Design and synthesis of naphthalimide group-bearing thioglycosides as novel ?-N-acetylhexosaminidases inhibitors.

ABSTRACT: GH20 human ?-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these ?-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (Ki?=?0.91?µM against hsHexB; Ki?>?100?µM against hOGA) and compound 15b (Ki?=?3.76?µM against hOGA; Ki?=?30.42?µM against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure-activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific ?-N-acetylhexosaminidase inhibitors.

SUBMITTER: Shen S 

PROVIDER: S-EPMC6009855 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature