Probing binding determinants in center P of the cytochrome bc1 complex using novel hydroxy-naphthoquinones

Abstract

Atovaquone is a substituted 2-hydroxy-naphthoquinone used therapeutically against Plasmodium falciparum (malaria) and Pneumocystis pathogens. It acts by inhibiting the cytochrome bc1 complex via interactions with the Rieske iron-sulfur protein and cytochrome b in the ubiquinol oxidation pocket. As the targeted pathogens have developed resistance to this drug there is an urgent need for new alternatives. To better understand the determinants of inhibitor binding in the ubiquinol oxidation pocket of the bc1 complex we synthesized a series of hydroxy-naphthoquinones bearing a methyl group on the benzene ring that is predicted to interact with the nuclear encoded Rieske iron-sulfur protein. We have also attempted to overcome the metabolic instability of a potent cytochrome bc1 complex inhibitor, a 2-hydroxy-naphthoquinone with a branched side-chain, by fluorinating the terminal methyl group. We have tested these new 2-hydroxy-naphthoquinones against yeast and bovine cytochrome bc1 complexes to model the interaction with pathogen and human enzymes and determine parameters that affect efficacy of binding of these inhibitors. We identified a hydroxy-naphthoquinone with a trifluoromethyl function that has potential for development as an anti-fungal and anti-parasitic therapeutic.

The hydroxy-naphthoquinone lapachol arrests mycobacterial growth and immunomodulates host macrophages

“…They act between cytochromes b and c 1 of the bc1 complex [62][63][64][65][66]. Therapeutical naphthoquinones (e.g.…”

Design of anti-parasitic and anti-fungal hydroxy-naphthoquinones that are less susceptible to drug resistance

“…1B), featuring a metabolically stable trifluoromethyl function and amethyl substituted aromatic ring (Fig. 1C and Refs 12, 13). The racemic mixture of R- and S-10576 had first been tested by Fieser and coworkers as an anti-malarial [14], who showed that although it was effective against avian malaria, it was ineffective in humans.…”

Biological evaluation of hydroxynaphthoquinones as anti-malarials

“…To improve drug bioavailability, several atovaquone analogs were prepared and changes were made to the naphthoquinone moiety, especially the alkyl side chain, because it is known that modifying this chain can alter drug activity [7] and counteract drug resistance [11-13]. Recently, it was demonstrated that 2-methyl-heptyl or 2-methyl-heptyl-trifluoromethyl 2-hydroxy-1,4-naphthoquinones were highly effective against atova-quone-resistant P. falciparum [14]. …”