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

Erin V. McConnell, Igor Bruzual, Sovitj Pou, Rolf Winter, Rozalia A. Dodean, Martin J. Smilkstein, Alina Krollenbrock, Aaron Nilsen, Lev N. Zakharov, Michael Riscoe, Joseph Doggett

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5 Citations (Scopus)

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(1H)-Quinolones with 3-position substituents may inhibit either site based on quinolone ring substituents. 4(1H)-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(1H)-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(1H)-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.

Original languageEnglish (US)
JournalACS Infectious Diseases
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Qi
4-Quinolones
Electron Transport Complex III
Toxoplasmosis
Quinolones
Toxoplasma
Plasmodium falciparum
Atovaquone
Babesiosis
Cytochromes b
Ubiquinone
Veterinary Medicine
Structure-Activity Relationship
Drug Resistance
Pharmaceutical Preparations
Malaria
Amino Acid Sequence
Catalytic Domain
Parasites
ELQ-400

Keywords

  • cytochrome bc
  • malaria
  • Plasmodium falciparum
  • therapeutics
  • Toxoplasma gondii
  • toxoplasmosis

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

@article{b1513f0650a54592b54528d0a416dd9a,
title = "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(1H)-Quinolones with 3-position substituents may inhibit either site based on quinolone ring substituents. 4(1H)-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(1H)-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(1H)-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.",
keywords = "cytochrome bc, malaria, Plasmodium falciparum, therapeutics, Toxoplasma gondii, toxoplasmosis",
author = "McConnell, {Erin V.} and Igor Bruzual and Sovitj Pou and Rolf Winter and Dodean, {Rozalia A.} and Smilkstein, {Martin J.} and Alina Krollenbrock and Aaron Nilsen and Zakharov, {Lev N.} and Michael Riscoe and Joseph Doggett",
year = "2018",
month = "1",
day = "1",
doi = "10.1021/acsinfecdis.8b00133",
language = "English (US)",
journal = "ACS Infectious Diseases",
issn = "2373-8227",
publisher = "American Chemical Society",

}

TY - JOUR

T1 - 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

AU - McConnell, Erin V.

AU - Bruzual, Igor

AU - Pou, Sovitj

AU - Winter, Rolf

AU - Dodean, Rozalia A.

AU - Smilkstein, Martin J.

AU - Krollenbrock, Alina

AU - Nilsen, Aaron

AU - Zakharov, Lev N.

AU - Riscoe, Michael

AU - Doggett, Joseph

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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(1H)-Quinolones with 3-position substituents may inhibit either site based on quinolone ring substituents. 4(1H)-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(1H)-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(1H)-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.

AB - 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(1H)-Quinolones with 3-position substituents may inhibit either site based on quinolone ring substituents. 4(1H)-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(1H)-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(1H)-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.

KW - cytochrome bc

KW - malaria

KW - Plasmodium falciparum

KW - therapeutics

KW - Toxoplasma gondii

KW - toxoplasmosis

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U2 - 10.1021/acsinfecdis.8b00133

DO - 10.1021/acsinfecdis.8b00133

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JF - ACS Infectious Diseases

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