The Halogen Effect in [Cu(NHC)X] Compounds: A Case Study on the Anti-Leishmania and Antiviral Activity of [Cu(IPr)X]

Abstract:

In this study, we investigated the activity and properties of three neutral Cu(I) N-heterocyclic carbene (NHC) complexes—[1,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene]copper(I) with Cl, Br, and I, specifically [Cu(IPr)Cl], [Cu(IPr)Br], and [Cu(IPr)I]—to evaluate the impact of halogen substitution on anti-Leishmania and antiviral activity. The compounds were synthesized using reported methods. ¹³C NMR spectroscopy provided insights into the electronic nature of the Cu─X bond by analyzing the NHC C² chemical shift. Notably, the iodine derivative exhibited distinct chemical properties compared to its counterparts, displaying a more covalent Cu─I bond. As a result, [Cu(IPr)I] was more susceptible to nucleophilic attack, as confirmed by HOMO–LUMO gap calculations using DFT. Furthermore, this derivative demonstrated the highest lipophilicity and the strongest antioxidant activity in the series, as evidenced by the DPPH assay, surpassing butylated hydroxytoluene (BHT) used as a positive control. Bovine serum albumin (BSA) binding assays indicated weak interaction (10³ M⁻¹) across all compounds, with no significant differences observed. In anti-Leishmania assays, [Cu(IPr)I] exhibited the best selectivity index (SI = 4.0), showing greater toxicity to the parasite (EC<inf>50</inf> = 1.5 µM) while being less toxic to the host cell (CC<inf>50</inf> = 6.0 µM). However, this trend did not extend to antiviral studies against the chikungunya virus, where [Cu(IPr)Br] displayed the highest replication inhibition (EC<inf>50</inf> = 0.807 µM) and the best selectivity index (SI = 4.8). Our findings highlight that halogen substitution plays a crucial role in modulating the biological activity of neutral linear metal-NHC complexes.

Año de publicación:

2025

Keywords:

• Copper compounds
• Halogen
• N-Heterocyclic carbenes
• Neglected diseases

Fuente:

scopus