Gluco-1 H-imidazole: A New Class of Azole-Type β-Glucosidase Inhibitor

TY - JOUR

T1 - Gluco-1 H-imidazole

T2 - A New Class of Azole-Type β-Glucosidase Inhibitor

AU - Schröder, Sybrin P

AU - Wu, Liang

AU - Artola, Marta

AU - Hansen, Thomas

AU - Offen, Wendy A

AU - Ferraz, Maria J.

AU - Li, Kah-Yee

AU - Aerts, Johannes M F G

AU - Van Der Marel, Gijsbert A.

AU - Codée, Jeroen D C

AU - Davies, Gideon J

AU - Overkleeft, Herman S.

N1 - © 2018 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2018

Y1 - 2018

N2 - Gluco-azoles competitively inhibit glucosidases by transition-state mimicry and their ability to interact with catalytic acid residues in glucosidase active sites. We noted that no azole-type inhibitors described, to date, possess a protic nitrogen characteristic for 1 H-imidazoles. Here, we present gluco-1 H-imidazole, a gluco-azole bearing a 1 H-imidazole fused to a glucopyranose-configured cyclitol core, and three close analogues as new glucosidase inhibitors. All compounds inhibit human retaining β-glucosidase, GBA1, with the most potent ones inhibiting this enzyme (deficient in Gaucher disease) on a par with glucoimidazole. None inhibit glucosylceramide synthase, cytosolic β-glucosidase GBA2 or α-glucosidase GAA. Structural, physical and computational studies provide first insights into the binding mode of this conceptually new class of retaining β-glucosidase inhibitors.

AB - Gluco-azoles competitively inhibit glucosidases by transition-state mimicry and their ability to interact with catalytic acid residues in glucosidase active sites. We noted that no azole-type inhibitors described, to date, possess a protic nitrogen characteristic for 1 H-imidazoles. Here, we present gluco-1 H-imidazole, a gluco-azole bearing a 1 H-imidazole fused to a glucopyranose-configured cyclitol core, and three close analogues as new glucosidase inhibitors. All compounds inhibit human retaining β-glucosidase, GBA1, with the most potent ones inhibiting this enzyme (deficient in Gaucher disease) on a par with glucoimidazole. None inhibit glucosylceramide synthase, cytosolic β-glucosidase GBA2 or α-glucosidase GAA. Structural, physical and computational studies provide first insights into the binding mode of this conceptually new class of retaining β-glucosidase inhibitors.

KW - Journal Article

U2 - 10.1021/jacs.8b02399

DO - 10.1021/jacs.8b02399

M3 - Article

C2 - 29601200

SP - 1

EP - 4

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

ER -