Synthesis and biological evaluation of novel d-glucose-derived 1,2,3-triazoles as potential antibacterial and antifungal agents

Abstract

A series of novel d-glucose-derived 1,2,3-triazoles have been synthesized in excellent yields via Cu(I)-catalyzed 1,3-dipolar cycloaddition by using methyl α-d-glucopyranoside as starting material. All the new compounds were confirmed by ¹H NMR, ¹³C NMR, IR, MS, and HRMS spectra, and their antimicrobial activities were screened against Gram-Positive, Gram-Negative bacteria, and fungi. Bioactive assay manifested that some of the synthesized glucose-derived 1,2,3-triazoles exhibited good antibacterial and antifungal activities. Notably, compound 5k gave the most potent efficiency with MIC₅₀ value of 6 µM against Candida albicans, which was nine-fold more active than the reference drug Fluconazole. It also exhibited good antibacterial activity against Escherichia coli with the MIC₅₀ value of 10.8 µM compared to Chloramphenicol while the corresponding hydrochloride 4k revealed remarkable inhibitory against Bacillus subtilis with an MIC₅₀ value of 11 µM.

Introduction

The incidence of systemic microbial infections has been rapidly increasing and becoming a major threat to public health due to the dramatic upper-rising drug resistance in the past few decades. Especially, the occurrence of multi-drug resistant bacteria and fungi has emerged as a significant problem in both community and hospital acquired infections (De Marco et al., 2007; Dismukes, 2006). Among the various drugs responsible for antimicrobial activity, triazoles especially 1,2,4-triazole derivatives as an important type of nitrogen-containing aromatic heterocyclic compounds with excellent safety profile, favorable pharmacokinetic characteristics and wide biological activities showed wide range of potential applications (Peng et al., 2013a; Wang and Zhou, 2011a; Zhou and Wang 2012). This encouraged numerous researchers to engage in the development of novel 1,2,4-triazole-based antimicrobial agents with high efficiency, broad spectrum, and low toxicity in recent years (Fang et al., 2010; Wang et al., 2012; Zhang et al., 2013a). Up to now, a large number of 1,2,4-triazole antimicrobial agents (such as Itraconazole, Fluconazole, Voriconazole and Ravuconazole) have been successfully developed and widely used in clinic (Wang and Zhou, 2011a; Zhang et al., 2012). Nevertheless, the therapeutic use of these drugs is often accompanied with problems of drug resistance, undesired side effects, and limited bioavailability (Odd, 2010). Therefore, lots of efforts have been directed to optimize and modify the structure of well-known azole drugs according to the empirical development of structure–activity relationship (SAR) and prodrug theory (Hecker and Erion, 2008; Zhang et al., 2011a; Zhang and Zhou, 2011b). Apart from this, another increasing prevalent and effective strategy is to design and develop new classes of antimicrobial agents with different chemical structures and new mechanism of action from traditional drugs to improve their activities while retaining good bioavailability and safety profiles (Shi and Zhou, 2011; Zhang et al., 2012; Zhang et al., 2010). Heterocyclic compounds with special structures have displayed interesting properties in medicinal aspects (Peng et al., 2013b; Zhang et al., 2014b), and their syntheses and researches have attracted numerous attentions (Zhang et al., 2014a).

1,2,3-Triazole and its derivatives as another important class of triazoles possessing myriad potential applications in chemical synthesis, material science, and biology, have aroused progressive attention in recent years with the introduction of ‘click chemistry’ for its easy and efficient synthesis (Hawker and Wooley, 2005; Moses and Moorhouse, 2007; Wang et al., 2011b; Wang et al., 2010). In particular, 1,2,3-triazole serving as a potential pharmacophore, which was found to be potent antineoplastic (Wu et al., 2009), antibacterial (Phillips et al., 2009), antifungal (Aher et al., 2009), antitubercular (Gill et al., 2008), and anti-HIV agents (Giffin et al., 2008; Whiting et al., 2006), has occupied an important position in medicinal chemistry owing to its chemotherapeutic value (Somu et al., 2006; Tron et al., 2008; Wei et al., 2011). So far lots of 1,2,3-triazole drugs such as antibacterial cefatrizine and tazobactam as well as antiepileptic rufinamide have been extensively used in clinic, and some 1,2,3-triazole compounds as clinical candidates such as antibacterial radezolid have shown large potential (Mohebbi et al., 2014). It is especially noteworthy that 1,2,3-triazole derivatives may be considered as new entry to azole antifungal agents (Aher et al., 2009). Also, some 1,2,3-triazole derivatives were used as DNA cleaving agents (Kamal et al., 2008), potassium channel activator (Calderone et al., 2008), and cannabinoid CB1 receptor (Hou et al., 2009) and so on. 1,2,3-Triazole was stable to metabolic degradation and capable of forming hydrogen bonds, which was favoring in binding of biomolecular targets and improving solubility (Horne et al., 2004; Lv et al., 2014). Moreover, 1,2,3-triazole as an attractive bridge group, which could connect two pharmacophores to give an innovative bifunctional drug, has become increasingly useful and important in constructing bioactive molecules and functional molecules (Tron et al., 2008). Noticeably, the bioisosteric replacement between 1,2,3-triazole and its bioisoster 1,2,4-triazole, amide, or even other nitrogen-containing aromatic heterocycles is of special interest in medicinal chemistry, which represents an efficient concept for the discovery and development of novel triazole drugs. Furthermore, triazole scaffolds with extended chemical space could enhance biological activity effectively (Huber et al., 2009; Pokrovskaya et al., 2009). In addition, many investigations demonstrated that biological activity of azole derivatives was significantly influenced by the introduction of variable aromatic substituents. For example, halogen substitution or strong electron-withdrawing substitution were found to increase lipid solubility to a certain extent and could efficiently enhance the antimicrobial activity (Cui et al., 2013; Yin et al., 2014; Zhang et al., 2013b). The substitution of aromatic ring by fluorine or chlorine and other electron-withdrawing substituted aromatic rings represented a valuable strategy and were extensively employed in drug discovery.

Promoted by all above observations and considering that sugar moiety with polyhydroxyl groups has been extensively employed in drug design, frequently used to improve water solubility and usually introduced into artificial receptors to increase the interaction between receptors and guests for molecular recognition (Amblard et al., 2009; Thibodeaux et al., 2007), a series of novel d-glucose-derived 1,2,3-triazoles bearing various substituted phenyl rings were designed and synthesized in this contribution. All these newly synthesized compounds were evaluated for their antibacterial and antifungal activities. Incorporation of glucose was helpful to improve the water solubility of target molecules. Various substituted phenyl groups were introduced into the target compounds in order to investigate their SARs.

Results and discussion

Chemistry

The synthetic route for the preparation of d-glucose-derived 1,2,3-triaozles 3–5 was outlined in Scheme 1. The intermediate aryl azides were prepared from commercially available arylamines, which were treated with t-butyl nitrite and NaN₃ in t-BuOH to afford corresponding aryl azides with 75.2–90.0 % yields. Addition of small quantity of water increased the reaction rate considerably (Das et al., 2005). Compound 2 was synthesized in 80.9 % yield by the reaction of methyl 4,6-O-benzylidene-α-d-glucopyranoside with propargyl bromide in the presence of NaH using anhydrous Tetrahydrofuran (THF) as solvent. In the propargylation of methyl 4,6-O-benzylidene α-d-glucopyranoside, the reaction temperature, dropwise rate, and dosage of propargyl bromide as well as the nature of solvent exerted great influence on the reaction. Generally, slow addition of excess propargyl bromide (six equivalent of protected α-d-glucopyranoside) at low temperature such as ice-salt bath together with assurance of an anhydrous and anaerobic system facilitated the reaction and raised the yields apparently. No mono-propargyl-α-d-glucoside was obtained. Either the temperature higher than 50 °C or addition of all propargyl bromide at once resulted in a very complex system, which was difficult to separate. On the other hand, the effect of solvent was another quite important factor in the propargylation of glucoside. Our observation indicated that anhydrous aprotic solvent THF could give good reactivity and excellent yields.

Scheme 1

Synthetic route of novel glucose-derived 1,2,3-triazoles 5a–k Reagents and conditions: (i) PhCHO/ZnCl₂; (ii) NaH/abs.THF, propargyl bromide; (iii) aryl azides (2 equiv), CuSO₄•5H₂O (0.1 equiv), sodium ascorbate (0.2 equiv), DMSO/H₂O = 4:1 (v/v); (iv) 5 % hydrochloric acid; (v) 25 % NH₃ aq

The cycloaddition of acetylenic compound 2 with aryl azides using catalytic amount of copper sulfate and sodium ascorbate in t-BuOH/H₂O at room temperature afforded 1,4-disubstituted triazole compounds 3a–k in moderate to good yields ranging from 78.0 % to 97.4 %. The 4,6-O-benzylidene group of compounds 3a–k were easily deprotected with 5 % hydrochloric acid. After the reaction was completed, the solvent was evaporated and the resulting residue was washed with petroleum ether (30–60 °C) in order to remove benzaldehyde. This afforded the pure hydrochlorides 4a–k in almost quantitive yields. Subsequently, the salts 4a–k were neutralized with 25 % analytic grade ammonium hydroxide to give compounds 5a–k.

Analysis of spectra

All the new compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS, and HRMS spectra. Their spectral analyses were consistent with the assigned structures and listed in the experimental section. The mass spectra for benzimidazole compounds gave a major fragment of [M + H]⁺ according to their molecular formula.

The structures of the synthesized compounds 3a–k, 4a–k, and 5a–k were in accordance with their spectral analyses. MS of all the compounds displayed [M + Na]⁺ and [M + H]⁺ peaks corresponding to their molecular weights. Besides, triazole hydrochlorides 4a–k showed a [M + Na–2HCl]⁺ fragment ion peak in the mass spectra. (Fig. 1).

Fig. 1

Structures of some antimicrobial d-glucose-derived 1,2,3-triazole derivatives

In the ¹H NMR of compound 3a, triazole protons appeared as two distinct singlets at δ 8.23 and 8.02 ppm, indicating the different chemical environment of two triazole rings resulting from the chiral glucose. From the optimized 3D structure of compound 3a (Fig. 2), the distance between the lone pair of triazole N-3 linked by glucoside C-2 position and triazole 5-H linked glucoside C-3 chain (3.341 Ǻ) was closer than the distance between the one pair of triazole N-3 linked by glucoside C-3 position and triazole 5-H linked glucoside C-2 chain (7.860 Ǻ). Electronic effects resulted in the large downfield of triazole 5-H linked glucoside C-3 chain (Fig. 3). From the ¹³C NMR spectrum of compound 3a, two set of signals of triazole C-4 at δ 145.96 and 145.20 ppm or triazole C-5 at δ 120.62 and 120.13 ppm accounted for the above spatial influence of two triazole rings. Also, the ¹H NMR spectrum of compound 3a showed a singlet at δ 5.57 ppm due to the presence of benzylidene group, which could be confirmed by the ¹³C NMR signal of Ph-CH at δ 101.50 ppm. Similar patterns were observed in ¹H NMR and ¹³C NMR spectra of compounds 3b–k as well.

Fig. 2

The optimized 3D structure of compound 3a

Fig. 3

The ¹H NMR spectrum of compound 3a

From the ¹H NMR of compound 4a, the proton of Ph-CH, which appeared at δ 5.57 ppm of compound 3a, disappeared. The proton of triazole ring in hydrochloroates 4a–k showed large downfield shift of 0.3–0.9 ppm compared to the protected α-d-glucopyranoside derived bis-triazoles 3a–k, which can be ascribed to the presence of positive charges in the triazole system. All the anomeric 1-H signals in compounds 5a–k gave small coupling constants J values (2.9–3.6 Hz). This demonstrated that these d-glucose derivatives possessed α configuration. Thus, substitutions did not result in a change of the α-d-glucoside configuration.

In addition, the optical rotations of all the compounds showed a certain degree of regularity. All the compounds remained dextrorotation and the optical rotation pattern was observed that α values of hydrochlorides 4a–k were larger than their corresponding α-d-glucopyranoside derived bis-triazoles 5a–k, which were almost equal to compounds 3a–k.

Biological activity

The in vitro antimicrobial screening for all the synthesized compounds was evaluated for two Gram-Positive bacteria (Staphylococcus aureus ATCC 29213, Bacillus. subtilis), three Gram-negative bacteria (Escherichia coli ATCC 25922, Pseudomonas aeruginosa, B. proteus), and two fungi (Candida albicans ATCC 76615, Aspergillus fumigatus) using two-fold serial dilution technique recommended by National Committee for Clinical Laboratory Standards (NCCLS) with the positive control of clinically antimicrobial drugs Chloromycin and Fluconazole. The results of all the tested compounds were reported as minimal inhibitory concentrations (MIC₅₀, μM), and were shown in Table 1.

Table 1 In vitro antimicrobial activity of compounds 3–5

Antibacterial activity

The antibacterial data revealed that most of the benzylidene protected glucose-derived bis-triazoles gave poor antibacterial activities. But some deprotected 1,2,3-triazoles and their hydrochlorides showed moderate or even excellent antibacterial activity against tested strains.

The in vitro antibacterial evaluation demonstrated that benzylidene protected glucose triazole 3c bearing chloro moiety at meta position of benzene showed moderate inhibitory against S. aureus ATCC 29213 among all the protected glucose 1,2,3-triazoles, whereas its corresponding deprotected glucose triazole 5c exhibited excellent inhibitory activity against S. aureus with an MIC₅₀ value of 27.8 µM superior to its hydrochloride 4c and compound 3c. While introduction of chloro substituent in C-4 position of aryl triazole 5c afforded 3,4-dichloro substituted phenyl triazole 5f, which showed dramatically decreased inhibitory against S. aureus with the MIC₅₀ value of 200 µM in contrast to monochlorophenyl compound 5c. Furthermore, compounds 5h and 5k gave moderate inhibitory against S. aureus compared to their antifungal activity, and the corresponding hydrochloride 4k of compound 5k showed excellent activity against B. subtilis with an MIC₅₀ value of 11 µM superior to the protected glucose triazole 3k and deprotected derivative 5k with MIC₅₀ values of 173 and 196 µM, respectively. Compounds 5g and 5h contaning 3-fluoro-4-chlorophenyl and trifluoromethyl, respectively, as well as their hydrochlorides 4g and 4h could significantly inhibit the growth of B. proteus and E. coli at concentrations ranging from 12.5 to 52 µM except for their efficient antifungal activity against C. albicans. In addition, 3,4-dichlorophenyl triazole 5f and its hydrochloride 4f also showed moderate inhibitory against B. proteus compared to Chloramphenicol. More importantly, the bioactive data revealed that deprotected glucose bis-triazoles 5k possessed the most potent inhibitory against E. coli ATCC 25922 (MIC₅₀ = 10.8 µM) superior to its hydrochloride 4k.

From the overall results, it can be concluded that their antimicrobial activity was obviously influenced by substituents in benzene ring. As expected, some halogen-substituted or electron-withdrawing substituted aromatic compounds, which may result in the different electronic distribution of all listed compounds, really displayed good activity against tested strains. Especially, 1,2,3-triazoles 5f–h and 5k bearing 2,4-dichlorophenyl, 3-fluoro-4-chlorophenyl, trifluoromethyl, as well as ethoxycarbonylphenyl, respectively, and their hydrochlorides showed good antimicrobial activity. While meta-chloro substituted phenyl triazole 5c only gave excellent antibacterial activity against S. aureus in this study. As a result, it is necessary to further investigate these biologically active compounds as antimicrobial agents.

Antifungal activity

The antifungal tests indicated that some of the newly synthesized compounds showed potent activity in vitro. As seen in Table 1, glucose-derived 1,2,3-triaozles 5f, 5g, 5h, and their corresponding hydrochlorides 4f, 4g, and 4h, as well as compound 5k exhibited efficient activities against C. albicans with MIC₅₀ values ranging from 6 to 50 µM superior to reference drug Fluconazole. It was specially noted that deprotected glucose-derived bis-1,2,3-triazole 5k bearing ethoxycarbonyl group at para position in substituted benzene showed better inhibitory against C. albicans than its hydrochloride 4k, with an MIC₅₀ value of 6 µM, nine-fold more potent than Fluconazole.

From the antifungal activity data in Table 1, it was also observed that compounds 5f, 5g, and 5h exhibited better antifungal activity against C. albicans than their corresponding hydrochlorides. Triazole derivatives 4g and 5g with 3-fluoro-4-chlorophenyl moiety against C. albicans were superior to 3,4-dichlorophenyl triazoles 4f and 5f. The increased activity could be ascribed to the replacement of chloro substituent by fluoro moiety in C-3 position of phenyl triazoles 4f and 5f, which changed the electronic distribution and physical–chemical properties of the whole molecule and thereby influence the absorption, distribution, and metabolism of the bioactive molecules. Accordingly, strong electron withdrawing trifloromethyl substituted phenyl triazole 5h possessed potent inhibitory activity against C. albicans with the MIC₅₀ value of 25 µM, which was equivalent to that of compound 5f. Meanwhile, compound 5h possessed the best acitivity against A. fumigatus with the MIC₅₀ value of 50 µM superior to the reference drug Fluconazole among all the tested compounds, while its hydrochloride 4h gave a little weaker activity than compound 5h. In addition, para-methoxyl substituted phenyl triazole 5b and compound 5g displayed moderate antifungal activity against A. fumigatus. Other 1,2,3-triazoles gave poor or no inhibitory against A. fumigatus.

The above discussion demonstrated that the substituents in 1,2,3-triazole ring played an important role in antifungal activity, they could not only broaden their antifungal spectrum but also greatly increase the potency. Glucose-derived bis-1,2,3-triazoles containing electron withdrawing substituents such as dichloro, 3-fluoro-4-chloro, trifluoromethyl, and ethoxycarbonyl moieties, were in favor of improving antifungal activity. Especially, bis-triazoles 5f, 5g, and 5h along with their hydrochlorides, as well as compound 5k exhibited equal or even better inhibitory compared to Fluconazole. This results manifested that 1,2,3-triazole and its derivatives are of biological importance. Further study in vivo of these bioactive compounds as antifungal agents is in progress.

Conclusion

In conclusion, we have successfully prepared a series of novel glucose-derived 1,2,3-triazoles through an easy, convenient, and efficient synthetic route starting from commercially available methyl α-d-glucoside. All the new compounds were confirmed by NMR, IR, UV, and MS spectra, and their antimicrobial activities were evaluated against S. aureus, E. coli, B. proteus, B. subtilis, P. aeruginosa, C. albicans, and A. fumigatus. Based on the biological data, compound 5c with chloro group at meta position of benzene exhibited excellent activity against S. aureus with an MIC₅₀ value of 27.8 µM in comparison with Chloramphenicol. Compounds 5f–h and 5k as well as their corresponding hydrochlorides showed the most potent antimicrobial activity, even comparable or superior to the clinical drugs (Fluconazole and Chloramphenicol). The type of substituents in benzene ring had noticeable effect on the antimicrobial activity of glucose-derived 1,2,3-triazoles. These results showed that the present series containing 1,2,3-triazole as a lead is necessary to further investigate for new antimicrobial agents with potent activity and minimal toxicity.

Experimental

General methods

All air and moisture sensitive reactions were carried out in flame dried, N₂-flushed, double-neck round bottom flask sealed with rubber septa, and the reagents were injected with a syringe. THF was freshly distilled from sodium-benzophenone. Methyl 4,6-O-benzylidene α-d-glucopyranoside was prepared from methyl α-d-glucopyraoside (1). Aryl azides were prepared according to the procedure described as in the literature (Lv et al., 2014). All other chemicals and reagents were obtained from commercial suppliers and used without further purification. TLC analyses were done using pre-coated silica gel plates and visualization was done using UV lamp at 254 nm and I₂. ¹H and ¹³C NMR spectra were recorded on Bruker AV-300 or Varian-Mercury 400 spectrometer instrument (Bruker Bioscience, Varian, Palo Alto, CA, respectively, both USA). The chemical shifts were given with respect to tetramethylsilane (¹H: δ 0 ppm) and CDCl₃ (¹³C: δ 77.0 ppm). The following abbreviations were used to designate aryl groups: SUGAR = α-d-glucopyranoside, Ph = phenyl. Coupling constants were determined directly from ¹H NMR spectra. The mass spectra were recorded on FINIGAN TRACE GC/MS (Thermo Electron Corporation, Bremen, Germany). FT-IR spectra were carried out on Bruker RFS100/S spectrophotometer (Bio-Rad, Cambridge, MA, USA) using KBr pellets in the 400–4,000 cm⁻¹ range. Absorption spectra were recorded on TU1901 UV–vis spectrometer (China). Melting points were recorded on X−6 melting point apparatus. Optical rotations were measured on a JASCO P-1010 Polarimeter (JASCO Corporation, Japan) at λ = 589 nm.

Methyl 4,6-O-benzylidene-2,3-di-O-propargyl-α-d-glucopyranoside (2)

To a solution of 5.0 g (17.7 mmol) methyl 4,6-O-benzylidene α-d-glucopyranoside (Tankam et al., 2007) in 80 mL anhydrous THF was added 3.3 g (0.14 mol) sodium hydride. The suspension was stirred for 45 min and cooled with an ice-salt bath. With vigorous stirring, 4.8 mL of propargyl bromide was added slowly, and the reaction mixture was stirred for 2 days at room temperature. Brash ice was added carefully until no gas was generated. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (40 mL × 3). The combined ethyl acetate solutions were washed with saturated NaCl solution, dried with anhydride sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to column chromatography on flash chromatography on silica gel using ethyl acetate-petroleum (1:4, v/v) as eluent to give methyl 4,6-O-benzylidene-2,3-di-O-propargyl-α-d-glucopyranoside (2) as white solid (5.14 g, 80.9 %). Mp 75–77 °C. ¹H NMR (300 MHz, CDCl₃, J in Hz): δ 7.42–7.40 (m, 2H, Ph 3-H, 5-H), 7.31–7.29 (m, 3H, Ph 2-H, 4-H, 6-H), 5.47 (s, 1H, Ph CH), 4.81 (d, 1H, ³ J _1,2 = 3.7, SUGAR 1-H), 4.40–4.35 (m, 4H, 2C≡CCH₂), 4.21 (dd, 1H, ³ J _6eq,5 = 4.1, ² J _6eq,6ax = 9.6, SUGAR 6-H _eq), 3.93 (t, 1H, ³ J _3,2 = ³ J _3,4 = 9.2, SUGAR 3-H), 3.67 (ddd, 1H, ³ J _5,6eq = 4.1, ³ J _5,4 = 9.6, ³ J _5,6ax = 10, SUGAR 5-H), 3.66–3.62 (m, 2H, SUGAR 2-H, 6-H _ax,), 3.55 (t, 1H, ³ J _4,3 = 9.2, ³ J _4,5 = 9.6, SUGAR 4-H), 3.38 (s, 3H, OCH₃), 2.39–2.36 (m, 1H,≡CH), 2.10 (s, 1H,≡C–H) ppm.

General procedure for the Cu(I)-catalyzed synthesis of glucose-derived 1,2,3-triazoles 3a–k

To a solution of 500 mg (1.40 mmol) methyl 4,6-O-benzylidene-2,3-di-O-propargyl-α-d-glucopyranoside 2 in 15 mL of a t-BuOH–water mixture (4:1, v/v) was added aryl azides. Hereafter, 55 mg (0.28 mmol) sodium ascorbate and 35 mg (0.14 mmol) of copper (II) sulfate pentahydrate was added successively, and the mixture was stirred for 1.5 days at room temperature. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (10 mL × 3). The combined ethyl acetate solutions were washed with saturated NaCl solution, dried with anhydride sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to column chromatography on flash silica gel using ethyl acetate-petroleum (5:1, v/v) as eluent to give pure products 3a–k.

4,4′-(6-Methoxy-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diyl)bis(oxy)bis(methylene)bis(1-p-tolyl-1H-1,2,3-triazole) (3a)

Clay yellow solid. Yield: 97.4 %. Mp 106–107 °C. [α]$_{\text{D}}^{25}$ +65.5° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 289 nm; IR (KBr) ν: 3,137, 3,037, 2,966, 2,919, 2,858, 1,634, 1,614, 1,522, 1,450, 1,368, 1,219, 1,189, 1,148, 1,107, 1,091.9, 1,049 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.23 (s, 1H, triazole H), 8.02 (s, 1H, triazole H), 7.61 (d, 2H, ³ J = 8.3, Ar H), 7.52–7.43 (m, 4H, Ar H), 7.36 (t, 3H, ² J = 2.6, Ph 2-H, 4-H, 6-H), 7.28–7.21 (m, 4H, Ph 3-H, 5-H, Ar H), 5.57 (s, 1H, Ph-CH), 5.11–5.07 (m, 2H, OCH₂), 4.98 (s, 2H, OCH₂), 4.91 (d, 1H, ³ J _1,2 = 3.5, SUGAR 1-H), 4.30 (dd, 1H, ³ J _6eq,5 = 4.4, ² J _6eq,6ax = 9.8, SUGAR 6-H _eq), 4.14 (t, 1H, ³ J _4,3 = ³ J _2,3 = 9.2, SUGAR 3-H), 3.86 (ddd, 1H, ³ J _5,6eq = 4.4, ³ J _5,4 = 9.6, ³ J _5,6ax = 10, SUGAR 5-H), 3.79–3.70 (m, 2H, SUGAR 2-H, 6-H _ax), 3.64 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.2, SUGAR 4-H), 3.44 (s, 3H, OCH₃), 2.39 (s, 6H, Ar-CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 145.96, 145.20, 138.64, 138.45, 137.19, 134.63, 130.11, 130.05, 129.01, 128.27, 126.06, 121.52, 120.82, 120.26, 120.13, 101.50, 98.42, 81.82, 79.19, 78.06, 68.99, 66.40, 64.72, 62.21, 55.25, 21.00 ppm; EI-MS m/z: 647 [M + Na]⁺, 625 [M + H]⁺.

4,4′-(6-Methoxy-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diyl)bis(oxy)bis(methylene)bis(1-(4-methoxyphenyl)-1H-1,2,3-triazole) (3b)

Syrup. Yield: 92.1 %. [α]$_{\text{D}}^{25}$ +47.5° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 288 nm; IR (KBr) ν: 3,125, 3,043, 2,973, 2,919, 2,865, 1,645, 1,629, 1,530, 1,464, 1,363, 1,226, 1,146, 1,107, 1,045 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.26 (s, 1H, triazole H), 8.00 (s, 1H, triazole H), 7.65 (d, 2H, ³ J = 8.8, Ar H), 7.49–7.48 (m, 3H, Ar H), 7.45 (s, 1H, Ar H), 7.37 (d, 3H, ⁴ J = 2.6, Ph 2-H, 4-H, 6-H), 7.00 (d, 2H, ⁴ J = 2.6, Ph 3-H, 5-H), 6.95–6.87 (m, 2H, Ar H), 5.57 (s, 1H, Ph-CH), 5.16–5.04 (m, 2H, OCH₂), 4.99 (s, 2H, OCH₂), 4.93 (d, 1H, ³ J _1,2 = 3.3, SUGAR 1-H), 4.30 (dd, 1H, ³ J _6eq,5 = 4.2, ² J _6eq,6ax = 9.7, SUGAR 6-H _eq), 4.05 (t, 1H, ³ J _2,3 = ³ J _4,3 = 9.2, SUGAR 3-H), 3.85 (s, 6H, 2Ph-OCH₃), 3.80–3.70 (m, 3H, SUGAR 2-H, 5-H, 6-H _ax), 3.61 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.2, SUGAR 4-H), 3.44 (s, 3H, OCH₃) ppm; EI-MS m/z: 679 [M + Na]⁺, 657 [M + H]⁺.

4,4′-(6-Methoxy-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diyl)bis(oxy)bis(methylene)bis(1-(3-chlorophenyl)-1H-1,2,3-triazole) (3c)

Light yellow solid. Mp 76–77 °C. Yield: 86.1 %. [α]$_{\text{D}}^{25}$ +56.1° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 290 nm; IR (KBr) ν: 3,425, 3,118, 3,100, 2,917, 2,871, 1,597, 1,493, 1,466, 1,377, 1,088, 1,044 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.38 (s, 1H, triazole H), 8.08 (s, 1H, triazole H), 7.86 (s, 1H, Ar H), 7.73 (s, 1H, Ar H), 7.68 (d, ³ J = 6.2, 1H, Ar H), 7.59 (t, 3H, ³ J = 6.2, Ar H), 7.45–7.37 (m, 7H, Ar H), 5.57 (s, 1H, Ph-CH), 5.13–5.02 (m, 2H, OCH₂), 4.98 (s, 2H, OCH₂), 4.93 (d, 1H, ³ J _1,2 = 2.9, SUGAR 1-H), 4.31 (dd, 1H, ³ J _6eq,5 = 4.3, ² J _6eq,6ax = 9.8, SUGAR 6-H _eq), 4.05 (t, 1H, ³ J _4,3 = ³ J _2,3 = 9.2, SUGAR 3-H), 3.87 (ddd, 1H, ³ J _5,6eq = 4.3, ³ J _5,4 = 9.6, ³ J _5,6ax = 10, SUGAR 5-H), 3.79–3.69 (m, 2H, SUGAR 2-H, 6-H _ax), 3.64 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.2, SUGAR 4-H), 3.45 (s, 3H, OCH₃) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 146.19, 145.57, 137.69, 137.13, 135.47, 135.40, 130.74, 130.69, 129.12, 128.68, 128.55, 128.31, 126.05, 121.61, 120.95, 120.58, 120.51, 118.29, 118.11, 101.55, 98.32, 81.81, 77.99, 68.98, 66.13, 64.60, 62.21, 55.29 ppm; EI-MS m/z: 687 [M + Na]⁺, 665 [M + H]⁺.

4,4′-(6-Methoxy-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diyl)bis(oxy)bis(methylene)bis(1-(4-chlorophenyl)-1H-1,2,3-triazole) (3d)

White solid. Mp 168–169 °C. Yield: 95.3 %. [α]$_{\text{D}}^{25}$ +36.0° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 289 nm; IR (KBr) ν: 3,144, 3,094, 2,918, 2,863, 1,503, 1,455, 1,404, 1,375, 1,230, 1,177, 1,044, 1,091, 1,044 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.32 (s, 1H, triazole H), 8.05 (s, 1H, triazole H), 7.73 (d, 2H, ³ J = 8.9, Ar H), 7.59 (t, 6H, ³ J = 8.9, Ar H), 7.42–7.39 (m, 5H, Ar H), 5.57 (s, 1H, Ph-CH), 5.13–5.03 (m, 2H, OCH₂), 4.97 (s, 2H, OCH₂), 4.93 (d, 1H, ³ J _1,2 = 3.5, SUGAR 1-H), 4.31 (dd, 1H, ³ J _6eq,5 = 4.3, ² J _6eq,6ax = 9.8, SUGAR 6-H _eq), 4.04 (t, 1H, ³ J _4,3 = ³ J _2,3 = 9.2, SUGAR 3-H), 3.86 (ddd, 1H, ³ J _5,6eq = 4.3, ³ J _5,4 = 9.6, ³ J _5,6ax = 10, SUGAR 5-H), 3.78–3.69 (m, 2H, SUGAR 2-H, 6-H _ax), 3.64 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.2, SUGAR 4-H), 3.45 (s, 3H, OCH₃) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 146.37, 145.65, 137.23, 135.40, 134.42, 134.21, 129.86, 129.80, 129.13, 128.34, 126.12, 121.55, 121.35, 120.83, 101.61, 98.35, 81.84, 79.42, 78.01, 69.03, 66.29, 64.63, 62.26, 55.31 ppm; EI-MS m/z: 687 [M + Na]⁺, 665 [M + H]⁺.

4,4′-(6-Methoxy-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diyl)bis(oxy)bis(methylene)bis(1-(4-bromophenyl)-1H-1,2,3-triazole) (3e)

White solid. Mp 87–89 °C. Yield: 85.7 %. [α]$_{\text{D}}^{25}$ +60.5° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 287 nm; IR (KBr) ν: 3,138, 3,012, 2,932, 2,914, 2,870, 1,638, 1,561, 1,498, 1,455, 1,401, 1,372, 1,230, 1,176, 1,152, 1,090, 1,044 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.32 (s, 1H, triazole H), 8.06 (s, 1H, triazole H), 7.69–7.61 (m, 4H, Ar H), 7.57 (d, 2H, ³ J = 8.7, Ar H), 7.51–7.49 (m, 2H, Ph 3-H, 5-H), 7.45 (d, 2H, ³ J = 8.7, Ar H), 7.38–7.3 (m, 3H, Ph 2-H, 4-H, 6-H), 5.57 (s, 1H, Ph-CH), 5.10–5.02 (m, 2H, OCH₂), 4.96 (s, 2H, OCH₂), 4.93 (d, 1H, ³ J _1,2 = 3.5, SUGAR 1-H), 4.31 (dd, 1H, ³ J _6eq,5 = 4.3, ² J _6eq,6ax = 9.8, SUGAR 6-H _eq), 4.02 (t, 1H, ³ J _4,3 = ³ J _2,3 = 9.2, SUGAR 3-H), 3.85 (ddd, 1H, ³ J _5,6eq = 4.3, ³ J _5,4 = 9.6, ³ J _5,6ax = 10, SUGAR 5-H), 3.79–3.69 (m, 2H, SUGAR 2-H, 6-H _ax), 3.64 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.2, SUGAR 4-H), 3.45 (s, 3H, OCH₃) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 146.38, 145.68, 137.22, 135.86, 132.82, 132.76, 129.12, 128.33, 126.11, 122.30, 122.09, 121.77, 121.58, 121.40, 120.76, 101.60, 98.34, 81.84, 79.40, 78.00, 69.02, 66.26, 64.61, 62.25, 55.30 ppm; EI-MS m/z: 777 [M + Na]⁺, 755 [M + H]⁺.

4,4′-((6S,7S,8S,8aR)-6-Methoxy-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diyl)bis(oxy)bis(methylene)bis(1-(3,4-dichlorophenyl)-1H-1,2,3-triazole) (3f)

White solid. Mp 178 °C. [α]$_{\text{D}}^{25}$ +33.9° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 294 nm; IR (KBr) ν: 3,179, 3,123, 2,935, 2,862, 1,546, 1,461, 1,380, 1,268, 1,106 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, J in Hz) δ: 8.40 (s, 1H, triazole H), 8.07 (s, 1H, triazole H), 7.98 (d, 1H, ³ J = 2.4, Ar H), 7.83 (d, 1H, ³ J = 2.4, Ar H), 7.69–7.65 (m, 1H, Ar H), 7.58 (d, 1H, ³ J = 8.8, Ar H), 7.53–7.42 (m, 4H, Ar H), 7.40–7.36 (m, 3H, Ph 2-H, 4-H, 6-H), 5.56 (s, 1H, Ph-CH), 5.10–5.00 (m, 2H, OCH₂), 4.97–4.92 (m, 3H, OCH₂, SUGAR 1-H), 4.30 (dd, 1H, ³ J _6eq,5 = 4.8, ² J _6eq,6ax = 10.4, SUGAR 6-H _eq), 4.02 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.2, SUGAR 3-H), 3.83 (ddd, 1H, ³ J _5,6eq = 4.3, ³ J _5,4 = 9.6, ³ J _5,6ax = 10, SUGAR 5-H), 3.78–3.68 (m, 2H, SUGAR 2-H, 6-H _ax), 3.63 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.6, SUGAR 4-H), 3.45 (s, 3H, OCH₃) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 146.49, 145.92, 137.25, 135.99, 135.94, 133.98, 133.92, 132.82, 132.69, 131.43, 131.37, 129.17, 128.36, 126.13, 122.13, 122.06, 121.53, 120.93, 119.33, 119.13, 101.66, 98.37, 81.95, 79.42, 78.03, 69.06, 66.11, 64.62, 62.30, 55.35 ppm; EI-MS m/z: 755 [M + Na]⁺, 733 [M + H]⁺.

4,4′-((6S,7S,8S,8aR)-6-Methoxy-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diyl)bis(oxy)bis(methylene)bis(1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazole) (3g)

White solid. Mp 137–139 °C. [α]$_{\text{D}}^{25}$ +38.5° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 295 nm; IR (KBr) ν: 3,165, 3,036, 2,961, 2,885, 1,600, 1,531, 1,458, 1,376, 1,210, 1,035 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, J in Hz) δ: 8.38 (s, 1H, triazole H), 8.06 (s, 1H, triazole H), 7.92–7.91 (m, 1H, Ar H), 7.79–7.76 (m, 1H, Ar H), 7.71–7.67 (m, 1H, Ar v), 7.50–7.48 (m, 2H, Ph 3-H, 5-H), 7.44–7.40 (m, 1H, Ar H), 7.37–7.34 (m, 3H, Ph 2-H, 4-H, 6-H), 7.30–7.26 (m, 1H, Ar H), 7.23–7.18 (m, 1H, Ar H), 5.55 (s, 1H, Ph-CH), 5.10–5.01 (m, 2H, OCH₂), 4.99–4.91 (m, 3H, OCH₂, SUGAR 1-H), 4.29 (dd, 1H, ³ J _6eq,5 = 4.4, ² J _6eq,6ax = 10, SUGAR 6-H _eq), 4.02 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.2, SUGAR 3-H), 3.83 (ddd, 1H, ³ J _5,6eq = 4.4, ³ J _5,4 = 9.2, ³ J _5,6ax = 10, SUGAR 5-H), 3.74–3.60 (m, 3H, SUGAR 2-H, 4-H, 6-H _ax), 3.44 (s, 3H, OCH₃) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 159.07, 158.96, 156.57, 156.46, 146.34, 145.74, 137.19, 133.50, 133.45, 133.41, 129.10, 128.28, 126.07, 122.82, 122.74, 122.53, 122.45, 122.33, 122.26, 121.69, 121.11, 120.14, 120.06, 119.92, 119.84, 117.64, 117.57, 117.42, 117.34, 101.57, 98.32, 81.84, 79.38, 77.99, 68.98, 66.08, 64.56, 62.24, 55.28 ppm; EI-MS m/z: 723 [M + Na]⁺.

4,4′-((6S,7S,8S,8aR)-6-Methoxy-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diyl)bis(oxy)bis(methylene)bis(1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazole) (3h)

White solid. Mp 225–226 °C. [α]$_{\text{D}}^{25}$ +34° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 298 nm; IR (KBr) ν: 3,112, 3,079, 2,976, 2,860, 1,580, 1,463, 1,352, 1,275, 1,016 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, J in Hz) δ: 8.44 (s, 1H, triazole H), 8.15 (s, 1H, triazole H), 7.94 (d, 2H, ³ J = 8.4, Ar H), 7.77 (d, 2H, ³ J = 8.4, Ar H), 7.70 (s, 4H, Ar H), 7.52–7.49 (m, 2H, Ph 3-H, 5-H), 7.38–7.35 (m, 3H, Ph 2-H, 4-H, 6-H), 5.57 (s, 1H, Ph-CH), 5.14–5.02 (m, 2H, OCH₂), 4.99–4.95 (m, 3H, OCH₂, 1-H), 4.31 (dd, 1H, ³ J _6eq,5 = 4.8, ² J _6eq,6ax = 10.0, SUGAR 6-H _eq), 4.05 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.2, SUGAR 3-H), 3.85 (ddd, 1H, ³ J _5,6eq = 4.8, ³ J _5,4 = 9.2, ³ J _5,6ax = 10, SUGAR 5-H), 3.78–3.71 (m, 2H, SUGAR 2-H, 6-H _ax), 3.64 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.2, SUGAR 4-H), 3.45 (s, 3H, OCH₃) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 146.65, 145.99, 139.33, 139.28, 137.26, 131.16, 130.97, 130.83, 130.64, 130.50, 130.31, 130.17, 129.98, 129.17, 128.36, 127.10, 127.07, 127.03, 126.99, 126.96, 126.92, 126.16, 124.88, 122.17, 121.49, 120.90, 120.36, 120.13, 101.68, 98.34, 81.88, 79.58, 78.02, 69.05, 66.20, 64.60, 62.31, 55.34 ppm; EI-MS m/z: 733 [M + H]⁺.

4,4′-(6-Methoxy-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diyl)bis(oxy)bis(methylene)bis(1-(3-nitrophenyl)-1H-1,2,3-triazole) (3i)

Yellow solid. Mp 175–176 °C. Yield: 78.3 %. [α]$_{\text{D}}^{25}$ +42.6° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 295 nm; IR (KBr) ν: 3,155, 3,012, 2,920, 2,871, 1,536, 1,455, 1,354, 1,225, 1,089, 1,048 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.70 (s, 1H, Ar H), 8.60 (s, 1H, Ar H), 8.54 (s, 1H, triazole H), 8.31–8.25 (m, 4H, triazole H, Ar H), 8.00 (d, 1H, ³ J = 8.0, Ar H), 7.68 (t, 1H, ³ J = 8.2, Ar H), 7.51–7.50 (m, 2H, Ph 3-H, 5-H), 7.37–7.35 (m, 3H, Ph 2-H, 4-H, 6-H), 5.58 (s, 1H, Ph-CH), 5.15–5.08 (m, 2H, OCH₂), 5.04–5.00 (m, 2H, OCH₂), 4.96 (d, 1H, ³ J _1,2 = 3.3, SUGAR 1-H), 4.32 (dd, 1H, ³ J _6eq,5 = 4.3, ² J _6eq,6ax = 9.8, SUGAR 6-H _eq), 4.06 (t, 1H, ³ J _4,3 = ³ J _2,3 = 9.2, SUGAR 3-H), 3.88 (ddd, 1H, ³ J _5,6eq = 4.3, ³ J _5,4 = 9.2, ³ J _5,6ax = 9.9, SUGAR 5-H), 3.80–3.70 (m, 2H, SUGAR 2-H, 6-H _ax), 3.66 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.2, SUGAR 4-H), 3.47 (s, 3H, OCH₃) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 148.78, 146.60, 146.03, 137.60, 137.53, 137.12, 130.92, 130.86, 129.11, 128.31, 126.07, 125.85, 125.63, 123.11, 122.96, 121.81, 121.19, 115.26, 115.15, 101.56, 98.24, 81.84, 79.35, 77.98, 68.95, 65.95, 64.57, 62.20, 55.31 ppm; EI-MS m/z: 709 [M + Na]⁺, 687 [M + H]⁺.

4,4′-(6-Methoxy-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diyl)bis(oxy)bis(methylene)bis(1-(4-nitrophenyl)-1H-1,2,3-triazole) (3j)

Light yellow solid. Mp 110 °C. Yield: 83.5 %. [α]$_{\text{D}}^{25}$ +39.2° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 298 nm; IR (KBr) ν: 3,139, 2,923, 2,857, 1,599, 1,526, 1,451, 1,372, 1,344, 1,232, 1,089, 1,045 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.56 (s, 1H, triazole H), 8.42 (d, 2H, ³ J = 8.9, Ar H), 8.32 (d, 2H, ³ J = 8.9, Ar H), 8.25 (s, 1H, triazole H), 8.09 (d, 2H, ³ J = 8.9, Ar H), 7.78 (d, 2H, ³ J = 8.9, Ar H), 7.53 (t, 2H, ⁴ J = 3.6, Ph 3-H, 5-H), 7.41 (t, 3H, ⁴ J = 3.6, Ph 2-H, 4-H, 6-H), 5.59 (s, 1H, Ph-CH), 5.17–5.06 (m, 2H, OCH₂), 5.01–4.96 (m, 3H, OCH₂, SUGAR 1-H), 4.32 (dd, 1H, ³ J _6eq,5 = 4.3, ² J _6eq,6ax = 9.8, SUGAR 6-H _eq), 4.04 (t, 1H, ³ J _4,3 = ³ J _2,3 = 9.2, SUGAR 3-H), 3.88 (ddd, 1H, ³ J _5,6eq = 4.3, ³ J _5,4 = 9.2, ³ J _5,6ax = 9.9, SUGAR 5-H), 3.80–3.71 (m, 2H, SUGAR 2-H, 6-H _ax), 3.66 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.2, SUGAR 4-H), 3.46 (s, 3H, OCH₃) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 146.92, 146.27, 137.18, 129.28, 128.44, 126.18, 125.52, 125.46, 121.67, 121.08, 120.48, 120.18, 101.66, 98.16, 81.75, 79.62, 77.89, 68.99, 66.04, 64.53, 62.25, 55.35 ppm; EI-MS m/z: 709 [M + Na]⁺.

Diethyl 4,4′-(4,4′-(6-methoxy-2-phenyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diyl)bis(oxy)bis (methylene)bis (1H-1,2,3-triazole-4,1-diyl))dibenzoate (3k)

White solid. Mp 183 °C. Yield: 78.0 %. [α]$_{\text{D}}^{25}$ +50.0° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 296 nm; IR (KBr) ν: 3,145, 2,991, 2,935, 2,868, 1,721, 1,609, 1,445, 1,409, 1,368, 1,291, 1,178, 1,088, 1,045, 1,004 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.44 (s, 1H, triazole H), 8.22–8.12 (m, 5H, triazole H, Ar H), 7.90 (d, 2H, ³ J = 8.6, Ar H), 7.68 (d, 2H, ³ J = 8.6, Ar H), 7.50 (t, 2H, ⁴ J = 3.3, Ph 3-H, 5-H), 7.40 (t, 3H, ⁴ J = 3.3, Ph 2-H, 4-H, 6-H), 5.60 (s, 1H, Ph-CH), 5.17–5.07 (m, 2H, OCH₂), 5.01 (s, 2H, OCH₂), 4.96 (d, 1H, ³ J _1,2 = 3.5, SUGAR 1-H), 4.45 (q, 4H, ³ J = 7.1, 2CH₂CH₃), 4.34 (dd, 1H, ³ J _6eq,5 = 4.3, ² J _6eq,6ax = 9.8, SUGAR 6-H _eq), 4.07 (t, 1H, ³ J _4,3 = ³ J _2,3 = 9.2, SUGAR 3-H), 3.87 (ddd, 1H, ³ J _5,6eq = 4.3, ³ J _5,4 = 9.2, ³ J _5,6ax = 10, SUGAR 5-H), 3.81–3.72 (m, 2H, SUGAR 2-H, 6-H _ax), 3.67 (t, 1H, ³ J _4,3 = ³ J _4,5 = 9.2, SUGAR 4-H), 3.47 (s, 3H, OCH₃), 1.45 (t, 6H, ³ J = 7.1, 2CH₃CH₂) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 165.39, 146.50, 145.82, 139.89, 137.22, 131.24, 131.19, 130.49, 130.29, 129.18, 128.37, 126.13, 121.48, 120.81, 119.77, 119.56, 101.65, 98.37, 81.87, 79.42, 78.01, 69.04, 66.24, 64.63, 62.27, 61.36, 55.32, 14.29 ppm; EI-MS m/z: 779 [M + K]⁺, 763 [M + Na]⁺, 740 [M]⁺.

