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Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model

Booker, M. L. and Bastos, C. M. and Kramer, M. L. and Barker, R. H. and Skerlj, R. and Sidhu, A. B. and Deng, X. and Celatka, C. and Cortese, J. F. and Guerrero Bravo J. E., and Crespo Llado K. N., and Serrano, A. E. and Angulo-Barturen I., and Jimenez-Diaz M. B., and Viera, S. and Garuti, H. and Wittlin, S. and Papastogiannidis, P. and Lin, J. W. and Janse, C. J. and Khan, S. M. and Duraisingh, M. and Coleman, B. and Goldsmith, E. J. and Phillips, M. A. and Munoz, B. and Wirth, D. F. and Klinger, J. D. and Wiegand, R. and Sybertz, E.. (2010) Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. Journal of Biological Chemistry, Vol. 285, H. 43. pp. 33054-33064.

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Official URL: http://edoc.unibas.ch/dok/A5842965

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Abstract

Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED(50) values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society of Biological Chemists
ISSN:0021-9258
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Jun 2012 06:55
Deposited On:08 Jun 2012 06:46

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