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Antimalarials targeting the ubiquinol-oxidation (Q_o) site of the <i>Plasmodium falciparum</i> bc₁ complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Q_o site. Recent findings showed a series of 2-aryl quinolones mediate inhibitions of this complex by binding to the ubiquinone-reduction (Qi) site, which offers a potential advantage in circumventing drug resistance. Since it is essential to understand how 2-aryl quinolone lead compounds bind within the Qi site, here we describe the co-crystallization and structure elucidation of the bovine cytochrome <i>bc₁</i> complex with three different antimalarial 4(1H)-quinolone sub-types, including two 2-aryl quinolone derivatives and a 3-aryl quinolone analogue for comparison. Currently, no structural information is available for <i>Plasmodial</i> cytochrome <i>bc₁</i>. Our crystallographic studies have enabled comparison of an in-silico homology docking model of <i>P. falciparum</i> with the mammalian’s equivalent, enabling an examination of how binding compares for the 2- versus 3-aryl analogues. Based on crystallographic and computational modeling, key differences in human and <i>P. falciparum</i> Q_i sites have been mapped that provide new insights that can be exploited for the development of next-generation antimalarials with greater selective inhibitory activity against the parasite <i>bc₁</i> with improved antimalarial properties.