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

13 May 2021

Palmer MJ, Deng X, Watts S, Krilov G, Gerasyuto A, Kokkonda S, El Mazouni F, White J, White KL, Striepen J, Bath J, Schindler KA, Yeo T, Shackleford DM, Mok S, Deni I, Lawong A, Huang A, Chen G, Wang W, Jayaseelan J, Katneni K, Patil R, Saunders J, Shahi SP, Chittimalla R, Angulo-Barturen I, Jiménez-Díaz MB, Wittlin S, Tumwebaze PK, Rosenthal PJ, Cooper RA, Aguiar ACC, Guido RVC, Pereira DB, Mittal N, Winzeler EA, Tomchick DR, Laleu B, Burrows JN, Rathod PK, Fidock DA, Charman SA, Phillips MA

Journal of Medicinal Chemistry
PMID: 33876936

Doi: 10.1021/acs.jmedchem.1c00173

 

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 () 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 against blood and liver schizont stages and show good efficacy in SCID mouse models. They are equally active against and field isolates and are selective for DHODHs versus mammalian enzymes.