HIV infections are still among the most serious global health problems causing about twomillion fatalities per year. The low fidelity of the viral reverse transcriptaseand the fast replication rate are the main driving factors for the highmutation rate of the HI virus. This leads to extensive resistance developmentdiminishing the efficacy of several marketed drugs thus necessitating asteadfast and continuous search for new inhibitors favorably possessing a newmechanism of action.Previous work inour group has revealed 3,4-disubstituted pyrrolidines to be a promisingstarting point for the development of non-peptidic nanomolar HIV proteaseinhibitors.Based on the initial X-ray structure, the 3,4-di-substituted pyrrolidines werefurther optimised. Several docking solutions also suggested 3,5-di-substitutedpiperidines to be equally suitable core fragments.The design,synthesis, first structure activity relationships as well as X-ray structuresof the enzyme-inhibitor complexes of these non-peptidic HIV protease inhibitorswill be presented.

New inhibitors for an old target: Pyrrolidines and piperidines - promising new scaffolds to block HIV protease

241st National Meeting (2011)

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