PT  - JOURNAL ARTICLE
AU  - Michelle M. Butler
AU  - Samanthi L. Waidyarachchi
AU  - Jinfeng Shao
AU  - Son T. Nguyen
AU  - Xiaoyuan Ding
AU  - Steven C. Cardinale
AU  - Lucas R. Morin
AU  - Steven M. Kwasny
AU  - Mai Ito
AU  - Jeanine Gezelle
AU  - María B. Jiménez-Díaz
AU  - Iñigo Angulo-Barturen
AU  - Robert T. Jacobs
AU  - Jeremy N. Burrows
AU  - Zachary D. Aron
AU  - Terry L. Bowlin
AU  - Sanjay A. Desai
TI  - Optimized Pyridazinone Nutrient Channel Inhibitors Are Potent and Specific Antimalarial Leads
AID  - 10.1124/molpharm.122.000549
DP  - 2022 Sep 01
TA  - Molecular Pharmacology
PG  - 172--182
VI  - 102
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/102/3/172.short
4100  - http://molpharm.aspetjournals.org/content/102/3/172.full
SO  - Mol Pharmacol2022 Sep 01; 102
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.