General procedure for the deprotection of compounds 3a–k

A mixture of analytic grade concentrated hydrochloric acid (1 mL), distilled water (3 mL), and methyl 4,6-O-benzylidene α-d-glucopyranoside bis-1,2,3-triazoles (500 mg) was stirred at 50 °C for 2 h. The solvents were evaporated under reduced pressure. The residue was washed with petroleum ether (30–60 °C) to remove benzaldehyde and dried to afford corresponding α-d-glucopyranoside bis-1,2,3-triazoles hydrochloride.

2-(Hydroxymethyl)-6-methoxy-4,5-bis((1-p-tolyl-1H-1,2,3-triazol-4-yl)methoxy)-tetrahydro-2H-pyran-3-ol hydrochloride (4a)

Syrup. Yield: 95.2 %. [α]$_{\text{D}}^{25}$ +80.2° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 290 nm; IR (KBr) ν: 3,409, 3,182, 3,015, 2,922, 2,876, 1,631, 1,519, 1,378, 1,243, 1,126, 1,047 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz): δ 8.84 (s, 1H, triazole H), 8.60 (s, 1H, triazole H), 7.71 (s, 4H, Ar H), 6.45 (s, 4H, Ar H), 5.22–4.97 (m, 5H, 2OCH₂, SUGAR 1-H), 3.96–3.84 (m, 4H, SUGAR 3-H, 5-H, 6-H), 3.58–3.47 (m, 2H, SUGAR 2-H, 4-H), 3.35 (s, 3H, OCH₃), 2.37 (s, 6H, 2Ph-CH₃) ppm; EI-MS m/z: 632 [M-2HCl + Na]⁺, 610 [M-2HCl + H]⁺.

2-(Hydroxymethyl)-6-methoxy-4,5-bis((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-tetrahydro-2H-pyran-3-ol hydrochloride (4b)

Syrup. Yield: 92.1 %. [α]$_{\text{D}}^{25}$ +76.2° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 289 nm; IR (KBr) ν: 3,450, 3,200, 3,010, 2,933, 2,870, 1,636, 1,524, 1,382, 1,246, 1,131, 1,049 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz): δ 8.91 (s, 1H, triazole H), 8.61 (s, 1H, triazole H), 7.74–7.64 (m, 4H, Ar H), 7.32 (d, 4H, Ar H), 5.81 (s, 6H, 2 CH₃O-Ph), 5.31–5.14 (m, 2H, OCH₂), 4.98–4.87 (m, 3H, OCH₂, SUGAR 1-H), 3.95 (d, 1H, ² J _6eq,6ax = 11.2, SUGAR 6-H _eq), 3.84 (s, 2H, SUGAR 3-H, 5-H), 3.73 (d, 1H, ² J _6eq,6ax = 11.4, SUGAR 6-H _ax), 3.57–3.49 (m, 2H, SUGAR 2-H, 4-H), 3.34 (s, 3H, OCH₃) ppm; EI-MS m/z: 591 [M-2HCl + Na]⁺.

4,5-Bis((1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(hydroxymethyl)-6-methoxy-tetrahydro-2H-pyran-3-ol hydrochloride (4c)

Light yellow solid. Mp 81–83 °C. Yield: 97.5 %. [α]$_{\text{D}}^{25}$ +94.6° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 293 nm; IR (KBr): ν: 3,407, 3,135, 3,026, 2,923, 2,891, 1,596, 1,552, 1,530, 1,512, 1,493, 1,465, 1,442, 1,345, 1,232, 1,192, 1,046.4 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz): δ 8.60 (s, 1H, triazole H), 8.48 (s, 1H, triazole H), 7.87–7.73 (m, 4H, Ar H), 7.48–7.44 (m, 4H, Ar H), 5.22–4.85 (m, 5H, 2OCH₂, SUGAR 1-H), 3.96–3.79 (m, 4H, SUGAR 3-H, 5-H, 6-H), 3.63 (s, 2H, SUGAR 2-H, 4-H), 3.39 (s, 3H, OCH₃), 3.26 (bs, 7H, 2OH including water) ppm; EI-MS m/z: 672 [M-2HCl + Na]⁺, 650 [M-2HCl]⁺.

4,5-Bis((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(hydroxymethyl)-6-methoxy-tetrahydro-2H-pyran-3-ol hydrochloride (4d)

White solid. Mp 102–103 °C. Yield: 98.1 %. [α]$_{\text{D}}^{25}$ +87.2° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 290 nm; IR (KBr) ν: 3,435, 3,126, 3,053, 2,920, 1,619, 1,561, 1,503, 1,459, 1,232, 1,193, 1,095, 1,047 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz): δ 9.28 (s, 1H, triazole H), 8.92 (s, 1H, triazole H), 7.89–7.80 (m, 4H, Ar H), 7.48 (t, ³ J = 7.3, Ar H), 5.32–4.86 (m, 6H, 2OCH₂, SUGAR 1-H, OH), 3.97–3.85 (m, 3H, SUGAR 5-H, 6-H), 3.68–3.49 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.31 (s, 3H, OCH₃), 2.42 (bs, 1H, OH) ppm; EI-MS m/z: 672 [M-2HCl + Na]⁺, 650 [M-2HCl]⁺.

4,5-Bis((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(hydroxymethyl)-6-methoxy-tetrahydro-2H-pyran-3-ol hydrochloride (4e)

Light yellow solid. Mp 104–105 °C. Yield: 98.9 %. [α]$_{\text{D}}^{25}$ +103.2° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 288 nm; IR (KBr) ν: 3,412.2, 3,156.7, 3,020.1, 2,970.8, 1,600.3, 1,560.2, 1,480.3, 1,470.8, 1,380.5, 1,335.2, 1,225.6, 1,159.7, 1,030.2, 1,011.4 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz): δ 8.50 (s, 1H, triazole H), 7.68 (s, 9H, triazole H, Ar H), 5.26 (s, 5H, 2OCH₂, SUGAR 1-H), 3.91–3.83 (m, 4H, SUGAR 3-H, 5-H, 6-H), 3.63 (s, 2H, SUGAR 2-H, 4-H), 3.41 (s, 3H, OCH₃) ppm; EI-MS m/z: 689 [M-2HCl + Na]⁺.

(3R,4S,5S,6S)-4,5-Bis((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(hydroxymethyl)-6-methoxy-tetrahydro-2H-pyran-3-ol hydrochloride (4f)

White solid. Mp 96–97 °C. Yield: 95.6 %. [α]$_{\text{D}}^{25}$ +96.4° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 296 nm; IR (KBr) ν: 3,458.4, 3,123.7, 3,016.2, 2,989.1, 1,620.8, 1,566.1, 1,476.8, 1,438.2, 1,379.5, 1,346.1, 1,262.0, 1,146.2, 1,036.4, 1,009.2 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.78 (s, 1H, triazole H), 8.56 (s, 1H, triazole H), 7.91–7.89 (m, 3H, Ar H), 7.80–7.74 (m, 3H, Ar H), 5.11–5.01 (m, 2H, OCH₂), 5.00–4.95 (m, 3H, OCH₂, SUGAR 1-H), 3.85 (s, 3H, SUGAR 5-H 6-H), 3.68–3.62 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.44 (s, 3H, OCH₃) ppm; EI-MS m/z: 645 [M-2HCl + Na]⁺.

(3R,4S,5S,6S)-4,5-Bis((1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(hydroxymethyl)-6-methoxy-tetrahydro-2H-pyran-3-ol hydrochloride (4g)

Syrup. Yield: 96.6 %. [α]$_{\text{D}}^{25}$ +77.6° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 298 nm; IR (KBr) ν: 3,412.2, 3,156.7, 3,020.1, 2,970.8, 1,600.3, 1,560.2, 1,480.3, 1,470.8, 1,380.5, 1,335.2, 1,225.6, 1,159.7, 1,030.2, 1,011.4 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, J in Hz) δ: 8.42 (s, 1H, triazole H), 8.28 (s, 1H, triazole H), 7.98–7.85 (m, 2H, Ar H), 7.83–7.79 (m, 2H, Ar H), 7.68–7.62 (m, 2H, Ar H), 5.10–5.01 (m, 2H, OCH₂), 4.99–4.93 (m, 3H, OCH₂, SUGAR 1-H), 3.83 (s, 3H, SUGAR 5-H, 6-H), 3.72–3.63 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.46 (s, 3H, OCH₃) ppm; EI-MS m/z: 613 [M-2HCl + Na]⁺.

(3R,4S,5S,6S)-2-(Hydroxymethyl)-6-methoxy-4,5-bis((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-tetrahydro-2H-pyran-3-ol hydrochloride (4h)

White solid. Mp 120 °C. Yield: 98.9 %. [α]$_{\text{D}}^{25}$ +92.8° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 301 nm; IR (KBr) ν: 3,423.0, 3,169.2, 3,013.2, 2,979.1, 1,631.8, 1,579.2, 1,476.5, 1,465.2, 1,384.2, 1,367.5, 1,320.2, 1,210.2.6, 1,167.1, 1,056.9, 1,010.7 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.56 (s, 1H, triazole H), 8.47 (s, 1H, triazole H), 7.96 (d, 4H, ³ J = 8.4, Ar H), 7.96 (d, 4H, ³ J = 8.4, Ar H), 5.11–5.00 (m, 2H, OCH₂), 4.10 (s, 3H, OCH₂, SUGAR 1-H), 3.94–3.81 (m, 4H, SUGAR 3-H, 5-H, 6-H), 3.63 (s, 2H, SUGAR 2-H, 4-H), 3.44 (s, 3H, OCH₃) ppm; EI-MS m/z: 733 [M-2HCl + Na]⁺.

