Discovery of rigid biphenyl Plasmodium falciparum DHFR inhibitors using a fragment linking strategy.

ABSTRACT: Plasmodium falciparum dihydrofolate reductase (PfDHFR), a historical target for antimalarials, has been considered compromised due to resistance inducing mutations caused by pyrimethamine (PYR) overexposure. The clinical candidate P218 has demonstrated that inhibitors could efficiently target both PYR-sensitive and PYR-resistant parasites through careful drug design. Yet, P218 clinical development has been limited by its pharmacokinetic profile, incompatible with single dose regimen. Herein, we report the design of new PfDHFR inhibitors using fragment-based design, aiming at improved lipophilicity and overall drug-like properties. Fragment-based screening identified hits binding in the pABA site of the enzyme. Using structure-guided d

SUBMITTER: Hoarau M 

PROVIDER: S-EPMC10507804 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature