Targeted Structure-Activity Analysis of Endochin-like Quinolones Reveals Potent Qi and Qo Site Inhibitors of Toxoplasma gondii and Plasmodium falciparum Cytochrome bc1 and Identifies ELQ-400 as a Remarkably Effective Compound against Acute Experimental Toxoplasmosis.

Abstract

Cytochrome bc1 inhibitors have been broadly studied as human and veterinary medicines and agricultural fungicides. For the most part, cytochrome bc1 inhibitors compete with ubiquinol at the ubiquinol oxidation (Qo) site or with ubiquinone at the quinone reduction (Qi) site. 4(1 H)-Quinolones with 3-position substituents may inhibit either site based on quinolone ring substituents. 4(1 H)-Quinolones that inhibit the Qi site are highly effective against toxoplasmosis, malaria, and babesiosis and do not inhibit human cytochrome bc1. We tested a series of 4(1 H)-Quinolones against wild-type and drug resistant strains of Toxoplasma gondii and Plasmodium falciparum. These experiments identified very potent compounds that inhibit T. gondii proliferation at picomolar concentrations. The most potent compounds target the Qo site, and for these compounds, an alkyl side chain confers potency against T. gondii greater than that of bulkier side chains. Our experiments also show that substituents on the quinolone ring influenced selectivity between T. gondii and P. falciparum and between Qo and Qi site-mediated activity. Comparison of the parasite cytochrome b sequences identified amino acids that are associated with drug resistance in P. falciparum that exist naturally in wild-type T. gondii. These underlying differences may influence drug susceptibility. Finally, a Qo site active 4(1 H)-quinolone-3-diarylether tested in a murine model of toxoplasmosis was superior to atovaquone, resulting in survival from Type I strain T. gondii infection. These experiments identify highly effective compounds for toxoplasmosis and provide valuable insight into the structure-activity relationship of cytochrome bc1 inhibitors.

• Authors: Erin V McConnell, Igor Bruzual, Sovitj Pou, Rolf Winter, Rozalia A Dodean, Martin J Smilkstein, Alina Krollenbrock, Aaron Nilsen, Lev N Zakharov, Michael K Riscoe, J Stone Doggett
• Journal: ACS infectious diseases (ACS Infect Dis) Vol. 4 Issue 11 Pg. 1574-1584 (11 09 2018) ISSN: 2373-8227 [Electronic] United States
• PMID: 30117728 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antiprotozoal Agents
• ELQ-400
• Phenyl Ethers
• Quinolones
• Electron Transport Complex III

Topics

• Animals
• Antiprotozoal Agents (pharmacology)
• Cells, Cultured
• Drug Discovery
• Drug Resistance
• Electron Transport Complex III (antagonists & inhibitors)
• Humans
• Malaria, Falciparum (drug therapy)
• Mice
• Molecular Structure
• Phenyl Ethers (pharmacology)
• Plasmodium falciparum (drug effects)
• Quinolones (pharmacology)
• Structure-Activity Relationship
• Toxoplasma (drug effects)
• Toxoplasmosis (drug therapy)