The four possible conformers of a new tetrakisguanidino calix[4]arene thought to interact deleteriously with bacterial membranes have been synthesized, characterized, and evaluated for their in vitro cytotoxicity and antibacterial activity against various reference Gram-negative and Gram-positive bacteria, as well as Mycobacterium tuberculosis. It appears that reversal of at least one phenolic unit results in clear increases in their activities. This can be attributed to the evolution towards bolaform structures, which are able to interact more deeply with the bacterial membrane. Indeed, the 1,3-alternate conformer 16 exhibits the best antibacterial activity (MIC<1.0 μg mL-1 on Staphylococcus aureus). Moreover, 16 displays very good antibacterial activities against an isoniazid-resistant strain of M. tuberculosis (MIC=1.2 μg mL-1 ), associated with the lowest cytotoxicity, thus making it the most potent compound of the series; this could open new ways of research in the field of anti-infective drug development to meet the huge current demand.
Keywords: Mycobacterium tuberculosis; antibacterial; calixarenes; conformation analysis; cytotoxicity.
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