2,4-Dialkyl-8,9,10,11-tetrahydrobenzo[g]pyrimido[4,5-c]isoquinoline-1,3,7,12(2H,4H)-tetraones as new leads against Mycobacterium tuberculosis

被引:20
作者
Claes, Pieter [1 ]
Cappoen, Davie [2 ]
Uythethofken, Cynthia [1 ]
Jacobs, Jan [1 ]
Mertens, Birgit [4 ]
Mathys, Vanessa [3 ]
Verschaeve, Luc [4 ,5 ]
Huygen, Kris [2 ]
De Kimpe, Norbert [1 ]
机构
[1] Univ Ghent, Fac Biosci Engn, Dept Sustainable Organ Chem & Technol, B-9000 Ghent, Belgium
[2] Sci Inst Publ Hlth, OD Communicable & Infect Dis, Sci Serv Immunol, B-1180 Uccle, Belgium
[3] Sci Inst Publ Hlth, OD Communicable & Infect Dis, Program TB & Mycobacteria, B-1180 Uccle, Belgium
[4] Sci Inst Publ Hlth, OD Publ Hlth & Surveillance, Toxicol Program, B-1050 Brussels, Belgium
[5] Univ Antwerp, Dept Biomed Sci, B-2610 Antwerp, Belgium
关键词
Benzo[g]pyrimido[4,5-c; isoquinolinetetraones; Tuberculosis; Mycobacterium tuberculosis; MDR M.tb; Acute toxicity; Genotoxicity; ANALOGS; ASSAY;
D O I
10.1016/j.ejmech.2014.03.024
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Given the re-emergence of tuberculosis in Europe and beyond, the search for novel bio-active compound classes against this disease is of utmost importance. As a result of a high intrinsic tolerance of the etiological agent, Mycobacterium tuberculosis, towards most antibiotics and xenobiotics, the search for such new compounds is far from trivial. Further exacerbated by the rapid generation and spread of drug resistant M. tuberculosis and fuelled by the HIV/AIDS pandemic, halting the tuberculosis epidemic is of paramount importance. As part of our program to design new 2-aza-anthraquinones with anti-mycobacterial activity, various dialkyltetrahydrobenzo[g]pyrimido[4,5-c]lisoquinolinetetraones were designed and synthesised. The compounds were submitted to a biological evaluation in which the activity against M.tb H37Rv(lux) was observed, as well as the acute toxicity towards J774 A.1 macrophages. From these results, the selectivity index was calculated. Furthermore, the activity of the most promising compounds was further studied against a multi-drug resistant LAM-1 strain and against intracellular replicating M.tb. The study was further extended with a comet assay and a VITOTOX (TM) assay to investigate the possibility of observable genotoxic effects caused by these compounds. (C) 2014 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:409 / 421
页数:13
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