Modular synthesis of antimalarial quinoline-based PGM metallarectangles

A new ditopic, quinoline-based ligand L (7-chloro-4-(pyridin-4-yl)quinoline) was synthesized via a Suzuki cross-coupling reaction. The ligand was utilized to synthesize the corresponding half-sandwich iridium(III) and ruthenium(II) binuclear complexes (1c and 1d) and the subsequent metallarectangles (2c, 2d, 3c, and 3d), via [2 + 2] coordination-driven self-assembly. Single-crystal X-ray diffraction confirmed the proposed molecular structure of the binuclear complex [{IrCl₂(Cp*)}₂(μ-L)] (1c) and DFT calculations were used to predict the optimized geometry of the rectangular nature of [{Ir(μ-Cl)(Cp*)}₄(μ-L)₂](CF₃SO₃)₄ (2c). All of the metallarectangles were isolated as their triflate salts and characterized using various spectroscopic (¹H, ¹³C{¹H}, DOSY NMR, and IR spectroscopy) and analytical techniques (ESI-MS). The synthesized compounds were screened against the NF54 chloroquine-sensitive (CQS) and K1 chloroquine-resistant (CQR) strains of Plasmodium falciparum. Incorporation of the ubiquitous quinoline core and metal complexation significantly enhanced the in vitro biological activity, with an increase in the nuclearity correlating with an increase in the resultant antiplasmodial activity. This was observed across both parasitic strains, alluding to the potential of supramolecular metallarectangles to act as antiplasmodial agents. Inhibition of haemozoin formation was considered a potential mechanism of action and selected metallarectangles exhibit β-haematin inhibition activity with near comparable activity to chloroquine.