Design and Synthesis of Benzimidazole-Iminosugars and Their Inhibitory Activities against Glycosidases

doi:10.6023/cjoc202101055

Abstract

Based on our previous studies that benzimidazole-fused tricyclic iminosugars 1 and 2derived fromD-ribose inhibitedβ-glucosidase significantly, a series of novel tricyclic iminosugars 6a~6c and 7a~7c derived fromL -ribose and 2-deoxy-D-ribose, respectively, were designed and synthesized through the key Mitsunobu reaction. Additionally, based on the drug design method of isosterism, a series of tricyclic iminosugars derivitives 13a,13b and 17a~17e containing amino group on C-2 position, and 28a and 28b with alkoxyl group on C-4 position on sugar ring were designed. Compounds 13a and 13b were synthesized through substitution reaction of benzylamine and methylsulfonide hydroxy (OMs), while compounds 17a~17e were prepared through ring opened reaction of amine and the three-membered epoxy intermediate 15, compounds 28a and 28b were synthesized through nucleophilic substitution reaction of 4-OH and halohydrocarbon. The inhibitory activities of compounds 6a~6c,7a~7c,13a,13b,15,17a~17e,19,28a and 28bagainstα-glucosidase (Aspergillus niger),β-glucosidase (almonds) andα-galatosidase (coffee beans) were tested. The results showed that the tested compounds exhibited no or weakα-glucosidase andα-galatosidase inhibitory activities at 10 μmol/L. Some compounds exhibited good inhibitory activities againstβ-glucosidase. Among them, the epoxy intermediate 15 and compound 17a(2-amino) were the best ones with IC₅₀values of 10.5 and 11.7 μmol/L, respectively, but lower than that of the positive control 1. The results further suggested that such fused tricyclic iminosugars were the excellent and specific inhibitors againstβ-glucosidase.

Key words: fused tricyclic iminosugar, Mitsunobu reaction, glycosidase inhibitors, benzimidazole, epoxy intermediate

Cite this article

Xu Liu, Lulu Su, Zhaoxi Zhou, Liping Niu, Ligang Gao, Huanhuan Ju, Fengxing Li, Xiaoliu Li, Hua Chen. Design and Synthesis of Benzimidazole-Iminosugars and Their Inhibitory Activities against Glycosidases[J]. Chinese Journal of Organic Chemistry, 2021, 41(7): 2861-2874.

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Fig. & Tab. 15

Figure 1. Structures of β-glucosidase inhibitors 1 and 2

Scheme 1. Synthesis of benzimidazole-iminosugars 6a~6c derived from L-ribose

Figure 2. Benzimidazole-iminosugars 7a~7c derived from 2-deoxy-D-ribose

C-5 (六元环)	δ	C-4 (五元环)	δ
6a-1	44.3	6a-2	59.8
6b-1	44.5	6b-2	58.9
6c-1	44.2	6c-2	57.9
7a-1	45.9	7a-2	61.0
7b-1	45.9	7b-2	60.1
7c-1	45.6	7c-2	60.0

Table 1. Chemical shift of the ring closing carbon in compounds 6a~6c and 7a~7c

Figure 3. Key HMBC and NOESY correlations of compounds 6a-1 and 6c-2

Scheme 2. Synthesis of compounds 10 and 11

Scheme 3. Synthesis of compounds 13a and 13b

Scheme 4. Synthesis of compounds 17a~17e

Figure 4. NOESY correlations of compounds 13a and 19, and the X-ray crystallographic structure of compound 11

Scheme 5. Synthesis of compound 19

Scheme 6. Possible mechanism for the nucleophilic substitution on C-2 position

Figure 5. Key HMBC and NOESY correlations of compound 17e

Scheme 7. Synthesis of mesylated compound 22

Scheme 8. Synthesis of derivatives 28 and 28b with alkoxyl group on C-4 position

化合物	抑制率/%
化合物	α-葡萄糖糖苷酶 (黑曲霉)	β-葡萄糖糖苷酶 (杏仁)	α-半乳糖糖苷酶 (咖啡豆)
6a-1	—^a	—	—
6a-2	—	—	6.4
6b-1	—	—	—
6b-2	—	—	—
6c-1	—	—	—
6c-2	1.2	1.6	—
7a-1	—	2.0	—
7a-2	—	—	8.2
7b-1	—	—	5.2
7b-2	—	—	2.1
7c-1	—	1.4	—
7c-2	—	—	—
13a	—	—	—
13b	—	—	32.6
15	—	54.5 (10.5^b)	9.8
17a	—	50.4 (11.7)	12.2
17b	—	3.4	8.6
17c	—	—	—
17d	—	—	—
17e	—	—	—
19	—	24.1	—
28a	—	—	—
28b	—	—	—
1		70.6 (6.4)

Table 2. Inhibitory activities of compounds 6a~6c, 7a~7c, 13a, 13b, 15, 17a~17e, 19, 28a and 28b against glycosidases

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