Bokor, Éva

Docsa, Tibor

Gergely, Pál

Somsák, László

ACS Medicinal Chemistry Letters

DEA University of Debrecen Electronic Archive

1 C‑Glucopyranosyl-1,2,4-triazoles As New Potent Inhibitors of2 Glycogen Phosphorylase3 Éva Bokor,† Tibor Docsa,‡ Paĺ Gergely,‡ and Laśzlo ́ Somsaḱ*,†4†Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary5‡Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem teŕ 1, H-4032 Debrecen,6 Hungary7 *S Supporting Information8 ABSTRACT: Glycogen phosphorylase inhibitors are consid-9 ered as potential antidiabetic agents. 3-(β-D-Glucopyranosyl)-10 5-substituted-1,2,4-triazoles were prepared by acylation of O-11 perbenzoylated N1-tosyl-C-β-D-glucopyranosyl formamidrazone and subsequent removal of the protecting groups. The best12 inhibitor was 3-(β-D-glucopyranosyl)-5-(2-naphthyl)-1,2,4-triazole (Ki = 0.41 μM against rabbit muscle glycogen phosphorylase13 b).14 KEYWORDS: 1,2,4-Triazole, C-glucopyranosyl derivative, bioisoster, glycogen phosphorylase, inhibitor15 Inhibitors of enzymes are among classics of medicinal16 chemistry, and many drug molecules’ activity is due to17 decreasing the eﬃciency of these catalytic proteins.1 In a18 chemical biological approach, ﬁnding an enzyme inhibitor is the19 result of a good match of the biological and chemical spaces20 represented by a binding site of an enzyme and a small21 molecule, respectively, ﬁtting to each other with considerable22 strength. Among several methods to design inhibitors,23 bioisosteric replacement of structural elements of existing24 molecules is widely applied and in many cases results in higher25 activity or other advantageous property of the new compound.226 Glycogen phosphorylase (GP) is the main regulatory enzyme27 of glycogen metabolism. GP, catalyzing the rate determining28 step of glycogen degradation in the liver by phosphorolysis, is29 directly responsible for the regulation of blood glucose levels.30 Therefore, GP has been a validated target in combating31 noninsulin-dependent or type 2 diabetes mellitus (T2DM), and32 its inhibitors are considered as potential antidiabetic agents.33 The biochemical and pharmacological background of this34 research has been thoroughly summarized in several reviews of35 the past decade; therefore, the reader is kindly referred to those36 papers.3−5 Furthermore, possible application of GP inhibitors37 in intervention of other diseased states associated with GP38 activity (e.g., cardiovascular disorders,6 ischemic lesions,7,8 and39 tumorous growth7) has also been under investigations.40 Several classes of compounds9,10 were shown to be inhibitors41 of GP. The most widely studied group of molecules is that of42 glucose derivatives,11,12 which bind primarily to the active site43 of GP.13 The best glucose derivatives are submicromolar44 inhibitors of rabbit muscle GPb, the prototype of GPs.1445 Glucopyranosylidene-spiro-thiohydantoin (Ki = 29.8 μM46 against rat liver GP) was shown to exert considerable in vivo47 blood sugar diminishing activity.15c1 48 N-Acyl-β-D-glucopyranosylamines (compounds 1 in Chart 1)49 were among the ﬁrst GP inhibitors,16 and many analogous50 derivatives were investigated.17−20 In this series, N-(2-51naphthoyl)-β-D-glucopyranosylamine (1 R = 2-naphthyl) was52the best inhibitor,18 which also served as a lead structure for53bioisosteric replacements. As illustrated in Chart 1, enzymatic54tests21 as well as crystallographic studies19 revealed high55similarity of amide (1) and 1,2,3-triazole (2) type inhibitors56both in binding strength and structural features of the enzyme−57inhibitor complexes. Kinetic tests of bioisosteric oxadiazoles22,23583−5 demonstrated that the constitution of the heterocycle had59a strong bearing on the inhibition: the most eﬃcient inhibitor60in these series was 5-(β-D-glucopyranosyl)-3-(2-naphthyl)-611,2,4-oxadiazole (5), which had a similar eﬃciency to that of 1.62Other investigations on C-glucopyranosyl heterocycles with63condensed rings showed that benzothiazole 7 was much less64eﬃcient than benzimidazole 8.24 An X-ray crystallographic65study of the RMGPb−8 complex revealed a speciﬁc H-bond66between NH of the heterocycle and the main chain CO of67His377,25 and the stronger binding of 8 was attributed to this68interaction, which cannot exist in the case of 7.69On the basis of these preliminaries, synthesis and study of701,2,4-triazoles of type 6 were envisaged anticipating that the H-71bond donor capacity of this heterocycle would result in72stronger inhibitors of GP.733-Glycosyl-5-substituted-1,2,4-triazoles were described in the74literature mainly with furanoid rings in reactions of C-75glycofuranosyl (thio)formimidates with hydrazide or amidra-76zone reagents26−28 or transforming a 2,5-anhydro-D,L-allono-77lactone derivative with aminoguanidine.29 3-Glycopyranosyl-5-78substituted-1,2,4-triazoles could not be located in the literature;79the only C-glycopyranosyl-1,2,4-triazoles were 1,3,5-trisubsti-80tuted derivatives obtained from glycosyl cyanides with 1-aza-2-81azoniaallene salts30 or with hydrazonoyl chlorides in the82presence of Yb(OTf)3.31Received: April 22, 2013Accepted: May 17, 2013Letterpubs.acs.org/acsmedchemlett© XXXX American Chemical Society A dx.doi.org/10.1021/ml4001529 | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXXvnh00 | ACSJCA | JCA10.0.1465/W Unicode | research.3f (R3.5.i1:3915 | 2.0 alpha 39) 2012/12/04 10:21:00 | PROD-JCA1 | rq_1372769 | 5/20/2013 10:59:53 | 483 Synthesis of the desired 3-glucopyranosyl-5-substituted-1,2,4-84 triazoles of type 6 was planned by adaptation of a literature85 protocol32 in which acylation of N1-tosylamidrazones gave 3,5-86 disubstituted-1-tosyl-1,2,4-triazoles. Removal of the N-tosyl87 group was foreseen under conditions usually applied for N-88 desulfonylation of nitrogen heterocycles.3389 To start the syntheses, O-perbenzoylated β-D-glucopyranosyl90 formimidate34 9 was reacted with tosylhydrazide to give thes1 91 necessary tosylamidrazone 10 in good yield (Scheme 1).92 Reaction of 10 with acetyl chloride furnished tosyl-triazole 11a,93 which was N-detosylated by tetrabutylammonium ﬂuoride94 (TBAF) to 12a. With acetoxyacetyl chloride 10 gave a mixture95 of 11b and 12b indicating that the N-tosyl group is prone to96 splitting oﬀ under the acylation conditions. The crude mixture97 of 11b and 12b was treated with TBAF to produce 12b in 61%98 yield for the two steps. Acylations of 10 with aromatic acid99 chlorides were accompanied by complete N-detosylation100 thereby simplifying the preparation of 12d−f, which were101 obtained in good yields. Removal of the O-acyl protecting102 groups was eﬀected under Zempleń conditions to give test103 compounds 6a and 6c−f in good to excellent yields.1043-(β-D-Glucopyranosyl)-5-substituted-1,2,4-triazoles 6 were105assayed against RMGPb as described earlier,35 and the kinetic106results, showing the compounds to be competitive inhibitors,107 t1are summarized in Table 1. Methyl (6a) and hydroxymethyl108(6c) derivatives proved weak inhibitors in the micromolar109range and were signiﬁcantly less eﬃcient than the parent110amides 1a and 1c, respectively. Appending unsubstituted111aromatic groups to the 1,2,4-triazole ring as in 6d and 6f ledChart 1. Selected Inhibitors of Glycogen Phosphorylase andTheir EﬃciencyaaKi [μM] against RMGPb for R = 2-naphthyl.bA Ki value of 2.4 μMwas measured independently by Oikonomakos and co-workers.22Scheme 1. Synthesis of 3-(β-D-Glucopyranosyl)-5-substituted-1,2,4-triazoles (6)Table 1. Inhibitiona of RMGPb by Compounds 6 andComparison to Other Nonclassical BioisosteresaKi [μM]bCalculated from the IC50 value by using a web-based tool.36ACS Medicinal Chemistry Letters Letterdx.doi.org/10.1021/ml4001529 | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXXB112 to a remarkable strengthening of the inhibition. While 1,2,4-113 oxadiazoles 5d and 5f were practically equipotent with the114 corresponding amides 1d and 1f, triazoles 6d and 6f inhibited115 the enzyme by ∼1 order of magnitude stronger, respectively.116 This indicated that the possibility for the formation of a H-117 bond was advantageous for the binding, rendering compound118 6f to one of the most eﬃcient glucose analogue inhibitors of119 GP known to date. Introduction of a t-butyl substituent in the120 4-position of the phenyl group as in 6e resulted in a much121 weaker inhibitor. This observation may reveal that the active122 site of GP, where these compounds may bind to, can not123 accommodate a bulky aliphatic moiety.124 Further studies to establish the binding peculiarities of these125 inhibitors by X-ray crystallographic investigation of the126 enzyme−inhibitor complexes as well as molecular dockings to127 predict other eﬃcient derivatives based on this skeleton are in128 progress.129 In conclusion, a new method was elaborated for the synthesis130 of hitherto unknown 3-(β-D-glucopyranosyl)-5-substituted-131 1,2,4-triazoles. These compounds inhibited rabbit muscle132 GPb, and the 5-(2-naphthyl) derivative with its submicromolar133 inhibition proved one of the best inhibitors of the enzyme.134 ■ ASSOCIATED CONTENT135 *S Supporting Information136 Representative synthetic procedures, enzyme kinetic measure-137 ments, and compound characterization. This material is138 available free of charge via the Internet at http://pubs.acs.org.139 ■ AUTHOR INFORMATION140 Corresponding Author141 *(L.S.) Tel: +3652512900, ext. 22348. Fax: +3652512744. E-142 mail: somsak@tigris.unideb.hu.143 Funding144 This work was supported by the Hungarian Scientiﬁc Research145 Fund (OTKA CK77712, CNK80709, and PD105808) as well146 as TÁMOP 4.2.1./B-09/1/KONV-2010-0007 and TÁMOP-147 4.2.2.A-11/1/KONV-2012-0025 projects implemented through148 the New Hungary Development Plan, coﬁnanced by the149 European Social Fund. T.D. thanks the Hungarian Academy of150 Sciences for a Jańos Bolyai research fellowship.151 Notes152 The authors declare no competing ﬁnancial interest.153 ■ REFERENCES(1)154 Smith, H. J.; Simons, C. Enzymes and Their Inhibition, Drug155 Development; CRC Press: Boca Raton, FL, 2005.(2)156 Lima, L. M. A.; Barreiro, E. J. Bioisosterism: a useful strategy for157 molecular modification and drug design. Curr. Med. 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C-Glucopyranosyl-1,2,4-triazoles As New Potent Inhibitors of Glycogen Phosphorylase

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C-Glucopyranosyl-1,2,4-triazoles As New Potent Inhibitors of Glycogen Phosphorylase

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