1H NMR spectroscopic identification of protonable sites in cryptolepines with C-11 substituents containing two amino functionalities

Knowledge of protonable sites and acid dissociation constants of cryptolepine derivatives having C-11 substituents containing two amino functionalities is of great importance to the understanding of the mechanism of their antimalarial action, which may contribute to their further development as drug candidates. In this work, we applied 1H NMR titration to investigate the acid-base characteristics of these polyprotic compounds in the pH range 3-13. We identified three acid-base equilibria with most acid dissociation constants (pK a*) being greater than 10.5, which prevented us from using the potentiometric method. Overall, 1H NMR titration was sensitive and suitable for the determination of pK a values for these drug leads. Copyright © 2012 John Wiley & Sons, Ltd.