发现苯并咪唑类似物作为一种新型白细胞介素-5 抑制剂。
Discovery of benzimidazole analogs as a novel interleukin-5 inhibitors.
机构信息
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon, 34134, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, 16419, Republic of Korea.
College of Pharmacy, Chungbuk National University, Cheongju, 19421, Republic of Korea.
出版信息
Eur J Med Chem. 2019 Nov 1;181:111574. doi: 10.1016/j.ejmech.2019.111574. Epub 2019 Jul 30.
A series of novel hydroxyethylaminomethylbenzimidazole analogs 5a-y were synthesized and evaluated for their IL-5 inhibitory activity using pro-B Y16 cell line. Among them, 2-(((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)amino)butan-1-ol (5e, 94.3% inhibition at 30 μM, IC = 3.5 μM, cLogP = 4.132) and 3-cyclohexyl-2-(((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)amino) propan-1-ol (5k, 94.7% inhibition at 30 μM, IC = 5.0 μM, cLogP = 6.253) showed the most potent inhibitory activity. The essential feature of SAR (Fig. 5) indicated that the chromenone ring can be replaced by a benzimidazole ring to maintain the inhibitory activity. In addition, the hydroxyethylaminomethyl group was suitable for the IL-5 inhibitory activity. Moreover, the hydrophobic substituents on carbon play an important role in the IL-5 inhibitory activity of these analogs. However, N-substituted analogs did not improve inhibitory activity. In addition, MTT assay of 5e and 5k with normal B lymphoblasts revealed that they had no significant effects on cell viability.
一系列新型羟乙氨基甲基苯并咪唑类似物 5a-y 被合成，并通过 Pro-B Y16 细胞系评估其对 IL-5 的抑制活性。其中，2-(((4-(环己基甲氧基)-1H-苯并[d]咪唑-2-基)甲基)氨基)丁-1-醇（5e，在 30μM 时抑制率为 94.3%，IC=3.5μM，cLogP=4.132）和 3-环己基-2-(((4-(环己基甲氧基)-1H-苯并[d]咪唑-2-基)甲基)氨基)丙-1-醇（5k，在 30μM 时抑制率为 94.7%，IC=5.0μM，cLogP=6.253）表现出最强的抑制活性。SAR 的重要特征（图 5）表明，色烯酮环可以被苯并咪唑环取代以保持抑制活性。此外，羟乙氨基甲基基团适合于 IL-5 的抑制活性。此外，碳上的疏水性取代基对这些类似物的 IL-5 抑制活性起着重要作用。然而，N-取代的类似物并没有提高抑制活性。此外，5e 和 5k 对正常 B 淋巴母细胞的 MTT 测定表明，它们对细胞活力没有显著影响。
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