Microwave-Assisted Synthesis and Enzyme Stabilization Study of <i>N</i> -Alkyl Praziquantel Analogs for Arylsulfatase B: Possible Leads for Mucopolysaccharidosis VI Therapy

Mutations in the lysosomal enzyme arylsulfatase B result in the genetic disorder mucopolysaccharidosis VI. Current treatment for mucopolysaccharidosis VI requires intravenous enzyme replacement therapy which suffers from incomplete biodistribution. Alternative therapeutic approaches based on small molecules acting as enzyme stabilizers or pharmacological chaperones facilitate the transport of mutant enzymes to the lysosome and may offer improved biodistribution. Herein we describe the development of a facile microwave-assisted reductive amination to synthesize N-alkyl substituted analogs of praziquantel. The analogs were then tested for their ability to stabilize wild-type arylsulfatase B against thermal denaturation. We identify one analog that does not inhibit recombinant arylsulfatase B but can stabilize it against thermal denaturation as a potential lead compound in the treatment of mucopolysaccharidosis VI.