Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention
Zhe Nie, Roger V. Bonnert, Jet Tsien, Xiaoyi Deng, Chris Higgs, Farah El Mazouni, Xiaoyu Zhang, Renzhe Li, Nhi Ho, Victoria A. Feher, Janet L. Paulsen, David M. Shackleford, Kasiram Katneni, Gong Chen, Alice C. F. Ng, Mitchell P. McInerney, Wen Wang, Jessica Saunders, Daniel Collins, Dandan Yan, Peng Li, Michael Campbell, Rahul Patil, Atanu Ghoshal, Pallab Mondal, Abhijit Kundu, Rajesh Chittimalla, Muralikumar Mahadeva, Sreekanth Kokkonda, John White, Rishi Das, Partha Mukherjee, Íñigo Angulo‐Barturen, Marı́a Belén Jiménez-Dı́az, Robert D. Malmstrom, Morgan Lawrenz, Agustina Rodriguez-Granillo, Pradipsinh K. Rathod, Diana R. Tomchick, Michael Palmer, Benoı̂t Laleu, Tian Qin, Susan A. Charman, Margaret A. Phillips
Abstract
cell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts.