Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning

Kaiser, Marcel; Mäser, Pascal; Tadoori, Leela Pavan; Ioset, Jean‐Robert; Brun, Reto

doi:10.1371/journal.pone.0135556

Cited by 96 publications

(68 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This validated biological transformation is critical for trypanosome survival, and hence has served as a platform for the development of selective antitrypanosomal compounds. Several pharmaceuticals, including members of the tricyclic antidepressants such as clomipramine ( 46 ) and the phenothiazine antipsychotics such as chlorpromazine ( 47 ), have been found to inhibit TPR . Structurally, these compounds both feature substituted phenyl rings, joined by a single atom bridge (amine in this case) held rigidly in a specific conformation by the formation of a third ring.…”

Section: Kinetoplastids (Trypanosomiasis and Leishmaniasis)mentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

View full text Add to dashboard Cite

The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

show abstract

Section: Kinetoplastids (Trypanosomiasis and Leishmaniasis)mentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

View full text Add to dashboard Cite

show abstract

“…One of the hits is pentamidine isethionate, which is a well-known anti-leishmanial drug (33). Two azole-containing antifungal compounds including oxiconazole nitrate and tioconazole were reported to have leishmaniacidal activity in vitro (34, 35). …”

Section: Discussionmentioning

confidence: 99%

Development of a semi-automated image-based high-throughput drug screening system

Fasel

2018

Front Biosci

View full text Add to dashboard Cite

We previously reported that the innate sensing of the endosymbiont Leishmania RNA virus 1 (LRV1) within Leishmania (Viannia) guyanensis through Toll-like receptor 3, worsens the pathogenesis of parasite infection in mice. The presence of LRV1 has been associated with the failure of first-line treatment in patients infected with LRV1 containing -L. guyanensis and -L. braziliensis parasites. Here, we established a semi-automated image-based high-throughput drug screening (HTDS) protocol to measure parasiticidal activity of the Prestwick chemical library in primary murine macrophages infected with LRV1-containing L. guyanensis. The two-independent screens generated 14 hit compounds with over sixty-nine percent reduction in parasite growth compared to control, at a single dose in both screens. Our screening strategy offers great potential in the search for new drugs and accelerates the discovery rate in the field of drug repurposing against Leishmania. Moreover, this technique allows the concomitant assessment of the effect of drug toxicity on host cell number.

show abstract

“…All series which were not cidal, or which had been the subject of previously reported studies, were subsequently excluded. 25−31 The screening cascade is shown in Figure 1. 22 …”

Section: Hit Discoverymentioning

confidence: 99%

Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi

Brand

Viayna

et al. 2017

J. Med. Chem.

View full text Add to dashboard Cite

Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas’ disease.

show abstract

Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning

Cited by 96 publications

References 58 publications

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Development of a semi-automated image-based high-throughput drug screening system

Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi

Contact Info

Product

Resources

About