2-{3-[4-(Alkylsulfinyl)phenyl]-1-benzofuran-5-yl}-5-methyl-1,3,4-oxadiazole Derivatives as Novel Inhibitors of Glycogen Synthase Kinase-3β with Good Brain Permeability

Saitoh, Morihisa; Kunitomo, Jun-ichi; Kimura, Eiji; Iwashita, Hiroki; Uno, Yumiko; Onishi, Tomohiro; Uchiyama, Noriko; Kawamoto, Takahiro; Tanaka, Toshimasa; Mol, Clifford D.; Dougan, D.R.; Textor, Garret P.; Snell, G.; Takizawa, Masayuki; Itoh, Fumio; Kori, Masakuni

doi:10.1021/jm900647e

Cited by 110 publications

(62 citation statements)

References 36 publications

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“…[17][18][19][20] Benzimidazole constitutes an indispensible construction motif for the development of compounds of medicinal interest due to its diverse pharmaceutical applications and its derivatives have also been identified as strong GSK-3β inhibitors. [21][22][23] Suitable structural combinations of benzimidazole core with various pharmacophores in a single molecular framework have resulted in improved GSK-3β inhibitory potential and alleviation of associated disorders. 22 The thiadiazole as well as its bioisosteric oxadiazole heterocyclic frameworks have been regarded as the privileged scaffolds for GSK-3 inhibitory activity.…”

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confidence: 99%

“…[21][22][23] Suitable structural combinations of benzimidazole core with various pharmacophores in a single molecular framework have resulted in improved GSK-3β inhibitory potential and alleviation of associated disorders. 22 The thiadiazole as well as its bioisosteric oxadiazole heterocyclic frameworks have been regarded as the privileged scaffolds for GSK-3 inhibitory activity. 24,25 Also, the carbohydrazide motif possesses favourable H-bond donors as well as acceptors for it to interact strongly with the GSK-3β target site and hence could give higher GSK-3β inhibition (and consequently better antidepressant activity).…”

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Synthesis of benzimidazole based thiadiazole and carbohydrazide conjugates as glycogen synthase kinase-3β inhibitors with anti-depressant activity

Khan

Tantray

Hamid

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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Synthesis of benzimidazole based thiadiazole and carbohydrazide conjugates as glycogen synthase kinase-3β inhibitors with anti-depressant activity

Khan

Tantray

Hamid

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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“…Compounds with 1,3,4-oxadiazole-2-thiones cores have occupied a specific place in medicinal and synthetic chemistry because of their extensive range of biological activities such as antibacterial [2], antifungal, anti-inflammatory, antiviral, anticancer [1], enzyme inhibitor [3], anticonvulsant and anti-diabetic properties [4]. The 1,3,4-oxadiazole nucleus undergoes a variety of chemical reactions such as electrophilic and nucleophilic substitutions, as well as photochemical and thermal reactions [5].…”

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Abstract Purpose: To design and synthesize a series of new structural motifs of urease inhibitors, 3-[{(substituted phenyl) amino} methyl]-5-(3, 4, 5-trimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones and 3-{[(pyridin-2-yl)amino]methyl}- 5-(3,4,5-trimethoxy phenyl)-1,3,4-oxadiazole-2(3H) 4,5,9,10,12,13, values in the range of 5. 93 ± 0.13 to 9.76 ± 0.11,

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Synthesis, biological evaluation and molecular docking studies of Mannich bases derived from 1, 3, 4-oxadiazole- 2-thiones as potential urease inhibitors

Akram¹,

Saeed²,

ahmed³

et al. 2018

Trop. J. Pharm Res

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“…1) and this compound significantly reduced tau phosphorylation in a mouse model. 3) Compound (S)-1 initially was obtained by the resolution of racemic-1 using chiral high performance liquid chromatography (HPLC). Although separation by HPLC was a sufficient method for the preparation of small quantities of (S)-1, large scale production was expected to be problematic for this compound.…”

