Synthesis of a PUGNAc-imidazole hybrid and its characterization as an inhibitor of human O-GlcNAcase through enzyme kinetics and X-ray structural analysis.

Albert Eschenmoser zum 80. Geburtstag mit herzlichen Glückwünschen zugeeignet.The gluco-configured C(2)-substituted tetrahydroimidazopyridines 8 -14 were prepared and tested as inhibitors of the b-glucosidases from Caldocellum saccharolyticum and from sweet almonds, and of the a-glucosidase from brewer's yeast. All new imidazopyridines are nanomolar inhibitors of the b-glucosidases and micromolar inhibitors of the a-glucosidase. The 3-phenylpropyl derivative 14 proved the strongest inhibitor of the Caldocellum b-glucosidase (K i = 0.9 nM), only slightly weaker than the known 2-phenylethyl analogue 7, and the propyl derivative 13 is the strongest inhibitor of the sweet almond b-glucosidases (K i = 3.2 nM), again slightly weaker than 7. There is no strong dependence of the inhibition on the nature of the C(2)-substituent and no clear correlation between the inhibitory strength of the known manno-configured imidazopyridines 2 -6 and the gluco-analogues 8 -12. While most manno-imidazopyridines are competitive inhibitors, the glucoanalogues proved non-competitive inhibitors of the Caldocellum b-glucosidase and mixed-type or partial mixedtype inhibitors of the sweet almond b-glucosidases. We also found that the manno-configured inhibitors 2 -6 [17] for which there were no gluco-configured counterparts are particularly strong inhibitors of snail b-mannosidase, ca. 3 -5 times stronger than 1 (K i = 20 nM) [17], the manno-analogue of the glucoconfigured 2-phenylethyl imidazopyridine 7 that is so far the strongest known inhibitor of a retaining b-glucosidase (K i = 0.1 nM, C. saccharolyticum) [15]. The parallel effect of the C(2)-substituents on the strength of the inhibition suggested that the gluco-configured imidazopyridines 8 -12 corresponding to 2 -6 should be stronger inhibitors than 7. However, a comparison of the gluco-and manno-configured C(2)-substituted imidazopyridines shows that the analogous effect of the C(2)-substituent on the strength of the inhibition is not reflected by a similarity of the type of inhibition (mixed, competitive, or non-competitive), casting some doubt on the validity of the above extrapolation. In view of these considerations and of our interest in very strong glucosidase inhibitors, we decided to prepare the gluco-analogues 8 -12. Considering the strong inhibition by the

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Heterocyclic compounds are well-known for their use in the synthesis of drugs and drug intermediates. This review provides a systematic survey on the chemical synthesis of complex heterocyclic compounds containing multistereocentres using 3-arylidene-4-chromanones in the last two decades. Regioselective and stereoselective synthesis of complex heterocycles involving 3-arylidene-chromanones and 3-arylidene-thiochormanones are dealt under various reaction headings such as epoxidation, Michael addition, 1,3dipolar cycloaddition, [3 + 2] and [4 + 2] cycloaddition, Diels-Alder reaction, sulfa-Michael/aldol cascade reactions, asym-metric synthesis employing bifunctional catalysts, chiral phase-transfer catalysts, chiral squaramide catalysts, etc. These synthetic highlights demonstrate the utility of 3arylidene-4-chromanones and 3-arylidene-thiochormanones as versatile synthons for rapid assemblage of complex condensed heterocyles and spiro-fused heterocycles towards the development of pharmaceutically active compounds. A brief highlight on the synthetic methods of 3-arylidene-4chromanone derivatives is also dealt. This review creates a platform for further improvement on the skeletal design of potential drug candidates.