697260-51-8Relevant 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.
Heterogeneous Enantioselective Hydrogenation of Activated Ketones Catalyzed by Modified Pt-Catalysts: A Systematic Structure-Selectivity Study
Exner, Christian,Pfaltz, Andreas,Studer, Martin,Blaser, Hans-Ulrich
, p. 1253 - 1260 (2007/10/03)
A systematic structure-selectivity study was carried out for the enantioselective hydrogenation of activated ketones with chirally modified Pt/Al2O3 catalysts. For this, 18 modifiers containing an extended aromatic system able to form a strong adsorption complex with the Pt surface, and a suitable chiral group with an amino function capable to interact with the keto group of the substrate (HCd, Qd, HCn, Qn, and semi-synthetic derivatives, as well as synthetic analogues) were prepared and tested on 8 different activated ketones in AcOH and toluene under standard conditions. It was found that relatively small structural changes of the substrate and/or modifier structures strongly affected the enantioselectivity, and that no "best" modifier exists for all substrates. The highest ees for all substrates were obtained with quinuclidine-derived modifiers in combination with naphthalene or quinoline rings, either in AcOH (substrates 1-5 and 8, all carrying an sp3 carbon next to the keto group) or toluene (6 and 7, with an sp2 carbon next to the ketone). The presence and nature of the substituent R′ at the quinuclidine significantly affected the ee (positive and negative effects). Certain combinations of an aromatic system and an amino function were preferred: For the quinuclidine moiety, quinoline and to a somewhat lesser extent naphthalene were a better match, while for the pyrrolidinylmethyl group anthracene was better suited. Methylation of the OH group often had a positive effect for hydrogenations in AcOH but not in toluene. With the exception of 8, higher ees were obtained for the Cd/ Qn series [leading to (R)-products] than for the Cn/ Qd series [leading to (S)-products]. In several cases, opposite structure-selectivity trends were detected when comparing reactions in toluene and AcOH, indicating a significant influence of the solvent.
