Synthesis of 1,2,3-triazole glycoconjugates as inhibitors of a-glucosidases David R. da Rocha a , Wilson C. Santos b,d , Emerson S. Lima c , Vitor F. Ferreira a,⇑ a Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, CEG, Campus do Valonguinho, 24210-141 Niterói, RJ, Brazil b Universidade Federal Fluminense, Faculdade de Farmácia, Programa de Pós-Graduação em Ciências Aplicadas a Produtos Para Saúde (PPG-CAPS), Rua Mário Viana, 523, 24241-000 Niterói, Brazil c Universidade Federal do Amazonas, Faculdade de Ciências da Saúde, 69010-300 Manaus, AM, Brazil d Instituto Teófilo Hernando, Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Avda Arzobispo Morcillo, 4, 28029, Spain article info Article history: Received 3 November 2011 Received in revised form 22 December 2011 Accepted 25 December 2011 Available online 3 January 2012 Keywords: Triazole Glycoconjugates a-Glucosidase abstract Ten new 1,2,3-triazole glycoconjugates were synthesized from D-glucose and evaluated in in vitro assays for their ability to inhibit the enzyme a-glucosidase. Most of the compounds had low activity or were inactive when compared with acarbose. However, the derivative 1,2-O-isopropylidene-3-phenyl-5-(4- phenyl-1H-1,2,3-triazole-1-yl)-a-D-ribofuranose (19i) possessed activity comparable with the standard drug. The influence of the phenyl group on carbon 3 of the carbohydrate framework is discussed. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction A glycosidic bond is a covalent chemical bond between the anomeric carbon atom of a saccharide and some other group or mol- ecule. Many polysaccharides are formed from the union of monosac- charides by a- or b-glycosidic bonds. During the digestion process, these bonds are hydrolyzed by specific glycosidase enzymes that lib- erate the carbohydrate units as nutrients. 1 For instance, a-amylase enzymes are produced in the digestive system to break down the a-glycosidic bonds of starch. Several glycosidase enzymes are involved in important biological processes, 2 such as intestinal diges- tion and the lysosomal catabolism of glycoconjugates. Additionally, these enzymes are involved in virus production 3,4 and cancer metas- tasis 5–7 and are targets for anti-hyperglycemic pharmacological agents. In this regard, digestive a-glucosidases control rapid in- creases in blood glucose and therefore are therapeutically useful for the treatment of metabolic diseases such as diabetes mellitus. 8 Many organisms have endogenous inhibitors that control the activity of glycosidases and glycosyl transferases. For instance, nojirimycin (1) and deoxynojirimycin (2) are potent inhibitors for a- and b-glucosidases and are produced by several natural sources. Since the discovery of these compounds, several other glycosidase inhibitors have been isolated from plants and microorganisms. 9 The search for a-glucosidase inhibitors led to the isolation of acar- bose (3), marketed as Glucobay Ò and Precose, from the Actinopla- nes strain SE 50 and is used as a potent sucrase inhibitor (Fig. 1). 10 Acarbose consists of a polyhydroxylated aminocyclohexene derivative (valienamine) that is linked via its nitrogen atom to 6-deoxyglucose, which is a-(1?4)-linked to a maltose moiety (Fig. 1). This compound inhibits pig intestinal sucrase with an IC 50 of 0.5 mM. 11 After many clinical investigations, acarbose was introduced in the market in 1990 for the treatment of type 2 diabetes mellitus. 7 The inhibition of pancreatic a-amylase and intestinal a-glucosidases has demonstrated great value in the con- trol of blood glucose levels by slowing down the starch digestion rate. 12–16 The strong inhibition of human amylases by acarbose (IC 50 108.8 ± 12.3 lM) is attributed both to the partial planarity of the valienamine ring and to the presence of strong electrostatic interactions between the carboxyl groups at the active site and the protonated nitrogen atom of the inhibitor. Polysubstituted five-membered azaheterocycles have been de- scribed as potent glycosidase inhibitors. These heterocycles mimic the sugars moieties, and notable structural scaffolds include pyr- role-, imidazole-, 17,18 [1,2,3]-triazole- 19–24 , and tetrazolo-glyco- derivatives. 25,26 The importance of triazolic compounds is of particular interest for medicinal chemistry, and many of them have been employed as pharmaceutically active compounds or as prototypes for poten- tial drugs. In this regard, [1,2,3]-triazoles have gained increasing attention due to the ease of their incorporation into molecules via ‘click’ chemistry. 27,28 These heterocycles can actively partici- pate in hydrogen bonding and dipole–dipole interactions due to their strong dipole moments. Additionally, they are extremely sta- ble against hydrolysis and oxidative/reductive conditions. They are 0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2011.12.026 ⇑ Corresponding author. E-mail address: cegvito@vm.uff.br (V.F. Ferreira). Carbohydrate Research 350 (2012) 14–19 Contents lists available at SciVerse ScienceDirect Carbohydrate Research journal homepage: www.elsevier.com/locate/carres