Investigation of the effect of cucurbit[7]uril complexation on the photophysical and acid–base properties of the antimalarial drug quinine

Abstract

Host-guest complexation of mono and dicationic quinine with cucurbit[7]uril (CB7), a water-soluble macrocyclic host molecule, has been investigated. Job's plot, time-resolved anisotropy as well as concentration dependent NMR titration confirm the binding of two CB7 macrocycles with one quinine molecule. The binding affinity of dicationic quinine with CB7 is one order of magnitude higher than the binding constant of mono-cationic quinine. Such preferential binding results in one unit pK shift in the ground-state of the quinoline ring. However, using fluorescence spectroscopy we have obtained two acid-dissociation constants, one for quinoline ring nitrogen and the other for the nitrogen of the quinuclidine moiety. In the excited state, CB7 complexation causes one unit pK shift for the quinoline ring and 1.9 unit shift for the quinuclidine moiety. Interestingly, a large enhancement of fluorescence lifetime and anisotropy of quinine at pH 2.7 and pH 9.0 upon CB7 complexation was observed due to the restriction of conformational flexibility. Moreover, at pH 3.0, a large fluorescence enhancement of quinine due to CB7 complexation was observed and it was quite significant as compared to that of quinine in 0.1 (M) HCl without CB7. We believe that this study of quinine complexation with CB7 will reduce phototoxicity, increase bioavailability and offer an alternative standard for quantum yield measurements in an amiable condition.

Cucurbit[n]uril Host‐Guest Complexes of Acids, Photoacids, and Super Photoacids

“…There have been two recent investigations of the effects of CB[7] complexation of the antimalarial drug quinine ( 20 ) on its photophysical and acid‐base properties . Koner and co‐workers report that two CB[7] hosts can bind over the diprotonated guest (QH 2 2+ ), with the binding constants ( K 2 > K 1 ) decreasing slightly from pH 2 to pH 9, where the monoprotonated form (QH + ) dominates. The p K a value of 4.1 for the protonated quinoline nitrogen increases to 5.2 upon formation of the 2 : 1 complex.…”

Cellular metabolic activity marker via selective turn-ON detection of transporter protein using nitrobenzoxadiazole-based fluorescent reporter

“…the excitation polarizer. The single exponential fitting function was employed by iterative deconvolution method using supplied software DAS v6.2 as described earlier 27,28 . The quality of the fitted data was judged from the reduced chi-squared value (χ 2 ), calculated using the IBH software provided with the instrument.…”

Cucurbit[7]uril: an emerging candidate for pharmaceutical excipients

“…CB[7] also induced a p K a shift of the ocular therapeutic tropicamide (∼0.5 p K a units), promoting the dominance of the cationic form of this mydriatic drug in ocular pH (pH ∼7), thus potentially enhancing its permeation to the corneal epithelium, suggesting that CB[7] could serve as an alternative to acidified tropicamide, which has caused significant discomfort to the eyes . The antimalarial drug dicationic quinine formed 2:1 complexes with CB[7]; the binding constant of dicationic quinine is one order of magnitude higher than that of monocationic quinine (in which only the quinuclidine nitrogen was ionized), thus inducing a ∼1 p K a unit upward shift for the quinoline ring and a 1.9‐unit upward shift for the quinuclidine moiety of quinine . Meanwhile, the interactions between CB[7] and the fungicide fuberidazole (FBZ) also stabilized FBZ, as CB[7] induced an upward p K a shift of FBZ by 3.8 units with CB[7] preferentially bound to the protonated form ( K FBZH = 3.2 × 10 5 M –1 ) rather than the neutral form ( K FBZ = 5.0 × 10 2 M –1 ) .…”

“…36 The antimalarial drug dicationic quinine formed 2:1 complexes with CB [7]; the binding constant of dicationic quinine is one order of magnitude higher than that of monocationic quinine (in which only the quinuclidine nitrogen was ionized), thus inducing a ß1 pK a unit upward shift for the quinoline ring and a 1.9-unit upward shift for the quinuclidine moiety of quinine. 37 Meanwhile, the interactions between CB [7] and the fungicide fuberidazole (FBZ) also stabilized FBZ, as CB [7] induced an upward pK a shift of FBZ by 3.8 units with CB [7] preferentially bound to the protonated form (K FBZH = 3.2 × 10 5 M -1 ) rather than the neutral form (K FBZ = 5.0 × 10 2 M -1 ). 38 With the antihistamine drug tripelennamine (TRP), the formation of a CB[7]-TRP complex induced pK a shifts of 1.5 and 2.5 units of the ethyldimethylammonium and exocyclic nitrogen of TRP, respectively.…”