Parallel synthesis and yeast growth inhibition screening of succinamic acid libraries.

Libraries of succinamic acid derivatives resulting from the condensation of a series of succinic acid derivatives with amines are reported as putative khafrefungin analogues. A total of 480 compounds derived from the initial condensation of 8 scaffolds with 60 different amines have been synthesized using automated technology with the help of scavenger resins. A simple acetate hydrolysis of five of the above sublibraries afforded additional 300 compounds for a total of 780 compounds. Around 55% of the library members showed purities higher than 70% (HPLC-ELS-MS) thus proving the generality of this approach. Results on growth inhibition of the yeast Saccharomyces cerevisiae in the presence of selected library members are also reported as a preliminary evaluation of the antifungal activity.

Combinatorial approach to N-substituted aminocyclitol libraries by solution-phase parallel synthesis and preliminary evaluation as glucocerebrosidase inhibitors.

Libraries of N-substituted aminocyclitol derivatives of the scyllo and racemic chiro series by means of parallel solution-phase methodology with the help of robotic technology are described. Chemical diversity has been introduced by reaction of selected scaffolds with a set of aldehydes, acyl chlorides, sulfonyl chlorides, chloroformates, and amines to afford the corresponding amines, amides, sulfonamides, carbamates and ureas, respectively. The optimized methodology has proven excellent, in terms of overall purities of the resulting libraries, for the production of amides. Sulfonamides and carbamates have been obtained in slightly lower purities, while amines afforded modest results. Selected library members have been evaluated as inhibitors of recombinant glucocerebrosidase with K(i) values ranging in the low micromolar scale for the most active members.