新型四氢吡啶并[4,3-d]嘧啶衍生物的合成及抗弓形虫活性  

Synthesis and Anti-Toxoplasma Activity of Novel Tetrahydropyrido[4,3-d]pyrimidine Derivatives

作　　者：栾天 崔思娇 隋丽丽[1] 孙驰宇 张大军[1] LUAN Tian;CUI Sijiao;SUI Lili;SUN Chiyu;ZHANG Dajun(Department of Pharmacy,Shenyang Medical College,Shenyang 110034,China;Shenyang Food and Drug Inspection Institute,Shenyang 110124,China)

机构地区：[1]沈阳医学院药学院,沈阳110034 [2]沈阳市食品药品检验所,沈阳110124

出　　处：《高等学校化学学报》2023年第8期72-80,共9页Chemical Journal of Chinese Universities

基　　金：辽宁省教育厅面上项目(批准号:LJKMZ20221801);辽宁省科学技术计划项目(批准号:2020-MS-313);沈阳医学院博士科研启动基金(批准号:20205041)资助.

摘　　要：为开发高效、高选择性抗弓形虫药物,依据药物拼合原理,设计合成了20个新的四氢吡啶并[4,3-d]嘧啶衍生物.以1-苄基-3-乙氧羰基-4-哌啶酮盐酸盐为起始物,通过7步反应得到了目标化合物7a~7t,其化学结构均经过核磁共振波谱(1H NMR,13C NMR)、质谱(MS)以及元素分析联合确证.采用噻唑蓝(MTT)法考察了其体外抗弓形虫活性,并筛选出活性最理想的化合物;定量考察其对弓形虫二氢叶酸还原酶(TgDHFR)的抑制活性.研究结果表明,10个化合物的体外抗弓形虫活性优于阳性对照药乙胺嘧啶及磺胺嘧啶.化合物7p的体外抗弓形虫活性最理想,针对TgDHFR的半数抑制浓度(IC_(50))仅为15 nmol/L,而针对人源二氢叶酸还原酶(hDHFR)的IC_(50)值为1460 nmol/L,表现出很高的选择性.分子对接实验结果显示,化合物7p可通过5个氢键与TgDHFR强力结合,可对其进行深入研究以开发抗弓形虫的新药.To develop highly effective and highly selective anti-Toxoplasma drugs,twenty novel tetrahydropyridines[4,3-d]pyrimidine derivatives were designed and synthesized via the principle of pharmacochemical molecular combination.Ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride as starting material,the target compounds 7a—7t were obtained by seven step reaction.All target compounds were characterized via nuclear magnetic resonance spectroscopy(1H NMR,13C NMR),mass spectrometry and elemental analysis.Methyl thiazolyl tetrazolium(MTT)method was used to investigate the anti-Toxoplasm activity in vitro,and the compound with the best activity was selected to further quantify the inhibitory activity against Toxoplasm dihydrofolate reductase(TgDHFR).The results showed that ten compounds had higher anti-Toxoplasma activity compared with the positive control drugs pyrimeth⁃amine and sulfadiazine.Compound 7p exhibited the most potent anti-Toxoplasma activity and commendable selectivi⁃ty between TgDHFR and human dihydrofolate reductase(hDHFR)with half maximal inhibitory concentration(IC_(50))value of 15 nmol/L against TgDHFR and 1460 nmol/L against hDHFR.Molecular docking experiments showed that compound 7p could be strongly bound to TgDHFR through five hydrogen bonds,which could be deeply studied to develop new anti-Toxoplasma drugs.

关 键 词：弓形虫 二氢叶酸还原酶 四氢吡啶并[4 3-d]嘧啶 

分 类 号：O621.3[理学—有机化学] R914.5[理学—化学]