2-(Hydroxymethyl)-6-methoxy-4,5-bis((1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-tetrahydro-2H-pyran-3-ol hydrochloride (4i)

Yellow solid. Mp 114 °C. Yield: 98.6 %. [α]$_{\text{D}}^{25}$ +89.7° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 286 nm; IR (KBr) ν: 3,479, 3,016, 2,985, 1,647, 1,562, 1,486, 1,351, 1,238, 1,200, 1,013 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz): δ 9.00 (s, 1H, triazole H), 8.92 (s, 1H, triazole H), 8.63–8.55 (m, 2H, Ar H), 8.31–8.21 (m, 4H, Ar H), 7.86–7.78 (m, 2H, Ar H), 4.93–4.81 (m, 5H, 2OCH₂, SUGAR 1-H), 3.74–3.62 (m, 3H, SUGAR 5-H, 6-H), 3.50–3.32 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.30 (s, 3H, OCH₃) ppm; EI-MS m/z: 694 [M-2HCl + Na]⁺.

2-(Hydroxymethyl)-6-methoxy-4,5-bis((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-tetrahydro-2H-pyran-3-ol hydrochloride (4j)

Syrup. Yield: 99.2 %. [α]$_{\text{D}}^{25}$ +82.6° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 300 nm; IR (KBr) ν: 3,481, 3,015, 2,930, 1,626, 1,561, 1,489, 1,350, 1,241, 1,483, 1,056 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz): δ 8.96 (s, 2H, 2triazole H), 8.40–8.25 (m, 4H, Ar H), 8.07–7.99 (m, 4H, Ar H), 5.17–4.95 (m, 5H, 2OCH₂, SUGAR 1-H), 3.92–3.89 (m, 3H, SUGAR 5-H, 6-H), 3.74–3.60 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.37 (s, 3H, OCH₃) ppm; EI-MS m/z: 694 [M-2HCl + Na]⁺.

Diethyl 4,4′-(4,4′-(5-hydroxy-6-(hydroxymethyl)-2-methoxy-tetrahydro-2H-pyran-3,4-diyl)bis(oxy)bis (methylene) bis(1H-1,2,3-triazole-4,1-diyl))dibenzoate hydrochloride (4k)

Yellow solid. Mp 93–94 °C. Yield: 99.1 %. [α]$_{\text{D}}^{25}$ +110.3° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 294 nm; IR (KBr) ν: 3,409, 3,010, 2,993, 2,985, 1,719, 1,610, 1,519, 1,445, 1,381, 1,282, 1,109, 1,045 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.76 (s, 1H, triazole H), 8.18 (s, 5H, triazole H, Ar H), 7.91 (s, 4H, Ar H), 5.15–4.95 (m, 5H, 2OCH₂, SUGAR 1-H), 4.40 (q, 4H, ³ J = 6.5, 2CH₂CH₃), 3.95–3.83 (m, 4H, SUGAR 3-H, 5-H, 6-H), 3.49 (s, 2H, SUGAR 2-H, 4-H), 3.37 (s, 3H, OCH₃), 1.42 (t, 6H, ³ J = 6.5, 2CH₃CH₂) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 165.13, 165.01, 145.03, 139.35, 139.02, 131.22, 130.78, 123.08, 122.62, 120.13, 119.99, 97.50, 81.66, 79.42, 71.35, 69.71, 65.02, 63.67, 61.40, 55.10, 14.19 ppm; EI-MS m/z: 675 [M-2HCl + Na]⁺.

General procedure for the synthesis of target compounds 5a–k

The deprotected α-d-glucoside bis-1,2,3-triazole hydrochloride (100 mg) was dissolved in water (5 mL). The resulting solution was neutralized with 25 % analytic grade ammonium hydroxide under stirring, and then the mixture was evaporated to dryness. The solid residue was washed with CHCl₃ (20 mL × 3). The combined CHCl₃ solution was evaporated to afford the pure compounds 5a–k.

2-(Hydroxymethyl)-6-methoxy-4,5-bis((1-p-tolyl-1H-1,2,3-triazol-4-yl)methoxy)-tetrahydro-2H-pyran-3-ol (5a)

Yellow solid. Mp 83–84 °C. Yield: 98.5 %. [α]$_{\text{D}}^{25}$ +83.9° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 288 nm; IR (KBr) ν: 3,425, 3,145, 3,099, 2,916, 2,868, 1,593, 1,502, 1,467, 1,371, 1,321, 1,229, 1,092, 1,045 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.13 (s, 1H, triazole H), 8.07 (s, 1H, triazole H), 7.56 (t, 4H, ³ J = 7.9, Ar H), 7.27 (t, 4H, ³ J = 3.7, Ar H), 5.15 (d, 1H, ² J = 12.4, 1/2OCH₂), 5.00 (d, 1H, ² J = 12.4, 1/2OCH₂), 4.93 (s, 2H, OCH₂), 4.89 (d, 1H, ³ J _1,2 = 3.3, SUGAR 1-H), 3.92–3.86 (m, 3H, SUGAR 3-H, 6-H), 3.76–3.62 (m, 3H, SUGAR 2-H, 4-H, 5-H), 3.42 (s, 3H, OCH₃) 2.40 (s, 6H, 2CH₃), 1.82 (bs, 1H, OH) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 145.88, 145.26, 138.83, 134.59, 134.51, 130.15, 121.29, 120.88, 120.78, 120.32, 97.70, 81.98, 79.59, 71.11, 70.60, 70.49, 65.86, 64.28, 62.22, 55.05, 21.00 ppm; EI-MS m/z: 559 [M + Na]⁺, 537 [M + H]⁺.

2-(Hydroxymethyl)-6-methoxy-4,5-bis((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-tetrahydro-2H-pyran-3-ol (5b)

Syrup. Yield: 96.8 %. [α]$_{\text{D}}^{25}$ +69.6° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 289 nm; IR (KBr) ν: 3,500, 3,113, 2,941, 2,875, 1,656, 1,503, 1,462, 1,441, 1,095, 1,049 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz): δ 8.15 (s, 1H, triazole H), 8.05 (s, 1H, triazole H), 7.69–7.58 (t, 4H, Ar H), 7.20 (s, 4H, Ar H), 5.01–4.94 (m, 4H, 2OCH₂), 4.89 (s, 1H, ³ J _2,1 = 2.9, SUGAR 1-H), 3.88 (s, 3H, SUGAR 5-H, 6-H), 3.85 (s, 6H, 2CH₃O-Ph), 3.72–3.68 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.42 (s, 3H, OCH₃) ppm; EI-MS m/z: 591 [M + Na]⁺.

4,5-Bis((1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(hydroxymethyl)-6-methoxy-tetrahydro-2H-pyran-3-ol (5c)

Light yellow solid. Mp 81–83 °C. Yield: 97.5 %. [α]$_{\text{D}}^{25}$ +74.5° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 289 nm; IR (KBr) ν: 3,416, 3,013, 2,995, 2,987, 1,641, 1,530, 1,597, 1,548, 1,512, 1,493, 1,467, 1,442, 1,047 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.25 (s, 1H, triazole H), 8.23 (s, 1H, triazole H), 7.80 (s, 2H, Ar H), 7.63 (d, 2H, ³ J = 7.1, Ar H), 7.47–7.42 (m, 4H, Ar H), 5.15 (d, 1H, ³ J = 12.1, 1/2OCH₂), 5.03–4.91 (m, 4H, 3/2OCH₂, SUGAR 1-H), 3.88 (s, 3H, SUGAR 3-H, 6-H), 3.76–3.61 (m, 3H, SUGAR 2-H, 4-H, 5-H), 3.42 (s, 3H, OCH₃), 3.02 (bs, 4H, 2OH including water) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 145.87, 145.44, 137.53, 137.40, 135.44, 130.77, 128.87, 128.80, 121.51, 120.53, 118.26, 97.49, 81.66, 79.48, 71.20, 70.05, 65.64, 63.92, 61.63, 55.05 ppm; EI-MS m/z: 599 [M + Na]⁺, 577 [M + H]⁺, 545 [M-CH₃OH]⁺.

4,5-Bis((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(hydroxymethyl)-6-methoxy-tetrahydro-2H-pyran-3-ol (5d)

White solid. Mp 97–98 °C. Yield: 98.8 %. [α]$_{\text{D}}^{25}$ +67.2° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 288 nm; IR (KBr) ν: 3,425, 3,107, 2,924, 2,871, 1,651, 1,503, 1,462, 1,441, 1,095, 1,049 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.20 (s, 1H, triazole H), 8.08 (s, 1H, triazole H), 7.68 (t, 4H, ³ J = 8.8, Ar H), 7.48 (t, 4H, ³ J = 7.3, Ar H), 5.16 (d, 1H, ³ J = 12.5, 1/2OCH₂), 5.00–4.89 (m, 4H, 3/2OCH₂, SUGAR 1-H), 4.52 (bs, 1H, OH), 3.88 (s, 3H, SUGAR 3-H, 6-H), 3.70–3.61 (m, 3H, SUGAR 2-H, 4-H, 5-H), 3.44 (s, 3H, OCH₃), 2.42 (bs, 1H, OH) ppm; EI-MS m/z: 617 [M + K]⁺, 599 [M + Na]⁺, 577 [M + H]⁺.

