Design, synthesis and mechanistic exploration of anti-plasmodial Indolo[2,3- <i>b</i> ]quinoxaline-7-chloroquinoline hybrids

<b>Aim:</b> The aim of this study is to synthesize indolo[2,3-<i>b</i>]quinoxaline-4-aminoquinoline-based hybrids and evaluate their effectiveness against chloroquine-susceptible (3D7) and resistant (W2) <i>Plasmodium falciparum</i> strains, with expected inhibition of <i>P. falciparum</i> chloroquine resistance transporter (<i>Pf</i>CRT) and heme.<b>Methods:</b> The hybrids were synthesized and <i>in vitro</i> evaluated against both susceptible and resistant strains. Molecular docking and studies were conducted to assess the binding affinities for the <i>Pf</i>CRT protein. Additionally, heme-inhibition studies using hemin chloride provided valuable insights into the interaction between the ligand and heme. The binding constant (logK) was calculated, providing quantitative details about the strength of this interaction.<b>Conclusion:</b> The synthesized hybrids showed reasonable potency against both <i>P. falciparum</i> strains. The most potent hybrid <b>10d</b>, with fluorine-substitution exhibited good activity. Molecular docking studies indicated strong binding affinities for the <i>Pf</i>CRT protein. Heme inhibition studies further supported the potential of <b>10d</b> as an effective anti-plasmodial agent.