Abstract
The number of effective antituberculotic drugs is strongly limited to four first-line drugs in standard therapy. In case of resistances second-line antibiotics are used with a poor efficacy and tolerability. Therefore, novel antituberculotic drugs are urgently needed. We synthesized novel nonclassical 1,4-dihydropyridines and evaluated their antituberculotic properties depending on substituent effects. Preferred substituents could be identified. As related classical 1,4-dihydropyridines are known as inhibitors of the transmembrane efflux pump ABCB1 in cancer cells, we wondered whether a use of our compounds may be of favour to enhance the antituberculotic drug efficacy of the second-line antituberculotic drug clofazimine, which is a known substrate of ABCB1 by a suggested inhibition of a corresponding efflux pump in Mycobacterium tuberculosis (Mtb). For this, we determined the ABCB1 inhibiting properties of our compounds in a mouse T-lymphoma cell line model and then evaluated the drug-enhancing properties of selected compounds in a co-application with clofazimine in our Mtb strain. We identified novel enhancers of clofazimine toxicity which could prevent clofazimine resistance development mediated by an efflux pump activity.
Highlights
Tuberculosis (Tb) is the ninth cause of global death and the leading one from a single infectious agent, ranking above human immunodeficiency virus (HIV) [1,2]
The reaction proceeding was followed by thin layer chromatography (TLC) and mass spectrometry
If the 3-methoxy function moved to the 4-position of the 4-phenyl residue in compound we found a further reduction of the mycobacterial growth inhibition to 35%
Summary
Tuberculosis (Tb) is the ninth cause of global death and the leading one from a single infectious agent, ranking above human immunodeficiency virus (HIV) [1,2]. A resistance against both isoniazid and rifampicin results in a multidrug-resistant Tb (MDR-Tb) [1] In cases of such a resistance, second line antibiotics of the fluoroquinolone group or the injectable agents kanamycin, amikacin or capreomycin are used [5]. The therapy with those drugs is characterized by low efficacy, high toxicity, a long duration and a poor outcome of 54% [5,6]. A treatment of the so-called extensively drug-resistant Tb (MDR/XDR-Tb) which includes additional resistances against one fluoroquinolone and one-injectable agent is very difficult with an outcome of < 30% and
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