N-甲基异噻唑酮取代的间苯二甲酸衍生物的设计、合成及其抑制β-分泌酶活性

Design,synthesis and inhibitory activity against β-secretase of N-methyl isothiazolone substituted isophthalic acid derivatives

目的发现新结构的β-分泌酶抑制剂。方法基于β-分泌酶抑制剂的构效关系,设计合成了含羟乙胺结构片段的间位1,1-二氧代-N-甲基-2,3-(2H)-异噻唑酮取代的间苯二甲酸衍生物;采用时间分辨荧光法检测化合物对β-分泌酶的抑制活性。结果合成了8个目标化合物,利用MS和1H-NMR对化合物的结构进行了确证,利用HPLC对化合物的纯度进行了测定,利用旋光仪测定了化合物的比旋光度;活性数据显示有2个化合物对β-分泌酶有较强的抑制作用,其中化合物2c的IC50值为3.7 nmol.L-1。结论发现了新的β-分泌酶抑制剂,分析了其初步的构效关系,为进一步进行结构优化进而发现活性更好的化合物奠定了基础。

The introduction of β-amyloid hypothesis offers an alternative strategy of discovering new drug for the treatment of AD. According to the hypothesis, abnormal accumulation and deposition of β-amyloid peptides（Aft） in brain,which have neurological toxicity ,cause pallium to result in Alzheimer＇s disease, β-Amy- loid peptide is produced from amyloid precursor protein（β-APP） by gradually hydrolization with β-secretase （BACE-1） and γ-secretase. BACE-1 is a rate limiting enzyme of the generation ofβ-amyloid peptides, so it might be an ideal target of interfering in the process of Alzheimer＇s disease. Based on the structural feature of active site of β-secretase binding to the typical inhibitors and the structure of β-secretase inhibitors disco- vered in our laboratory, N-methyl isothiazolone substituted isophthalic acid derivatives were designed and synthesized. Eight target compounds were synthesized and their structures were confirmed by 1H-NMR and MS. The purity of these compounds was determined by HPLC. Time-resolved βuorescence method was used to evaluate inhibitory activity of these compounds against BACE-1. The results showed that four of these compounds had obvious inhibitory activity against β-secretase. Especially, the IC50 value of compound 2c and 2d against β-secretase was 3.7 and 12. 3 nmol. L-j respectively. Based on biological evaluation of target compounds against BACE-1 in vitro as well as Surβex Model of Sybyl 8.1 program to simulate interaction of target cpmpounds with BACE-1, the initial structure-activity relationship of these β-secretase inhibitors were summarized： 1 ） Inhibitory activity can be improved when P2＇ fragment is aromatic group because this group can generate π-π stacking interaction with Y198 residue of BACE-1 S2＇ subsite. 2） It is more advan-tageous to improve activity when P3＇ fragment is α-methylbenzylamine group. 3 ） When P2 fragment of 8- secretase inhibitor is 1,1-dioxido-N-methyl-2,3-（2H）-isothiazolone, aromatic groups used as P3, PI and P2＇ fragments are prefered to improve inhibitory activity against β-secretase. These results are useful to design and optimize the structure of this series of compounds and provide a direction to find more excellent BACE-I inhibitors with potent activity and selectivity in the future.