Chloroquinolines

Chloroquinolines are reactive groupings due to electron-deficient carbon to which the halogen is attached. This carbon is electron-deficient due to the combined electron-withdrawing effects of the chlorine substituent and the quinoline nitrogen. The electrophilic carbon is thus able to react readily with nucleophiles present in the body. The impact of this grouping on a molecule is illustrated by 6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (Figure 8.28). In contrast to many related compounds (chromone-carboxylates) lacking the chloroquinoline, 6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate is excreted as a

Fig. 8.28 Structure of 6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quino-line-2,8-dicarboxylate which, in contrast to many related compounds (chromone-carboxylates) lacking the chloroquinoline, is excreted as a glutathione conjugate.

Fig. 8.28 Structure of 6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quino-line-2,8-dicarboxylate which, in contrast to many related compounds (chromone-carboxylates) lacking the chloroquinoline, is excreted as a glutathione conjugate.

8.11 Toxicity Prediction - Computational Toxicology 115

glutathione conjugate [30] formed by nucleophilic attack on the halogen of the chloroquinoline function by the thiol group of glutathione and resultant halogen displacement. Other compounds are excreted as unchanged drug with no evidence of any metabolic breakdown. Moreover the reactivity of the chloroquinoline is illustrated by the observation that the reaction with glutathione occurs without enzyme (glu-tathione-S-transferase) present in vitro, albeit at a slower rate.

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