Synthesis of Bioactive Complex Small Molecule–CiprofloxacinConjugates and Evaluation of Their Antibacterial Activity
2020
Conjugates between pharmaceuticals
and small molecules enable access
to a vast chemical space required for the discovery of new lead molecules
with modified therapeutic potential. However, the dearth of specific
chemical reactions that are capable of functionalizing drugs and bioactive
natural products presents a formidable challenge for preparing their
conjugates. Here, we report a support-free CuI-nanoparticle-catalyzed
strategy for conjugating electron-deficient and electron-rich terminal
alkynes with a ciprofloxacin methyl ester. Our conjugation technique
exploits the late-stage functionalization of bioactive natural products
such as tocopherol, vasicinone, amino acids, and pharmaceuticals such
as aspirin and paracetamol to provide conjugates in excellent yields
under mild and green conditions. This protocol also enabled the synthesis
of (hetero)arene-ciprofloxacin 1,4-disubstituted 1,2,3-triazoles in
good yields and high regioselectivities. These synthesized ciprofloxacin
conjugates were evaluated in vitro for their antibacterial
activity against a panel of relevant bacteria. A significant number
of conjugates showed comparable activity against Gram-positive and
Gram-negative bacteria. Moreover, some conjugates exhibited less toxicity
than ciprofloxacin against two mammalian cell lines, suggesting the
utility for the future investigation of these compounds for in vivo efficacy and pharmacokinetic studies.
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