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Synthesis and antimycobacterial activity of analogues of the bioactive natural products sampangine and cleistopholine.

Abstract：

:Identification and investigation of novel classes and compounds for the treatment of tuberculosis remains of utmost importance in the fight against the disease. Despite many efforts, the weakly gram positive Mycobacterium tuberculosis keeps demanding its toll in human lives. For this reason a small library of substituted and unsubstituted aza analogues of cleistopholine and sampangine were synthesized in a short and straightforward manner and tested in vitro against M.tb. The compounds showed promising activity against the M.tb H37Rv strain and Minimal Inhibitory Concentrations (MIC) could be observed as low as 0.88 μM. Accompanied by moderate acute toxicity against C3A hepatocytes, the therapeutic index showed an acceptable range. Further tests confirmed the inhibition by up to 74% of intracellular growth of M.tb inside macrophages conferred by 1-hydroxybenzo[g]isoquinoline-5,10-diones. Activity of the library against other clinically relevant mycobacterial species such as Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans was confirmed. Furthermore the activity against a multi-drug-resistant MDR LAM-1 M.tb strain was tested and the MIC value situated around 1 μM. The lacking genotoxicity of a group of enamine substituted cleistopholine analogues indicates this group as a hit and encourages their use as a scaffold for further studies.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Claes P,Cappoen D,Mbala BM,Jacobs J,Mertens B,Mathys V,Verschaeve L,Huygen K,De Kimpe N

doi

10.1016/j.ejmech.2013.06.010

subject

Has Abstract

pub_date

2013-09-01 00:00:00

pages

98-110

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(13)00378-4

journal_volume

67

pub_type

杂志文章

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