非核苷类逆转录酶抑制剂DB02氨基酸衍生物的合成及抗HIV-1活性研究  

Design,synthesis and biological activity of DB02 amino acid derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors

作　　者：杨金轩 余乐 杨玉卓 罗荣华[1] 何严萍[2] 郑永唐[1] YANG Jin-xuan;YU Le;YANG Yu-zhuo;LUO Rong-hua;HE Yan-ping;ZHENG Yong-tang(Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China;Key Laboratory of Medicinal Chemistry for Natural Resource Ministry of Education,School of Chemical Science and Technology,Yunnan University,Kunming 650091,China;College of Traditional Chinese Medicine,Yunnan University of Chinese Medicine,Kunming 650500,China)

机构地区：[1]中国科学院昆明动物研究所,中国科学院动物模型与人类疾病机理重点实验室,云南昆明650223 [2]云南大学化学科学与工程学院,自然资源药物化学教育部重点实验室,云南昆明650091 [3]云南中医药大学中药学院,云南昆明650500

出　　处：《药学学报》2023年第2期405-412,共8页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82060670,U1702286,21967020);云南省重大科技专项计划课题(202103AC100005);中缅国际合作项目(2019YFE0109200).

摘　　要：为提高非核苷类HIV-1逆转录酶抑制剂DB02氨基酸酯衍生物的稳定性,本文基于生物电子等排原理,以具有更高化学稳定性的酰胺替代酯键,设计合成了24个DB02氨基酸酰胺衍生物2a~2x。采用MTT法及合胞体计数评估了其体外抗HIV-1活性。研究发现大部分目标化合物具有良好的抗HIV-1活性,其中活性最佳的5个化合物2d、2i、2l、2s、2w的抗病毒效果均优于先导化合物DB02,且具有优良的治疗指数(TI>1000.00)。这类化合物的构效关系研究为DB02衍生物的进一步开发提供了新的思路。To improve the stability of amino acid ester derivatives of DB02,a series of 24 amide derivatives of DB02 amino acids as non-nucleoside HIV-1 reverse transcriptase inhibitor were designed and synthesized based on bioisosterism by replacing amino acid ester scaffold with more stable amide bond.The anti-HIV-1 activity of these compounds was evaluated by MTT assay and counting the number of syncytia.Most of the target compounds showed a potential anti-HIV-1 activity,among which compounds 2d,2i,2l,2s,and 2w had better antiviral effect than lead compound DB02,with a therapeutic index>1000.00.Finally,the structure-activity relationship of these compounds was discussed,which provided new ideas for the further development of DB02 derivatives.

关 键 词：DB02 非核苷类逆转录酶抑制剂 氨基酸酰胺衍生物 抗HIV-1活性 构效关系 

分 类 号：R962[医药卫生—药理学]