Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors.

ABSTRACT: This work aims to synthesize new trehalase inhibitors selective towards the insect trehalase versus the porcine trehalase, in view of their application as potentially non-toxic insecticides and fungicides. The synthesis of a new pseudodisaccharide mimetic 8, by means of a stereoselective ?-glucosylation of the key pyrrolizidine intermediate 13, was accomplished. The activity of compound 8 as trehalase inhibitor towards C.riparius trehalase was evaluated and the results showed that 8 was active in the ?M range and showed a good selectivity towards the insect trehalase. To reduce the overall number of synthetic steps, simpler and more flexible disaccharide mimetics 9-11 bearing a pyrrolidine nucleus instead of the pyrrolizidine core were synthesized. The biological data showed the key role of the linker chain's length in inducing inhibitory properties, since only compounds 9 (?,?-mixture), bearing a two-carbon atom linker chain, maintained activity as trehalase inhibitors. A proper change in the glucosyl donor-protecting groups allowed the stereoselective synthesis of the ?-glucoside 9?, which was active in the low micromolar range (IC50 = 0.78 ?M) and 12-fold more potent (and more selective) than 9? towards the insect trehalase.

SUBMITTER: D'Adamio G 

PROVIDER: S-EPMC6017881 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other