Synthesis and Anti-HIV-1 Activity Evaluation for Novel 3a,6a-Dihydro-1H-pyrrolo[3,4-c]pyrazole-4,6-dione Derivatives.
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore and the halo-substituted phenyl functionality required for HIV-1 integrase (IN) inhibition represents a vibrant area of research within drug discovery. As reported herein, we have modified our recently disclosed 1-[2-(4-fluorophenyl)ethyl]-pyrrole-2,5-dione scaffolds to design 35 novel compounds with improved biological activities against HIV-1. These new compounds show single-digit micromolar antiviral potencies against HIV-1 and low toxicity. Among of them, compound 9g and 15i had potent anti-HIV-1 activities (EC50 < 5 μM) and excellent therapeutic index (TI, CC50/EC50 > 100). These two compounds have potential as lead compounds for further optimization into clinical anti-HIV-1 agents.
College of Life Sciences, China Jiliang University, Hangzhou 310018, Zhejiang, China. gnliu@cjlu.edu.cn.|CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China. gnliu@cjlu.edu.cn.
Guan-Nan
GN
Liu
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China. luorh@mail.kiz.ac.cn.
Rong-Hua
RH
Luo
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China. zhouyu@mail.shcnc.ac.cn.
Yu
Y
Zhou
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China. kmhz123@163.com.
Xing-Jie
XJ
Zhang
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China. jianl@mail.shcnc.ac.cn.
Jian
J
Li
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China. lmyang@mail.kiz.ac.cn.
Liu-Meng
LM
Yang
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China. zhengyt@mail.kiz.ac.cn.
Yong-Tang
YT
Zheng
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China. hliu@mail.shcnc.ac.cn.
Hong
H
Liu
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D019380:Anti-HIV Agents; D011720:Pyrazoles
AIDS; SAR; anti-HIV-1; integrase; synthesis