Synthesisand SAR Studies of Acyl-Thiourea Platinum(II)Complexes Yield Analogs with Dual-Stage Antiplasmodium Activity

Mixed-ligand platinum(II) complexes incorporating bipyridine and acyl-thiourea ligands were synthesized and evaluated for their <i>in vitro</i> growth inhibitory activity against the human malaria parasite Plasmodium falciparum (<i>Pf</i>). The substituents at four distinct sites were varied to identify structure–activity relationships for this series. Most complexes displayed potent <i>Pf</i>NF54 activity with IC₅₀ values in the nanomolar range and favorable cytotoxicity profiles. Five complexes (<b>C1</b>, <b>C11</b>, <b>C12</b>, <b>C15</b>, and <b>C17</b>) exhibited activity against both the asexual blood and sexual (gametocyte) stage parasites, with another complex (<b>C8</b>) exhibiting activity against late-stage gametocytes only. In addition, the complexes showed comparable ABS potency against the <i>Pf</i>K1 multidrug-resistant strain. The pharmacokinetic parameters of one analog (<b>C6</b>), which displayed good solubility and mouse microsomal metabolic stability, were measured. This work demonstrates the potential of acyl-thiourea platinum(II) complexes as selective, multistage-active antiplasmodium compounds as part of the search for new antimalarial agents.