cleistopholine and sampangine

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.

Topics: Alkaloids; Anthraquinones; Anti-Bacterial Agents; Aza Compounds; Biological Products; Dose-Response Relationship, Drug; Heterocyclic Compounds, 4 or More Rings; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium; Naphthyridines; Structure-Activity Relationship

Hetero analogues of the alkaloids cleistopholine and sampangine were prepared in order to investigate the significance of the (aza)quinoid partial structures for antimicrobial activity. Several analogues containing amino or sulfone groups showed high antimicrobial activities, indicating that the (aza)quinoid partial structures of the alkaloids are not an indispensable requisite for antimicrobial activity.

Topics: Alkaloids; Anthraquinones; Anti-Bacterial Agents; Antifungal Agents; Aza Compounds; Heterocyclic Compounds, 4 or More Rings; Naphthyridines; Structure-Activity Relationship