RT Journal Article
SR Electronic
T1 Optimized Pyridazinone Nutrient Channel Inhibitors Are Potent and Specific Antimalarial Leads
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 172
OP 182
DO 10.1124/molpharm.122.000549
VO 102
IS 3
A1 Michelle M. Butler
A1 Samanthi L. Waidyarachchi
A1 Jinfeng Shao
A1 Son T. Nguyen
A1 Xiaoyuan Ding
A1 Steven C. Cardinale
A1 Lucas R. Morin
A1 Steven M. Kwasny
A1 Mai Ito
A1 Jeanine Gezelle
A1 María B. Jiménez-Díaz
A1 Iñigo Angulo-Barturen
A1 Robert T. Jacobs
A1 Jeremy N. Burrows
A1 Zachary D. Aron
A1 Terry L. Bowlin
A1 Sanjay A. Desai
YR 2022
UL http://molpharm.aspetjournals.org/content/102/3/172.abstract
AB Human and animal malaria parasites increase their host erythrocyte permeability to a broad range of solutes as mediated by parasite-associated ion channels. Molecular and pharmacological studies have implicated an essential role in parasite nutrient acquisition, but inhibitors suitable for development of antimalarial drugs are missing. Here, we generated a potent and specific drug lead using Plasmodium falciparum, a virulent human pathogen, and derivatives of MBX-2366, a nanomolar affinity pyridazinone inhibitor from a high-throughput screen. As this screening hit lacks the bioavailability and stability needed for in vivo efficacy, we synthesized 315 derivatives to optimize drug-like properties, establish target specificity, and retain potent activity against the parasite-induced permeability. Using a robust, iterative pipeline, we generated MBX-4055, a derivative active against divergent human parasite strains. MBX-4055 has improved oral absorption with acceptable in vivo tolerability and pharmacokinetics. It also has no activity against a battery of 35 human channels and receptors and is refractory to acquired resistance during extended in vitro selection. Single-molecule and single-cell patch-clamp indicate direct action on the plasmodial surface anion channel, a channel linked to parasite-encoded RhopH proteins. These studies identify pyridazinones as novel and tractable antimalarial scaffolds with a defined mechanism of action.SIGNIFICANCE STATEMENT Because antimalarial drugs are prone to evolving resistance in the virulent human P. falciparum pathogen, new therapies are needed. This study has now developed a novel drug-like series of pyridazinones that target an unexploited parasite anion channel on the host cell surface, display excellent in vitro and in vivo ADME properties, are refractory to acquired resistance, and demonstrate a well defined mechanism of action.