Herein, we report the identification, design, and synthesis of a series of 4-substituted 2-amino-3,4-dihydroquinazolines with hairpin turn side chains as novel inhibitors of BACE-1. The dihydroquinazoline derivatives were rationally designed by modifying the amide group and relocating the α -hydrophobic substituent on the hairpin turn side chain of lead compound 2 to the C4-position on the 3,4-dihydroquinazoline scaffold to facilitate interactions with the S1, S2 and S1' subsites of BACE-1. Among these derivatives, two compounds exhibited potent BACE-1 inhibitory activity: 4-methyl-substituted (22a, BACE-1 CFA IC50 = 0.38 μM; BACE-1 WCA IC50 = 0.14 μM) and 4-cyclohexylmethyl-substituted (22b, BACE-1 CFA IC50 = 0.49 μM; BACE-1 WCA IC50 = 0.14 μM) 2-amino-3,4-dihydroquinazoline, each bearing a side chain of N-cyclohexyl-N-((1-methyl-1H-pyrazol-4-yl)methyl amide. The results suggest that the structural modifications maintain the hairpin turn topology similar to that of compound 2 and provide an additional interaction with the S2 subsite.

中文翻译：

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具有3-发夹转向侧链的4-取代的2-氨基-3,4-二氢喹唑啉类化合物是BACE-1的新型抑制剂。

在这里，我们报告鉴定，设计和合成一系列具有发夹转向侧链作为BACE-1的新型抑制剂的4-取代的2-氨基-3,4-二氢喹唑啉。通过修饰酰胺基并重新定位铅化合物2的发夹转角侧链上的α-疏水取代基至3,4-二氢喹唑啉骨架上的C4位，以促进与S1，S2和S3的相互作用，合理地设计了二氢喹唑啉衍生物。 BACE-1的S1'子站点。在这些衍生物中，两种化合物显示出有效的BACE-1抑制活性：4-甲基取代的（22a，BACE-1 CFA IC50 = 0.38μM; BACE-1 WCA的IC50 = 0.14μM）和4-环己基甲基取代的（22b，BACE -1 CFA IC50 = 0.49μM； BACE-1 WCA IC50 = 0.14μM）2-氨基-3,4-二氢喹唑啉，