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Chemical conjugation of 2-hexadecynoic acid to C5-curcumin enhances its antibacterial activity against multi-drug resistant bacteria

2015; Elsevier BV; Volume: 25; Issue: 22 Linguagem: Inglês

10.1016/j.bmcl.2015.10.022

1464-3405

David J. Sanabria‐Ríos, Yaritza Rivera-Torres, Joshua Rosario, Ricardo Gutierrez, Yeireliz Torres-García, Nashbly Montano, Gabriela Ortíz-Soto, Eddy Ríos‐Olivares, José W. Rodríguez, Néstor M. Carballeira,

Synthesis and Characterization of Heterocyclic Compounds

The first total synthesis of a C5-curcumin–2-hexadecynoic acid (C5-Curc–2-HDA, 6) conjugate was successfully performed. Through a three-step synthetic route, conjugate 6 was obtained in 13% overall yield and tested for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. Our results revealed that 6 was active against eight MRSA strains at MICs that range between 31.3 and 62.5 μg/mL. It was found that the presence of 2-hexadecynoic acid (2-HDA, 4) in conjugate 6 increased 4–8-fold its antibacterial activity against MRSA strains supporting our hypothesis that the chemical connection of 4 to C5-curcumin (2) increases the antibacterial activity of 2 against Gram-positive bacteria. Combinational index (CIn) values that range between 1.6 and 2.3 were obtained when eight MRSA strains were treated with an equimolar mixture of 2 and 4. These results demonstrated that an antagonistic effect is taking place. Finally, it was investigated whether conjugate 6 can affect the replication process of S. aureus, since this compound inhibited the supercoiling activity of the S. aureus DNA gyrase at minimum inhibitory concentrations (MIC) of 250 μg/mL (IC50 = 100.2 ± 13.9 μg/mL). Moreover, it was observed that the presence of 4 in conjugate 6 improves the anti-topoisomerase activity of 2 towards S. aureus DNA gyrase, which is in agreement with results obtained from antibacterial susceptibility tests involving MRSA strains.