Seite - (000067) - in Biomedical Chemistry: Current Trends and Developments

Figure 1.2.4: β-Elimination half-lives for the adducts from electron-deficient acrylonitriles and β- mercaptoethanol (BME) – adapted from Krishnan, 2014. 1.2.3 Case Study 1: Michael Acceptors to Treat Infectious Diseases Electrophilic compounds that act as irreversible enzyme inhibitors are generally considered unsuitable drugs by medicinal chemists because the covalent binding might lead to off target effects, and many compounds are metabolically unstable (Wilson, 2013). However, this mode of action is quite common in approved drugs and biologically active molecules that inhibit enzymes (Johansson, 2012). In fact, several electrophilic compounds containing a Michael acceptor were described as potent cysteine protease inhibitors (Powers, 2002; Santos, 2007). Typically, Michael acceptor cysteine protease inhibitors have a peptide component (or mimic) that binds to subsites of the cysteine protease target. These compounds have considerable potential utility for therapeutic intervention in a variety of diseases, such as malaria, Chagas’ disease and the common cold. Peptidyl Michael acceptor inhibitors were introduced by Hanzlik and co- workers as specific irreversible inhibitors of the cysteine protease papain (Hanzlik, 1984; Thompson, 1986; Liu, 1992). Following that work, several vinyl sulfones and α,β-unsaturated carbonyl derivatives have been developed as highly potent inhibitors for many other cysteine proteases (Fig. 1.2.5) (Olson, 1999; Roush, 2001; Kumar, 2012; Graczyk, 1999; Ekici, 2006; Glória, 2011; Dragovich, 2003; Tan, 2013).