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Enantioselective Synthesis of the Novel Chiral Sulfoxide Derivative as a Glycogen Synthase Kinase 3.BETA. Inhibitor

Saitoh

Kunitomo

Kimura

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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Alzheimer's disease (AD) is a neurodegenerative disorder manifested by cognitive and memory deterioration, progressive impairment of the activities involved in daily living, and behavioral disturbances. Glycogen synthase kinase 3b (GSK3b) inhibitors are thought to be attractive agents for the treatment of AD.1,2) Recently we reported a novel GSK-3b inhibitor ( Fig. 1) and this compound significantly reduced tau phosphorylation in a mouse model. 3)Compound (S)-1 initially was obtained by the resolution of racemic-1 using chiral high performance liquid chromatography (HPLC). Although separation by HPLC was a sufficient method for the preparation of small quantities of (S)-1, large scale production was expected to be problematic for this compound. Thus, we investigated asymmetric synthesis routes for (S)-1. Among the various methods of asymmetric oxidation for sulfides, 4) the method using a chiral titanium complex derived from a Sharpless reagent reported by Kagan and colleagues 5) is attractive. Our colleagues have previously applied this methodology to the synthesis of optically active lansoprazole.6) Therefore, we embarked upon optimizing reaction conditions for preparing (S)-1 from prochiral sulfides 2 (Chart 1). Results and DiscussionThe starting material, methyl sulfide 2 was prepared by the 6-step protocol previously reported.3) Spectroscopic data and X-ray crystal structures confirmed the configuration of (S)- 1.3) First, we attempted conditions similar to those used for the synthesis of chiral lansoprazole, 6) which used a stoichiometric amount of Ti(O-i-Pr) 4 , (ϩ)-diethyl tartrate (DET) as ligand, cumene hydroperoxide (CHP) as oxidant, and toluene or dichloromethane as solvent, in the presence of water. Because of the difficulty in separating the sulfoxide 1 and sulfone 3, we used substoichiometric CHP (0.83 eq) relative to sulfide. The condition using toluene as solvent resulted in production of undesired enantiomer with low enantiomeric excess (Table 1, entry 1). We assumed the low enantioselectivity was caused by low solubility of sulfide 2 in toluene. Therefore, we used dichloromethane as solvent and reaction proceeded in a homogenous solution to show improved enantiomeric excess of 66% ee (entry 2). From this result, we used dichloromethane in further investigations. Since (ϩ)-DET resulted in the conversion of sulfide 2 to the undesired (R)-1, we changed the ligand to (Ϫ)-DET. It is known that the amount of water significantly affects the selectivity of this reaction. 5) Although combination of Ti(O-i-Pr) 4 /H 2 O (1 : 1) is effective in enantioselective oxidation, 7) 0.5 eq of water ensured a good enantiomeric excess for this particular substrate (entries 3-5). Lower temperature was preferred in terms of selectivity and afforded good enantiomeric excess (entries 6-8). However, the reaction rate tended to be slow at low temperatures and reaction was not completed within 24 h at Ϫ40°C (entries 9, 10). Enantioselectivity was not affected by the use of molecular sieves (entry 11).7) Other ligands suc...

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2-{3-[4-(Alkylsulfinyl)phenyl]-1-benzofuran-5-yl}-5-methyl-1,3,4-oxadiazole Derivatives as Novel Inhibitors of Glycogen Synthase Kinase-3β with Good Brain Permeability

Cited by 110 publications

References 36 publications

Synthesis of benzimidazole based thiadiazole and carbohydrazide conjugates as glycogen synthase kinase-3β inhibitors with anti-depressant activity

Synthesis of benzimidazole based thiadiazole and carbohydrazide conjugates as glycogen synthase kinase-3β inhibitors with anti-depressant activity

Synthesis, biological evaluation and molecular docking studies of Mannich bases derived from 1, 3, 4-oxadiazole- 2-thiones as potential urease inhibitors

Enantioselective Synthesis of the Novel Chiral Sulfoxide Derivative as a Glycogen Synthase Kinase 3.BETA. Inhibitor

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