Open AccessArticle
Total Synthesis of the Antimycobacterial Natural Product Chlorflavonin and Analogs via a Late-Stage Ruthenium(II)-Catalyzed ortho-C(sp2)-H-Hydroxylation
by
Alexander Berger, Talea Knak, Anna-Lene Kiffe-Delf, Korana Mudrovcic, Vinayak Singh, Mathew Njoroge, Bjoern B. Burckhardt, Mohanraj Gopalswamy, Beate Lungerich, Lutz Ackermann, Holger Gohlke, Kelly Chibale, Rainer Kalscheuer and Thomas Kurz
Cited by 3 | Viewed by 4300
Abstract
The continuous, worldwide spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) endanger the World Health Organization’s (WHO) goal to end the global TB pandemic by the year 2035. During the past 50 years, very few new drugs have been approved by
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The continuous, worldwide spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) endanger the World Health Organization’s (WHO) goal to end the global TB pandemic by the year 2035. During the past 50 years, very few new drugs have been approved by medical agencies to treat drug-resistant TB. Therefore, the development of novel antimycobacterial drug candidates to combat the threat of drug-resistant TB is urgent. In this work, we developed and optimized a total synthesis of the antimycobacterial natural flavonoid chlorflavonin by selective ruthenium(II)-catalyzed
ortho-C(sp
2)-H-hydroxylation of a substituted 3′-methoxyflavonoid skeleton. We extended our methodology to synthesize a small compound library of 14 structural analogs. The new analogs were tested for their antimycobacterial in vitro activity against
Mycobacterium tuberculosis (
Mtb) and their cytotoxicity against various human cell lines. The most promising new analog bromflavonin exhibited improved antimycobacterial in vitro activity against the virulent H37Rv strain of
Mtb (Minimal Inhibitory Concentrations (MIC
90) = 0.78 μm). In addition, we determined the chemical and metabolic stability as well as the p
Ka values of chlorflavonin and bromflavonin. Furthermore, we established a quantitative structure–activity relationship model using a thermodynamic integration approach. Our computations may be used for suggesting further structural changes to develop improved derivatives.
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