Structural Modification of Benzimidazole-Iminosugars and Their Inhibitory Activities against β-Glycosidases

doi:10.6023/cjoc202105003

Abstract

The benzimidazole-fused tricyclic iminosugars 1 and 2 derived from D-ribose inhibited β-glucosidase significantly. On the basis of the structural modification on the phenyl ring of 1 and 2, thirty novel tricyclic iminosugars 11a~11g, 12a~12g, 13a~13h and 14a~14h bearing mono-substituent on the different positions on phenyl ring were synthesized through Mitsunobu reaction. The inhibitory activities of newly synthesized compounds were tested against β-glucosidase (almonds). The results showed that compound 13e and the mixture of 13f and 14f exhibited significantly β-glucosidase inhibitory activities with IC₅₀ values of 0.49 and 0.25 μmol/L, respectively, higher than that of the positive control, miglitol. The analysis of structure activity relationship (SAR) suggested that six-membered iminosugar ring in such fused tricyclic iminosugars was on the benefit of the compounds against β-glucosidase. The electron donor group on the 3' or 4' positions on the phenyl ring, such as methyl or methoxyl, would greatly promote the β-glucosidase inhibitory activities of the inhibitors.

Key words: fused tricyclic iminosugar, Mitsunobu reaction, β-glucosidase inhibitors, benzimidazole

Cite this article

Fengxing Li, Xin Lu, Xu Liu, Lulu Su, Xiaoliu Li, Hua Chen. Structural Modification of Benzimidazole-Iminosugars and Their Inhibitory Activities against β-Glycosidases[J]. Chinese Journal of Organic Chemistry, 2021, 41(9): 3643-3651.

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	Compd.	δ_C
	Compd.	a^a (R=F)	b^a (R=Cl)	c^a (R=Br)	d^a (R=CF₃)	e^a (R=OCH₃)	f^a (R=CH₃)	g^b (R=Cl)	h^b (R=CH₃)
C-4 (五元环)	11	61.5	61.6	61.1	61.2	61.2	60.9; 61.0^c	73.4	—^d
C-4 (五元环)	12	61.3	61.5	61.1	61.9	60.4	60.9; 61.0^c	73.4	—^d
C-5 (六元环)	13	44.4	44.4	44.4	44.5	44.5	44.3^c	44.7	44.5
C-5 (六元环)	14	44.4	44.4	43.9	44.5	44.4	44.3^c	47.1	47.0

	Compd.	δ_C
	Compd.	a^a (R=F)	b^a (R=Cl)	c^a (R=Br)	d^a (R=CF₃)	e^a (R=OCH₃)	f^a (R=CH₃)	g^b (R=Cl)	h^b (R=CH₃)
C-4 (五元环)	11	61.5	61.6	61.1	61.2	61.2	60.9; 61.0^c	73.4	—^d
C-4 (五元环)	12	61.3	61.5	61.1	61.9	60.4	60.9; 61.0^c	73.4	—^d
C-5 (六元环)	13	44.4	44.4	44.4	44.5	44.5	44.3^c	44.7	44.5
C-5 (六元环)	14	44.4	44.4	43.9	44.5	44.4	44.3^c	47.1	47.0

Compd.	R	Inhibition rate/% (100 μmol/L)	IC₅₀/(μmol•L^–1)	Compd.	R	Inhibition rate/% (100 μmol/L)	IC₅₀/(μmol•L^–1)
11a	3'-F	1.8	N.T.^b	13a	3'-F	92.4	2.46±0.23
12a	4'-F	13.4	N.T.	14a	4'-F	59.7	N.T.
11b	3'-Cl	—^a	N.T.	13b	3'-Cl	—	N.T.
12b	4'-Cl	—	N.T.	14b	4'-Cl	45.5	N.T.
11c	3'-Br	—	N.T.	13c	3'-Br	89.9	3.24±0.26
12c	4'-Br	—	N.T.	14c	4'-Br	88.5	3.34±0.49
11d	3'-CF₃	—	N.T.	13d	3'-CF₃	47.3	N.T.
12d	4'-CF₃	0.6	N.T.	14d	4'-CF₃	30.1	N.T.
11e	3'-OCH₃	52.0	N.T.	13e	3'-OCH₃	99.0	0.49±0.01
12e	4'-OCH₃	48.0	N.T.	14e	4'-OCH₃	79.1	N.T.
11f and 12f	3'-CH₃-4'-CH₃	58.7	N.T.	13f and 14f	3'-CH₃-4'-CH₃	96.9	0.25±0.01
11g	2'-Cl	—	N.T.	13g	2'-Cl	—	N.T.
12g	5'-Cl	—	N.T.	14g	5'-Cl	—	N.T.
13h	2'-CH₃	—	N.T.	14h	5'-CH₃	—	N.T.
2	H	91.7	2.85±0.24	Miglitol		99.4	0.63±0.14

Compd.	R	Inhibition rate/% (100 μmol/L)	IC₅₀/(μmol•L^–1)	Compd.	R	Inhibition rate/% (100 μmol/L)	IC₅₀/(μmol•L^–1)
11a	3'-F	1.8	N.T.^b	13a	3'-F	92.4	2.46±0.23
12a	4'-F	13.4	N.T.	14a	4'-F	59.7	N.T.
11b	3'-Cl	—^a	N.T.	13b	3'-Cl	—	N.T.
12b	4'-Cl	—	N.T.	14b	4'-Cl	45.5	N.T.
11c	3'-Br	—	N.T.	13c	3'-Br	89.9	3.24±0.26
12c	4'-Br	—	N.T.	14c	4'-Br	88.5	3.34±0.49
11d	3'-CF₃	—	N.T.	13d	3'-CF₃	47.3	N.T.
12d	4'-CF₃	0.6	N.T.	14d	4'-CF₃	30.1	N.T.
11e	3'-OCH₃	52.0	N.T.	13e	3'-OCH₃	99.0	0.49±0.01
12e	4'-OCH₃	48.0	N.T.	14e	4'-OCH₃	79.1	N.T.
11f and 12f	3'-CH₃-4'-CH₃	58.7	N.T.	13f and 14f	3'-CH₃-4'-CH₃	96.9	0.25±0.01
11g	2'-Cl	—	N.T.	13g	2'-Cl	—	N.T.
12g	5'-Cl	—	N.T.	14g	5'-Cl	—	N.T.
13h	2'-CH₃	—	N.T.	14h	5'-CH₃	—	N.T.
2	H	91.7	2.85±0.24	Miglitol		99.4	0.63±0.14

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