Antiplasmodial potential of organic and organometallic (Co–Co) 6-hydroxyflavone derivatives: design, synthesis, and crystallographic characterization

Malaria remains a major global health challenge, particularly due to the emergence of drug-resistant strains of Plasmodium falciparum, highlighting the urgent need for new therapeutic strategies. In this work, a series of O-propargylated and O-alkylated 6-hydroxyflavone derivatives 1, 2a,b, and 3a-c, was designed and synthesized, using 6-hydroxyflavone (6-HF) as starting material, also including organometallic dimetallatetrahedranes [Co2(CO)6(µ-HCC-6-HF)] (4a) and [Co2(CO)4(µ-dppm)(µ-HCC-6-HF)] (4b) featuring a Co–Co bond. All compounds were fully characterized using IR(ATR), NMR 1H and 13C{1H}. Furthermore, X-ray diffraction (XRD) was employed to resolve the crystal structures of six derivatives, allowing a thorough analysis of the intra- and intermolecular interactions. Cytotoxicity was assessed on human HeLa cells in order to determine the selectivity indices and evaluate their therapeutic potential. The results reveal that attachment of a dicobaltatetrahedrane entity significantly enhances the biological activity, with notable variations depending on the ligand environment and structural features. The two carbonyl clusters 4a-b represent, the first organometallic cobalt carbonyl complexes screened for their potential as antimalaria metallodrugs. Notably the Co–Co hexacarbonyl complex 4a displays among all screened 6-HF derivatives the most potent antiplasmodial activity (IC₅₀ = 0.69 ± 0.03 µg/mL ≙ 1.23 µM) combined with a moderate cytotoxicity (IC₅₀ ≈ 41.33 µg/mL ≙ 73.51 µM), leading to a high selectivity index (SI = 59.76). These findings demonstrate that the combination of a cobalt carbonyl cluster together with a flavone scaffold represents a promising strategy for enhancing antiplasmodial efficacy and supports further investigation of such bioorganometallic systems as potential antimalarial agents.

Key words: 6-hydroxyflavone, alkyne, dicobaltatetrahedrane, antiplasmodial activity, crystal structures, selectivity index.