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  • br Author contributions br Conflict of

    2021-09-18


    Author contributions
    Conflict of interest
    Acknowledgments We appreciate technical support of the Research Support Center at the Graduate School of Medical Sciences of the Kyushu University. This study was supported by the Uehara Memorial Foundation and a KAKENHI grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan to FTY (25460334, 17K08598) and MA (15K18990).
    Introduction
    Chemistry The esterfication of the carboxylic acids 1a, b afforded compounds 2a, b which were converted to the hydrazides 3a, b. The hydrazide 3c was commercially available. Reaction of the hydrazides 3a–c with carbon disulfide (CS2) afforded the oxadiazoles 4a–c (Scheme 1) [28], [31], [32]. The biphenyls 7a–h were prepared in two steps from commercial p-tolylboronic Torcetrapib and bromobenzene bearing substituents at the 1- to 4-position [33]. The biphenyl halides 7a–h were coupled with the heterocycles 4a–c to obtain the compounds 8a–h, 9a–f and 10a–f (Scheme 2). The thioethers 15–18 (a–d) (Scheme 3) were synthesized similar to method described in Scheme 1, Scheme 2[28], [34], [35]. The hydrazones 20a–d were prepared using isoniazid 19 (Scheme 4) and 4 different benzaldehydes [36], [37], [38]. The esterification of acid 21 to the ester 22 employed standard conditions, it was followed by reaction with acetic anhydride to provide the amide 23 (Scheme 5) [39], [40]. The thioethers 26a–d were synthesized according to the method described in Scheme 1, Scheme 2. Esterfication of compound 27, followed by cyclization gave compound 29 (Scheme 6) [41], [42]. Compound 30 was obtained using the conditions described for compound 23[40]. Saponification of the ester 30, followed by reaction with tert-butyl carbazate, gave compound 32[28], [43]. Cleavage of the tert-butylamine in 32 by TFA and submission to the reaction conditions described in Scheme 1, Scheme 2 provided the final product 35[28]. Bromination of the 4-hydroxybenzoic acid 36, gave compound 37 (Scheme 7) [44]. The dibenzofuran 38 was obtained by the combination of two reactions in a one-pot synthesis [45], [46]. The final compound 41 was prepared in relation to the method described in Torcetrapib Scheme 1, Scheme 2. The structures of all compounds were verified by mass spectrometry, 1H NMR and 13C NMR.
    Results and discussion The synthesized compounds were evaluated for GSK-3 inhibition in a commercial system based on the Z′-LYTE® technology, available from Invitrogen Life Technologies (Carlsbad, CA, USA), using human recombinant GSK-3α or GSK-3β as the enzyme source and further for their inhibitory activity in vitro against GSK-3β. Several compounds displayed more than 50% inhibitory activity against GSK-3β at 10 μM concentration. We focussed our interest on inhibitors with potential occupation of the entire ATP-binding pocket, and thereby to enhance potency and selectivity (Fig. 2). Heterocycles featuring the oxadiazole ring typically interact within the green marked area of GSK3 (Fig. 2). Our goal was to extend our compounds to the area highlighted in blue. Furthermore, we tried to enhance the potential interaction with the backbone by replacing heterocycles with phenyl rings bearing different acceptors and to investigate the contribution deriving from the rigidity of a tricyclic system [26]. The 3 heterocyclic fragments 4a–c were introduced as potential hinge binders in order to interact with the GSK-3 backbone: Asp133/Tyr134/Val135 (Scheme 1). The oxadiazole moiety is assumed to engage with the polar binding pocket, consisting of three amino acids (Lys85/Glu97/Asp200). Such interactions were previously reported for the GSK-3β inhibitor II and 20x (Fig. 1). We coupled the compounds 4a–c to biphenyl systems bearing different substituents on the second phenyl ring (Scheme 2). Most of these compounds showed remarkable activities and selectivities (Table 1).