16934-07-9Relevant articles and documents
A Cinchona Alkaloid Antibiotic That Appears to Target ATP Synthase in Streptococcus pneumoniae
Wang, Xu,Zeng, Yuna,Sheng, Li,Larson, Peter,Liu, Xue,Zou, Xiaowen,Wang, Shufang,Guo, Kaijing,Ma, Chen,Zhang, Gang,Cui, Huaqing,Ferguson, David M.,Li, Yan,Zhang, Jingren,Aldrich, Courtney C.
, p. 2305 - 2332 (2019/04/25)
Optochin, a cinchona alkaloid derivative discovered over 100 years ago, possesses highly selective antibacterial activity toward Streptococcus pneumoniae. Pneumococcal disease remains the leading source of bacterial pneumonia and meningitis worldwide. The structure-activity relationships of optochin were examined through modification to both the quinoline and quinuclidine subunits, which led to the identification of analogue 48 with substantially improved activity. Resistance and molecular modeling studies indicate that 48 likely binds to the c-ring of ATP synthase near the conserved glutamate 52 ion-binding site, while mechanistic studies demonstrated that 48 causes cytoplasmic acidification. Initial pharmacokinetic and drug metabolism analyses of optochin and 48 revealed limitations of these quinine analogues, which were rapidly cleared, resulting in poor in vivo exposure through hydroxylation pendants to the quinuclidine and O-dealkylation of the quinoline. Collectively, the results provide a foundation to advance 48 and highlight ATP synthase as a promising target for antibiotic development.
Positional isomerization of quinine and quinidine via rhodium on alumina catalysis: Practical one-step synthesis of Δ3,10-isoquinine and Δ3,10-isoquinidine
Portlock, David E.,Naskar, Dinabandhu,West, Laura,Seibel, William L.,Gu, Titan,Krauss, Howard J.,Peng, X. Sean,Dybas, Paul M.,Soyke, Edward G.,Ashton, Stephen B.,Burton, Jonathan
, p. 5365 - 5368 (2007/10/03)
The synthesis of Δ3,10-isoquinine (5Z,5E) and Δ3,10-isoquinidine (6Z,6E) was achieved in one-step through positional isomerization of the terminal alkene in the parent cinchona alkaloids using catalytic amounts of 5% Rh/Al2O3 and excess hydrochloric acid in refluxing 50% aqueous EtOH. The products were obtained in good yields as a mixture of E and Z geometric isomers and fully characterized using spectroscopic methods.
