Cyclopropyl Carboxamides: A New Oral Antimalarial Series Derived from the Tres Cantos Anti-Malarial Set (TCAMS)

Rueda, Lourdes; Castellote, Isabel; Castro-Pichel, Julia; Chaparro, María J.; Rosa, Juan Carlos de la; García-Pérez, Adolfo; Gordo, Mariola; Jiménez-Dı́az, Marı́a Belén; Kessler, Albane; Macdonald, Simon J. F.; Martínez, María Santos; Sanz, Laura M.; Gamo, Francisco Javier; Fernández, Esther

doi:10.1021/ml2001517

Cited by 27 publications

(23 citation statements)

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“…Examples of the acceleration of the life cycle of drug discovery projects using the in vivo screening described in this paper are cyclopropyl carboxamides [40], [41], and indoline-containing derivatives of serotonin receptor 5-HT 2 inhibitors [42]. Cyclopropyl carboxamides are compounds of a TCAMS series that were found to be very potent and rapidly parasiticidal in the P. berghei ED 90 -normalized in vivo screening assay.…”

Section: Discussionmentioning

confidence: 99%

A New In Vivo Screening Paradigm to Accelerate Antimalarial Drug Discovery

et al. 2013

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The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task.

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Section: Discussionmentioning

confidence: 99%

A New In Vivo Screening Paradigm to Accelerate Antimalarial Drug Discovery

et al. 2013

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“…3‐Aminopyridine MMV026468 ( 591 ), MMV019087 ( 592 ), and MMV016136 ( 593 ) have been reported as promising antiplasmodials. The insulin‐like growth factor 1 receptor and the insulin receptor are both human transmembrane tyrosine kinases, the dual inhibition of which has been exploited for the development of cancer chemotherapeutics.…”

Section: Malariamentioning

confidence: 99%

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

Veale

2019

ChemMedChem

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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.

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“…However, through divergent SAR analysis the team was able to create additional compounds with selective and potent activity against P. falciparum and with reduced activity against the human receptor, although in vivo efficacy still needs to be improved. A second class, the cyclopropyl carboxamides 30 , have potent in vitro activity against P. falciparum and at least one (GSK1057714) has in vivo activity in the P. falciparum SCID mouse model (Figure 2) 31 . However, in vitro resistance against these compounds emerged rapidly, raising concerns about resistance development in the field.…”

Section: Whole-cell Based Approachesmentioning

confidence: 99%

Antimalarial drug discovery — approaches and progress towards new medicines

2013

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Malaria elimination has recently been reinstated as a global health priority but current therapies seem to be insufficient for the task. Elimination efforts require new drug classes that alleviate symptoms, prevent transmission and provide a radical cure. To develop these next generation medicines, public-private partnerships are funding innovative approaches to identify compounds that target multiple parasite species at multiple stages of the parasite lifecycle. Here, we review the cell-, chemistry- and target-based approaches used to discover new drug candidates that are currently in clinical trials or undergoing preclinical testing.

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Cyclopropyl Carboxamides: A New Oral Antimalarial Series Derived from the Tres Cantos Anti-Malarial Set (TCAMS)

Cited by 27 publications

References 16 publications

A New In Vivo Screening Paradigm to Accelerate Antimalarial Drug Discovery

A New In Vivo Screening Paradigm to Accelerate Antimalarial Drug Discovery

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

Antimalarial drug discovery — approaches and progress towards new medicines

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