title: 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.
authors.affiliation: Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Claes
authors.forename: Davie
authors.initials: D
authors.lastname: Cappoen
authors.forename: Blaise Mavinga
authors.initials: BM
authors.lastname: Mbala
authors.forename: Jan
authors.initials: J
authors.lastname: Jacobs
authors.forename: Birgit
authors.initials: B
authors.lastname: Mertens
authors.forename: Vanessa
authors.initials: V
authors.lastname: Mathys
authors.forename: Luc
authors.initials: L
authors.lastname: Verschaeve
authors.forename: Kris
authors.initials: K
authors.lastname: Huygen
authors.forename: Norbert
authors.initials: N
authors.lastname: De Kimpe
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000880:Anthraquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009161:Mycobacterium / Q000187:drug effects* / Q000254:growth & development; D009287:Naphthyridines; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000880:Anthraquinones; D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D001688:Biological Products; D006576:Heterocyclic Compounds, 4 or More Rings; D009287:Naphthyridines; C511287:cleistopholine; C121572:sampangine
keywords: Acute toxicity; Antibiotics; Cleistopholine; Pyridinium ylids; Sampangine; Tuberculosis