91634-11-6Relevant articles and documents
Revisiting the synthesis of aryl nitriles: a pivotal role of CAN
Saikia, Rakhee,Park, Kwihwan,Masuda, Hayato,Itoh, Miki,Yamada, Tsuyoshi,Sajiki, Hironao,Mahanta, Sanjeev P.,Thakur, Ashim J.
, p. 1344 - 1351 (2021/02/27)
Facilitated by the dual role of Ceric Ammonium Nitrate (CAN), herein we report a cost-effective approach for the cyanation of aryl iodides/bromides with CAN-DMF as an addition to the existing pool of combined cyanation sources. In addition to being an oxidant, CAN acts as a source of nitrogen in our protocol. The reaction is catalyzed by a readily available Cu(ii) salt and the ability of CAN to generate ammonia in the reaction medium is utilized to eliminate the additional requirement of a nitrogen source, ligand, additive or toxic reagents. The mechanistic study suggests an evolution of CN?leading to the synthesis of a variety of aryl nitriles in moderate to good yields. The proposed mechanism is supported by a series of control reactions and labeling experiments.
HTS-based discovery and optimization of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor
Holm, Patrik,éles, János,Balázs, Ottilia,Fodor, László,Greiner, István,Horváth, Anita,Kóti, János,Kiss, László,Kolok, Sándor,Kostyalik, Diána,Krámos, Balázs,Lévay, Gy?rgy,Ledneczki, István,Lendvai, Balázs,Mahó, Sándor,Molnár, Katalin Dudás,Némethy, Zsolt,Szigetvári, áron,Tapolcsányi, Pál,Thán, Márta,Vágó, István,Vastag, Mónika,Visegrády, András
, (2021/06/22)
HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of α7 nACh receptor positive allosteric modulators. During the hit expansion, several derivatives, such as 4, 11, 17 demonstrated not only high in vitro potency, but also in vivo efficacy in the mouse place recognition test. The advanced hit molecule 11 was further optimized by the elimination of the putatively mutagenic aromatic-amine building block that resulted in a novel, aminomethylindole compound family. The most balanced physico-chemical and pharmacological profile was found in case of compound 55. Docking study revealed an intersubunit binding site to be the most probable for our compounds. 55 demonstrated favorable cognitive enhancing profile not only in scopolamine-induced amnesia (place recognition test in mice) but also in natural forgetting (novel object recognition test in rats). Compound 55 was, furthermore, active in a cognitive paradigm of high translational value, namely in the rat touch screen visual discrimination test. Therefore, 55 was selected as a lead compound for further optimization. Based on the obtained favorable results, the invented aminomethylindole cluster may provide a viable approach for cognitive enhancement through positive allosteric modulation of α7 nAChRs.
Design, synthesis and biological evaluation of 1-alkyl-5/6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbonitriles as novel xanthine oxidase inhibitors
Dai, Xiwen,Gao, Jun,Liu, Xuegui,Mao, Qing,Wang, Shaojie,Zhang, Bing,Zhang, Zhuo,Zou, Qian
, (2020/02/04)
Xanthine oxidase (XO) has emerged as an important target for the treatment of hyperuricemia and gout. In this study, to obtain novel nonpurine XO inhibitors, a series of 1-alkyl-5/6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbonitriles (1a-1u, 2c, 2e, 2h and 2n) were designed using a bioisosteric replacement strategy and were synthesized through a five-step procedure with good yields. Thereafter, the in vitro XO inhibitory potencies of these compounds were evaluated by spectrophotometry, showing inhibitory profiles in the micromolar/submicromolar range. Particularly, compound 1h emerged as the strongest XO inhibitor, with an IC50 value of 0.36 μM, which was approximately 21-fold more potent than the positive control allopurinol. Additionally, the structure-activity relationships revealed that the 5-oxo-4,5-dihydro-1,2,4-oxadiazole moiety linked at the 5-position of the indole scaffold was more preferable than the 6-position for the XO inhibitory potency. Enzyme kinetic studies indicated that compound 1h acted as a mixed-type XO inhibitor. Moreover, molecular modeling studies were performed on compound 1h to gain insights into its binding modes with XO. The results showed that the 5-oxo-4,5-dihydro-1,2,4-oxadiazole moiety could interact with Arg880 and Thr1010 in the innermost part of the active pocket through hydrogen bonds, while the cyano group could form hydrogen bonds with Asn768 and Lys771 in the subpocket. Furthermore, the in vivo hypouricemic effect of compound 1h was further investigated in a hyperuricemia rat model induced by potassium oxonate. The results suggested that compound 1h could effectively reduce serum uric acid levels at an oral dose of 10 mg/kg. Therefore, compound 1h could be a promising lead compound for the treatment of hyperuricemia and gout.
