The antimalarial compound ELQ‐400 is an unusual inhibitor of the bc₁ complex, targeting both Q_o and Q_i sites

Abstract

Edited by Peter BrzezinskiInhibitors of the mitochondrial respiratory chain cytochrome bc 1 complex, such as the antimalarial atovaquone and ELQ-300, and many well-studied compounds, are classified as either Q o or Q i site inhibitors based on their site of action. Here, we investigated the site of action of ELQ-400 that showed an unusual behaviour, being effective against parasites resistant to the Q o site inhibitor atovaquone or to the Q i site inhibitor ELQ-300. Analysis of yeast mutants and comparison with atovaquone and other ELQs strongly suggest that ELQ-400 targets both Q o and Q i sites. Dual site inhibition would be particularly efficient as it would lower the risk of acquired resistance. However, such compounds are seldom found, which could be explained by structural and mechanistic differences between the sites.

Activities of Endochin-Like Quinolones Against in vitro Cultured Besnoitia besnoiti Tachyzoites

“…Based on previous results on ELQ efficacy against T. gondii and N. caninum (18,24), we also selected ELQ-316 and its prodrug ELQ-334, as well as ELQ-400, for further studies. ELQ-400 has been shown to exhibit outstanding in vivo activity, better than atovaquone, in an acute toxoplasmosis mouse model (22), and there is evidence that it acts as a dual Qo and Qi site inhibitor (21).…”

“…Doggett et al (18) and Nilsen et al (19) reported the synthesis of novel endochin analogs with a diphenylether side chain at the third position, and various substitutions at the quinolone ring at position 5, 6, or 7. These include ELQ-300 and ELQ-316, which confer Qi site inhibition, and ELQ-400 (20), which has been reported to target both Qo and Qi sites of cytochrome b of S. cerevisiae and potentially other organisms (21). ELQ-316 inhibited T. gondii proliferation in vitro at sub-nanomolar concentrations.…”

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…Similarly, ELQ‐316 ( 623 ) has been shown to effectively inhibit the Q i subunit of cytochrome b in T. gondii . While not identified in the SAR studies, MMV671636 (ELQ‐400 624 ) was identified as an antiplasmodial uniquely capable of inhibiting both the Q 0 and Q i subunits of the cytochrome bc 1 complex, rendering it a particularly efficient inhibitor of respiration …”

“…However the inclusion of the additional 2‐(trifluoromethyl)pyridine resulted in a significant decrease in antiplasmodial activity . Diiodohydroxyquinoline ( 627 , MMV002817) also referred to as iodoquinol, is a poorly absorbed amoebicide, which chelates ferrous ions required for amoebic metabolism . While no link to filariasis or Wolbachia has been reported, it is possible that alteration of iron absorption may also influence cytochrome production.…”

Antimalarial Agents as Therapeutic Tools Against Toxoplasmosis—A Short Bridge between Two Distant Illnesses

“…Recently, McConnell et al studied the inhibitory effect of a library of ELQs on the cytochrome bc1 complexes of P. falciparum and T. gondii parasites, having concluded that, beside ELQ-271 and ELQ-316, the very promising candidate ELQ-400 (compound (e), Figure 1) was able to inhibit both the Qi and Qo sites, possibly due to the aforementioned structural flexibility, as well as the favorable substitution pattern [40,56]. In toxoplasmosis, this compound is thought to act on both acute and chronic stages, as demonstrated by the lack of parasites in the mice tissues, including the brain, suggesting an ability of the compound to cross the blood-brain barrier as well as a strong antiparasitic effect [40].…”