.ALPHA.-Glucosidase Inhibitors with a Phthalimide Skeleton. Structure-Activity Relationship Study.

Abstract

Alpha-glucosidase inhibitors with a phthalimide skeleton were prepared. Structure-activity relationship studies indicated a critical role for the hydrophobicity of the substituent at the nitrogen atom of the phthalimide skeleton. Introduction of electron-withdrawing groups, including a nitro group and chlorine, influenced the activity. Optimization studies led us to design 4,5,6,7-tetrachloro-N-phenylphthalimide (CPOP) and its N-phenylalkyl derivatives. CP0P and 4,5,6,7-tetrachloro-N-(4-phenylbutyl)phthalimide (CP4P) proved to be more potent alpha-glucosidase inhibitors than the known inhibitor 1-deoxynojirimycin.

Structural Development of Liver X Receptor (LXR) Antagonists Derived from Thalidomide-Related Glucosidase Inhibitors

“…[16][17][18] PPS-33 (6) is another competitive a-glucosidase inhibitor, but it also inhibits other enzymes, including maltase and dipeptidylpeptidase type IV.…”

“…[11][12][13][14][15][16][17][18] CP0P (4) is a non-competitive inhibitor of a-glucosidase, whereas CP4P (5) is a competitive inhibitor. [16][17][18] PPS-33 (6) is another competitive a-glucosidase inhibitor, but it also inhibits other enzymes, including maltase and dipeptidylpeptidase type IV. 19) The competitive inhibition of a-glucosidase by CP4P (5) and PPS-33 (6) indicated that these compounds might be structural mimics of glucose.…”

.ALPHA.-Glucosidase Inhibitors with a 4,5,6,7-Tetrachlorophthalimide Skeleton Pendanted with a Cycloalkyl or Dicarba-closo-dodecaborane Group.

“…[20][21][22] Structure-activity relationship studies on 4,5,6,7-tetrachloro-N-alkylphthalimide derivatives indicated that the hydrophobic group at the N(2) position is a critical factor for potent activity. 21,22) These findings led us to design several 4,5,6,7-tetrachlorophthalimide derivatives pendanted with a secondary alkyl group (5, 6), a cycloalkyl group (7-10), or a dicarba-closo-dodecaborane (carborane) (11) as the hydrophobic group at the N(2) position (Fig. 2).…”

Synthesis of N-substituted-3,4,5,6-tetrachlorophthalimide using trichloroacetimidate C-C bond formation method

“…6,7 Structural development studies showed that the hydrophobic groups at the N atom are of crucial effect. 8 Thus, N-Phenyl- 3,4,5,6-tetrachlorophthalimide (I) and N-(4-phenylbutyl)-3,4,5,6-tetrachloro-phthalimide (II) showed very potent α-Glucosidase inhibitory activity, being more potent than 1-deoxynojirimycin.…”