Biological evaluation of bisbenzaldehydes against four Mycobacterium species

• A library of 33 bisbenzaldehydes and analogs has been synthesized.
• Mycobacterium tuberculosis growth inhibition was observed at submicromolar concentrations.
• Activity against MDR M. tb and Mycobacterium bovis was observed for the hits.
• Intracellular growth of M. tb in macrophages was inhibited by twelve compounds.
• Low acute toxicity and absence of genotoxicity were observed.

A series of bisbenzaldehydes and structurally related analogs, conveniently synthesized via microwave-assisted reactions, were evaluated in vitro against drug susceptible and multi-drug resistant Mycobacterium tuberculosis, against virulent Mycobacterium bovis, against Mycobacterium ulcerans and against two Mycobacterium avium subspecies. Among the 33 substances that were tested, compound 12, i.e. 4,4′-[1,12-dodecanediyl(oxy)]bisbenzaldehyde, emerged as the most promising hit. Its activity was further confirmed in an intracellular growth inhibition assay of M. tb in murine J774 A.1 macrophages. None of the compounds showed significant cytotoxicity on human C3A hepatocytes in a neutral red dye uptake assay and no genotoxicity or mutagenicity was observed as demonstrated by a VITOTOX™ test and confirmed with a comet assay.

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