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キーワード:
drug resistance
epoxide hydrolases
new substances
stilbene
tuberculosis
要旨:
Objectives: Tuberculosis (TB) and multidrug- and extensively drug-resistant TB in particular are remaining a major global health challenge and efficient new drugs against TB are needed. This study evaluated the anti-tubercular activity of a natural stilbene and its synthetic derivatives against M. tuberculosis. Methods: Isopropylstilbene and its synthetic derivatives were analyzed for their anti-tubercular activity against M. tuberculosis ATCC 27294 as well as multidrug- and extensively drug-resistant M. tuberculosis clinical isolates by using MGIT 960 instrumentation and EpiCenter software equipped with TB eXiST module. Cytotoxic effects of drug candidates were determined by a MTT dye reduction assay using A549 adenocarcinomic human alveolar basal epithelial cells. Results: Growth of M. tuberculosis ATCC 27294 was suppressed by the natural isopropylstilbene HB64 as well as synthetic derivatives DB56 and DB55 at 25 microg/ml. Growth of clinical isolates MDR and XDR M. tuberculosis was suppressed by HB64 at 100 microg/ml as well as by synthetic derivatives DB56 and DB55 at 50 microg/ml and 25 microg/ml, respectively. No anti-tubercular activity was demonstrated for synthetic derivatives DB53, EB251, and RB57 at 100 microg/ml. Toxicity in terms of IC50 values of HB64, DB55 and DB56 were 7.92 microg/ml, 12.15 microg/ml and 16.01 microg/ml, respectively. Conclusions: Synthetical derivatives of stilbene might be effective candidates as anti-tubercular drugs. However, toxicity of these substances as determined by IC50 values might limit therapeutic success in vivo. Further investigations should address lowering the toxicity for parenteral administration by remodeling stilbene derivatives.
