edoc

Potent antimalarials with development potential identified by structure-guided computational optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series

Palmer, M. J. and Deng, X. and Watts, S. and Krilov, G. and Gerasyuto, A. and Kokkonda, S. and El Mazouni, F. and White, J. and White, K. L. and Striepen, J. and Bath, J. and Schindler, K. A. and Yeo, T. and Shackleford, D. M. and Mok, S. and Deni, I. and Lawong, A. and Huang, A. and Chen, G. and Wang, W. and Jayaseelan, J. and Katneni, K. and Patil, R. and Saunders, J. and Shahi, S. P. and Chittimalla, R. and Angulo-Barturen, I. and Jimenez-Diaz, M. B. and Wittlin, S. and Tumwebaze, P. K. and Rosenthal, P. J. and Cooper, R. A. and Aguiar, A. C. C. and Guido, R. V. C. and Pereira, D. B. and Mittal, N. and Winzeler, E. A. and Tomchick, D. R. and Laleu, B. and Burrows, J. N. and Rathod, P. K. and Fidock, D. A. and Charman, S. A. and Phillips, M. A.. (2021) Potent antimalarials with development potential identified by structure-guided computational optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series. Journal of medicinal chemistry, 64 (9). pp. 6085-6136.

Full text not available from this repository.

Official URL: https://edoc.unibas.ch/89313/

Downloads: Statistics Overview

Abstract

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
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
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:20 Dec 2022 15:26
Deposited On:20 Dec 2022 15:26

Repository Staff Only: item control page