Revisiting 2-Substituted-4(1H)-Quinolones for Targeting the Plasmodium falciparum Cytochrome bc₁ Complex

Quinolones substituted at the 2- and 3-positions with biaryl and diphenylether groups have been investigated for their antimalarial potential. ELQ-300, with a 3-position diphenyl ether, is at an advanced stage of preclinical development. Here, we synthesize the 2-position isomer of ELQ-300, i.e., HLQ-102, and describe synthetic procedures for preparing it that avoid the use of expensive catalysts and afford access to substituted quinolones bearing substituents in the 2-position as well as the benzenoid ring and with the critical 3-position CH₃ group. We profile HLQ analogs for their antimalarial activity along with pharmacokinetics of the selected lead molecule. Cross-resistance patterns indicate that, like its predecessor, HLQ-102 targets the Q_i site of the parasite cytochrome bc₁ complex. This finding suggests the existence of two separate troughs in the target protein capable of accommodating such large structural features regardless of whether it is placed at the 2- or 3-positon of the quinolone ring.