Cyclopropyl Carboxamides, a Chemically Novel Class of Antimalarial Agents Identified in a Phenotypic Screen

@article{Sanz2011CyclopropylCA,
  title={Cyclopropyl Carboxamides, a Chemically Novel Class of Antimalarial Agents Identified in a Phenotypic Screen},
  author={Laura M Sanz and Mar{\'i}a Bel{\'e}n Jim{\'e}nez-D{\'i}az and Benigno Crespo and Cristina De-C{\'o}zar and Mar{\'i}a Jes{\'u}s Almela and I{\~n}igo Angulo-Barturen and Pablo Casta{\~n}eda and Javier Ib{\'a}{\~n}ez and Esther Fern{\'a}ndez and Santiago Ferrer and Esperanza Herreros and Sonia Lozano and Mar{\'i}a Santos Mart{\'i}nez and Lourdes Rueda and Jeremy N. Burrows and Jose F. Garc{\'i}a-Bustos and Francisco Javier Gamo},
  journal={Antimicrobial Agents and Chemotherapy},
  year={2011},
  volume={55},
  pages={5740 - 5745}
}
ABSTRACT Malaria is one of the deadliest infectious diseases in the world, with the eukaryotic parasite Plasmodium falciparum causing the most severe form of the disease. Discovery of new classes of antimalarial drugs has become an urgent task to counteract the increasing problem of drug resistance. Screening directly for compounds able to inhibit parasite growth in vitro is one of the main approaches the malaria research community is now pursuing for the identification of novel antimalarial… 

A New In Vivo Screening Paradigm to Accelerate Antimalarial Drug Discovery

TLDR
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.

Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles

TLDR
One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change.

The Role of Metabolomics in Antiparasitic Drug Discovery

TLDR
There is an urgent need for the discovery of new drugs that are safe, effective, and act by novel mechanisms for protozoan parasites, as there are currently no safe and highly effective vaccines.

Identification and optimization of an aminoalcohol-carbazole series with antimalarial properties.

TLDR
The SAR study and optimization of early ADME and physicochemical properties direct the selection of a late lead compound that shows good efficacy when orally administrated in the in vivo P. berghei mouse model.

Contemporary Approaches for Malaria Drug Discovery

TLDR
This chapter focuses on the contemporary approaches in antimalarial drug discovery that promise the development of an effective strategy to combat malaria.

New chemotherapeutic strategies against malaria, leishmaniasis and trypanosomiases.

TLDR
This review deals with new drugs against Plasmodium, Leishmania and Trypanosoma parasites, focusing on the molecules that are in the most advanced stage of development.

A framework for assessing the risk of resistance for anti-malarials in development

TLDR
A standardized in vitro methodology to assess quantitatively these characteristics in Plasmodium falciparum during the early phases of the drug development process has been developed and is presented here and allows the identification of anti-malarial compounds with overt resistance risks and the prioritization of the most robust ones.

References

SHOWING 1-10 OF 34 REFERENCES

Thousands of chemical starting points for antimalarial lead identification

TLDR
Chemical structures and associated data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host–pathogen interaction related targets.

Spiroindolones, a Potent Compound Class for the Treatment of Malaria

TLDR
The preclinical profile for an optimized spiroindolone drug candidate, NITD609, shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.

Chemical genetics of Plasmodium falciparum

TLDR
A phenotypic forward chemical genetic approach to discover new antimalarial chemotypes and structures and biological activity of the entire library are disclosed, many of which showed potent in vitro activity against drug-resistant P. falciparum strains.

Novel Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Anti-malarial Activity in the Mouse Model*

TLDR
A series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH demonstrated good tolerability and oral exposure in the mouse, and ED50 values in the 4-day murine P. berghei efficacy model resulted in sterile cure.

In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen

TLDR
An efficient and robust high-throughput cell-based screen based on proliferation of Plasmodium falciparum in erythrocytes, which identified most known antimalarials and many novel chemical scaffolds, which likely act through both known and novel pathways.

Spirotetrahydro β-Carbolines (Spiroindolones): A New Class of Potent and Orally Efficacious Compounds for the Treatment of Malaria

TLDR
Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.

Multiple Antibiotics Exert Delayed Effects against the Plasmodium falciparum Apicoplast

TLDR
The loss of apicoplast function became apparent as the progeny of antibiotic-treated parasites initiated cell division, with the failure of schizonts to fully mature or for erythrocyte rupture to take place, which explains the slow antimalarial action of multiple antibiotics.

Variations in frequencies of drug resistance in Plasmodium falciparum.

  • P. RathodT. McErleanP. Lee
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1997
Continual exposure of malarial parasite populations to different drugs may have selected not only for resistance to individual drugs but also for genetic traits that favor initiation of resistance to

Qinghaosu (Artemisinin): The Price of Success

TLDR
Artemisinin combination treatments are now first-line drugs for uncomplicated falciparum malaria, but access to ACTs is still limited in most malaria-endemic countries and a global subsidy would make these drugs more affordable and available.

A Divergent SAR Study Allows Optimization of a Potent 5-HT2c Inhibitor to a Promising Antimalarial Scaffold.

TLDR
The antimalarial profile of the TCMDC-139046 series and efforts to avoid interaction with this receptor, while maintaining a good antiparasitic potency are presented.