Rational design and synthesis of novel triazole- and tetrazole-fused iminosugars as potential inhibitors of amyotrophic lateral sclerosis (ALS) linked SOD1 aggregation.

ABSTRACT

In this manuscript we report the first example of an iminosugar that inhibits superoxide dismutase fibrillation associated with the amyotrophic lateral sclerosis (ALS). The present work involves synthesis of novel triazole and tetrazole embedded iminosugars, synthesized in 11-13 high yielding steps starting from readily available tri-O-benzyl-D-glucal and proceeding through a concomitant azidation - thermal intramolecular [3 + 2] cycloaddition reaction as the key step. One of these pre-designed iminosugars was found to inhibit fibrillation of SOD1 and also has shown propensity to break pre-formed fibrils. Docking and MD simulation studies suggest that the most probable interaction of this compound is a hydrogen bonding with Arg69, a loop IV residue of SOD1, which has a crucial role in stabilizing the native conformation of SOD1.