Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.

Authors: Palmer, Michael J; Deng, Xiaoyi; Watts, Shawn; Krilov, Goran; Gerasyuto, Aleksey; Kokkonda, Sreekanth; El Mazouni, Farah; White, John; White, Karen L; Striepen, Josefine; Bath, Jade; Schindler, Kyra A; Yeo, Tomas; Shackleford, David M; Mok, Sachel; Deni, Ioanna; Lawong, Aloysus; Huang, Ann; Chen, Gong; Wang, Wen; Jayaseelan, Jaya; Katneni, Kasiram; Patil, Rahul; Saunders, Jessica; Shahi, Shatrughan P; Chittimalla, Rajesh; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Wittlin, Sergio; Tumwebaze, Patrick K; Rosenthal, Philip J; Cooper, Roland A; Aguiar, Anna Caroline Campos; Guido, Rafael V C; Pereira, Dhelio B; Mittal, Nimisha; Winzeler, Elizabeth A; Tomchick, Diana R; Laleu, Benoît; Burrows, Jeremy N; Rathod, Pradipsinh K; Fidock, David A; Charman, Susan A; Phillips, Margaret A

Published In J Med Chem, (2021 May 13)

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.

PubMed ID: 33876936 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

Back
to Top