In summary, a novel series of dihydrothiophenone derivatives as P. falciparum dihydroorotate dehydrogenase inhibitors were identified through virtual screening, and subsequent structural optimization and SAR analysis led to dozens of novel PfDHODH-specific inhibitors that achieved excellent inhibitory potency. Compounds in this series with three preferential structural fragments were regarded as potent PfDHODH inhibitors: (1) a larger alkyl group on the para-position of the phenyl ring or bicyclic systems such as “naphthyl-like” substituents as the hydrophobic group, (2) an ethoxycarbonyl group at the 3-position of the dihydrothiophenone ring or dihydrofuranone ring as the hydrophilic group, (3) a dihydrofuranone ring was a more potent skeleton than a dihydrothiophenone ring.
The potency of compounds described in this study was particularly encouraging for the development of antimalarial agents to conquer the widespread drug-resistance. The most potent inhibitors 25, 50, and 53 showed excellent inhibitory activity against PfDHODH (with IC50 values of 20, 6, and 18 nM) and high species selectivity over hDHODH. Moreover, the high inhibition potencies of these PfDHODH inhibitors were maintained in the low double-digit nanomolar range against Pf3D7 and PfDd2 cell strains in an in vitro assay. Furthermore, excellent correlation between inhibitory activity against PfDHODH and antimalarial potency in Pf3D7 and PfDd2 cells was observed for the dihydrothiophenone derivatives and dihydrofuranone derivatives. These results further suggested that PfDHODH is an effective target for antimalarial chemotherapy, and novel scaffolds found in this work might lead to the discovery of new antimalarial agents. A study on the crystal structure of the PfDHODH–inhibitor complexes and efforts to improve pharmacokinetic properties are underway to further understand SAR and make them “druggable”.