4,5-Bis((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(hydroxymethyl)-6-methoxy-tetrahydro-2H-pyran-3-ol (5e)

Light yellow solid. Mp 104–105 °C. Yield: 98.9 %. [α]$_{\text{D}}^{25}$ +68.9° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 287 nm; IR (KBr) ν: 3,388, 3,144, 3,083, 2,922, 1,593, 1,552, 1,490, 1,462, 1,409, 1,333, 1,222, 1,193, 1,051, 1,012 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.20 (s, 1H, triazole H), 8.07 (s, 1H, triazole H), 7.62 (d, 8H, ³ J = 6.4, Ar H), 5.14–5.02 (m, 1H, 1/2OCH₂), 5.00–4.91 (m, 4H, 3/2OCH₂, SUGAR 1-H), 3.87 (s, 3H, SUGAR 5-H, 6-H), 3.68–3.66 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.43 (s, 3H, OCH₃), 2.29 (bs, 5H, 2OH including water) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 146.16, 145.57, 135.68, 132.90, 122.57, 122.48, 121.78, 121.27, 120.74, 97.58, 81.87, 79.56, 70.97, 70.61, 65.79, 64.12, 62.29, 55.15 ppm; EI-MS m/z: 689 [M + Na]⁺.

(3R,4S,5S,6S)-4,5-Bis((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(hydroxymethyl)-6-methoxy-tetrahydro-2H-pyran-3-ol (5f)

White solid. Mp 96–97 °C. Yield: 95.6 %. [α]$_{\text{D}}^{25}$ +96.4° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 289 nm; IR (KBr) ν: 3,562.8, 3,210.1, 3,176.3, 3,019.1, 2,979.5, 1,625.3, 1,567.9, 1,475.2, 1,463.4, 1,376.2, 1,346.2, 1,216.3, 1,172.5, 1,049.3, 1,057.5 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.27 (s, 1H, triazole H), 8.17 (s, 1H, triazole H), 7.92 (d, 2H, ³ J = 6.2, Ar H), 7.59 (d, 4H, ³ J = 9.0, Ar H), 5.13–5.01 (m, 2H, OCH₂), 5.00–4.91 (m, 3H, OCH₂, SUGAR 1-H), 3.87 (s, 3H, SUGAR 5-H, 6-H), 3.68–3.59 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.44 (s, 3H, OCH₃) 2.69 (bs, 3H, 2OH including water) ppm; EI-MS m/z: 645 [M + H]⁺.

(3R,4S,5S,6S)-4,5-Bis((1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(hydroxymethyl)-6-methoxy-tetrahydro-2H-pyran-3-ol (5g)

Syrup. Yield: 96.6 %. [α]$_{\text{D}}^{25}$ +77.6° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 287 nm; IR (KBr) ν: 3,512.6, 3,102.5, 3,016.9, 2,876.2, 1,613.5, 1,567.9, 1,476.8, 1,456.4, 1,372.6, 1,320.4, 1,249.9, 1,162.6, 1,029.3 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.24 (s, 1H, triazole H), 8.15 (s, 1H, triazole H), 7.87 (s, 2H, Ar H), 7.64 (d, 2H, ⁴ J = 2.8, Ar H), 7.33–7.30 (m, 2H, Ar H), 5.14–5.03 (m, 2H, OCH₂), 5.01–4.91 (m, 3H, OCH₂, SUGAR 1-H), 3.87 (s, 3H, SUGAR 5-H, 6-H), 3.70–3.62 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.44 (s, 3H, OCH₃) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 159.60, 156.27, 146.26, 145.67, 133.36, 122.90, 122.70, 122.41, 121.51, 121.08, 120.10, 117.76, 117.49, 97.56, 81.79, 79.58, 71.03, 70.56, 65.80, 63.98, 62.17, 55.14 ppm; EI-MS m/z: 613 [M + H]⁺.

(3R,4S,5S,6S)-2-(Hydroxymethyl)-6-methoxy-4,5-bis((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-tetrahydro-2H-pyran-3-ol (5h )

White solid. Mp 120 °C. Yield: 98.9 %. [α]$_{\text{D}}^{25}$ +81.6° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 299 nm; IR (KBr) ν: 3,418.1, 3,179.2, 3,017.8, 2,975.2, 1,617.6, 1,564.1, 1,485.9, 1,443.5, 1,386.2, 1,373.7, 1,235.9, 1,167.2, 1,019.5 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.33 (s, 1H, triazole H), 8.26 (s, 1H, triazole H), 7.92–7.86 (m, 4H, Ar H), 7.77 (d, 4H, ³ J = 8.2, Ar H), 5.14–5.07 (m, 2H, OCH₂), 5.04–4.93 (m, 3H, OCH₂, SUGAR 1-H), 3.89 (s, 3H, SUGAR 5-H, 6-H), 3.74–3.66 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.44 (s, 3H, OCH₃), 3.35 (bs, 1H, OH) ppm; EI-MS m/z: 733 [M + H]⁺.

2-(Hydroxymethyl)-6-methoxy-4,5-bis((1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-tetrahydro-2H-pyran-3-ol (5i)

Yellow solid. Mp 95–96 °C. Yield: 97.8 %. [α]$_{\text{D}}^{25}$ +73.6° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 291 nm; IR (KBr) ν: 3,400, 3,010, 2,929, 1,619, 1,535, 1,496, 1,352, 1,233, 1,193, 1,045 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.63–8.60 (m, 2H, Ar H), 8.47 (s, 1H, triazole H), 8.41 (s, 1H, triazole H), 8.30–8.17 (m, 4H, Ar H), 7.78–7.73 (m, 2H, Ar H), 5.21–5.01 (m, 2H, OCH₂), 5.05–5.01 (m, 2H, OCH₂), 4.96 (d, 1H, ³ J _1,2 = 3.3, SUGAR 1-H), 3.88 (t, 3H, ³ J = 6.5, SUGAR 5-H, 6-H), 3.74–3.63 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.45 (s, 3H, OCH₃), 3.21 (bs, 2H, 2OH) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 148.85, 146.55, 146.00, 137.45, 130.99, 125.81, 123.20, 121.55, 121.34, 121.26, 115.22, 115.16, 97.51, 81.73, 79.56, 71.08, 70.43, 70.32, 65.81, 63.90, 61.92, 55.17 ppm; EI-MS m/z: 621 [M + Na]⁺.

2-(Hydroxymethyl)-6-methoxy-4,5-bis((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-tetrahydro-2H-pyran-3-ol (5j)

White solid. Mp 97–98 °C. Yield: 99.6 %. [α]$_{\text{D}}^{25}$ +86.3° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 289 nm; IR (KBr) ν: 3,416, 3,175, 3,011, 2,986, 1,596.6, 1,548, 1,512, 1,493, 1,467, 1,442, 1,047 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.47–8.37 (m, 4H, triazole H, Ar H), 8.33 (s, 1H, triazole H), 8.07–7.99 (m, 3H, Ar H), 7.72 (s, 1H, Ar H), 7.55 (s, 1H, Ar H), 5.19 (d, 1H, ³ J = 12, 1/2OCH₂), 5.05–4.95 (m, 4H, 3/2OCH₂, SUGAR 1-H), 4.33–4.29 (bs, 3H, 2OH incuding water), 3.89 (s, 3H, SUGAR 5-H, 6-H), 3.70–3.63 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.46 (s, 3H, OCH₃) ppm; EI-MS m/z: 637 [M + K]⁺, 621 [M + Na]⁺.

Diethyl 4,4′-(4,4′-(5-hydroxy-6-(hydroxymethyl)-2-methoxy-tetrahydro-2H-pyran-3,4-diyl)bis(oxy)bis (methylene) bis(1H-1,2,3-triazole-4,1-diyl))dibenzoate (5k)

White solid. Mp 187 °C. Yield: 99.6 %. [α]$_{\text{D}}^{25}$ +66.7° (c 0.5, CHCl₃); UV (CHCl₃): λ _max = 293 nm; IR (KBr) ν: 3,436, 3,101, 3,010, 2,995, 2,864, 1,736, 1,719, 1,498, 1,283, 1,112, 1,049 cm⁻¹; ¹H NMR (300 MHz, CDCl₃, J in Hz) δ: 8.30 (s, 1H, triazole H), 8.18 (d, 5H, ³ J = 8.8, triazole H, Ar H), 7.83 (t, 4H, ³ J = 8.8, Ar H), 5.18 (d, 1H, ² J = 12.5, 1/2OCH₂), 5.03–4.92 (m, 4H, 3/2OCH₂, SUGAR 1-H), 4.41 (q, 4H, ³ J = 6.5, 2CH₃CH₂), 3.88 (s, 3H, SUGAR 5-H, 6-H), 3.71–3.63 (m, 3H, SUGAR 2-H, 3-H, 4-H), 3.44 (s, 3H, OCH₃), 2.23 (bs, 1H, OH), 1.76 (bs, 1H, OH), 1.42 (t, 6H, ³ J = 6.5, 2CH₃CH₂) ppm; ¹³C NMR (75 MHz, CDCl₃) δ: 165.33, 146.30, 145.70, 139.70, 131.28, 130.58, 121.30, 120.76, 119.77, 97.59, 81.88, 79.60, 70.98, 70.63, 65.80, 64.11, 62.30, 61.44, 55.16, 14.28 ppm; EI-MS m/z: 675 [M + Na]⁺.

Antibacterial and antifungal assays

The in vitro minimal inhibitory concentrations (MICs) of the target compounds were determined by broth microdilution assay method in 96-well microtest plates according to the NCCLS (Kadi et al., 2007; Özbek et al., 2007). The tested microorganism strains were provided by the School of Pharmaceutical Sciences, Southwest University. Fluconazole and Chloramphenicol were obtained from their respective manufacturers served as controls.

All compounds were evaluated for their antibacterial activity against S. aureus (ATCC29213) and B. subtilis as Gram-positive, E. coli (ATCC25922), P. aeruginosa, Shigella dysenteriae and Eberthella typhosa as Gram-negative bacteria, as well as their antifungal activity against C. albicans (ATCC76615) and A. fumigatus. The minimum inhibitory concentration (MIC₅₀) values (in µM) were summarized in Table 1.