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 Qi 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.