Total Synthesis of the Antimycobacterial Natural Product Chlorflavonin and Analogs via a Late-Stage Ruthenium(II)-Catalyzed ortho-C(sp2)-H-Hydroxylation

The continuous, worldwide spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) endanger the World Health Organization&rsquo;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 <i>ortho</i>-C(sp<sup>2</sup>)-H-hydroxylation of a substituted 3&prime;-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 <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) 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 <i>Mtb</i> (Minimal Inhibitory Concentrations (MIC<sub>90</sub>) = 0.78 &mu;m). In addition, we determined the chemical and metabolic stability as well as the p<i>K</i><sub>a</sub> values of chlorflavonin and bromflavonin. Furthermore, we established a quantitative structure&ndash;activity relationship model using a thermodynamic integration approach. Our computations may be used for suggesting further structural changes to develop improved derivatives.