Page - (000076) - in Biomedical Chemistry: Current Trends and Developments

Figure 1.2.11: Fragmentation of 1,2,4-trioxolane to secondary carbon centred radical species and protease inhibitor, active against falcipain-2 from P. falciparum. Adapted from Gibbons, 2010. 1.2.5 Conclusions Designing selective covalent inhibitors remains one of the most attractive areas of Medicinal Chemistry, where concepts of Organic Chemistry and Biochemistry are used to discover compounds that react preferentially with the active site of the target enzyme. The chemical basis to design irreversible and reversible covalent inhibitors is now well established, providing the medicinal chemist with a variety of solutions to modulate intrinsic reactivity and reduce the likelihood of toxicity issues. The chemical toolbox is further expanded with the concept of molecular hybridization to modulate the reactivity of electrophilic warheads or even to mask these chemical functionalities. This chemical toolbox is already delivering interesting drug candidates into the pipelines of pharmaceutical companies, small biotech and academic laboratories. Acknowledgements: The authors thank Fundação para a Ciência e Tecnologia (Portugal) for financial support through iMed.ULisboa (UID/DTP/04138/2013) and grant PTDC/SAU-FAR/118459/2010, and the dedication and enthusiasm of our co-workers who were involved in some of the reactions described herein. MMMS acknowledges FCT, “Programa Operacional Potencial Humano” and the European Social Fund for the IF Programme (IF/00732/2013)