciparum strain were determined using a SYBR Green 1 fluorescence assay. The in vivo antimalarial activity of cycleanine (1) is then investigated in suppressive, prophylactic and curative murine malaria models after infection with a chloroquine-sensitive Plasmodium berghei strain. BBIQ alkaloids (1–5) exerted in vitro antiplasmodial activities with IC50 at low micromolar concentrations with the two semi-synthetic cycleanine analogues showing an improved potency and selectivity than cycleanine. At oral doses of 25 and 50mg/kg body weight of infected mice, cycleanine suppressed the levels of parasitaemia, and increased mean survival times significantly compared to the control groups. The metabolites and metabolic pathways of cycleanine (1) were also studied using high performance liquid chromatography electrospray ionization tandem mass spectrometry. Twelve novel metabolites were detected in rats after intragastic administration of cycleanine. The metabolic pathways of cycleanine were demonstrated to involve hydroxylation, dehydrogenation, and demethylation. Overall, these in vitro and in vivo results provide a basis for the future evaluation of cycleanine and its analogues as leads for further development.

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In vitro and in vivo antiplasmodial activity of extracts of selected Kenyan medicinal plants

African Journal of Pharmacy and Pharmacology ◽

10.5897/ajpp2013.3886 ◽

2015 ◽

Vol 9 (16) ◽

pp. 505-505 ◽

Cited By ~ 1

Author(s):

Jeruto P ◽

M Nyangacha R ◽

Mutai C

Keyword(s):

Medicinal Plants ◽

Antiplasmodial Activity

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Antiplasmodial and Cytotoxic Cytochalasins from an Endophytic Fungus, Nemania sp. UM10M, Isolated from a Diseased Torreya taxifolia Leaf

Molecules ◽

10.3390/molecules24040777 ◽

2019 ◽

Vol 24 (4) ◽

pp. 777 ◽

Cited By ~ 7

Author(s):

Mallika Kumarihamy ◽

Daneel Ferreira ◽

Edward Croom ◽

Rajnish Sahu ◽

Babu Tekwani ◽

...

Keyword(s):

Mouse Model ◽

Solid Tumor ◽

Endophytic Fungus ◽

Antimalarial Activity ◽

Vero Cells ◽

Antiplasmodial Activity ◽

Etoac Extract ◽

Bioassay Guided Fractionation

Bioassay-guided fractionation of an EtOAc extract of the broth of the endophytic fungus Nemania sp. UM10M (Xylariaceae) isolated from a diseased Torreya taxifolia leaf afforded three known cytochalasins, 19,20-epoxycytochalasins C (1) and D (2), and 18-deoxy-19,20-epoxy-cytochalasin C (3). All three compounds showed potent in vitro antiplasmodial activity and phytotoxicity with no cytotoxicity to Vero cells. These compounds exhibited moderate to weak cytotoxicity to some of the cell lines of a panel of solid tumor (SK-MEL, KB, BT-549, and SK-OV-3) and kidney epithelial cells (LLC-PK11). Evaluation of in vivo antimalarial activity of 19,20-epoxycytochalasin C (1) in a mouse model at 100 mg/kg dose showed that this compound had weak suppressive antiplasmodial activity and was toxic to animals.

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