title: Design, synthesis and anti-HIV-1 evaluation of hydrazide-based peptidomimetics as selective gelatinase inhibitors.
abstract: As our ongoing work on research of gelatinase inhibitors, an array of hydrazide-containing peptidomimetic derivatives bearing quinoxalinone as well as spiro-heterocyclic backbones were designed, synthesized, and assayed for their in vitro enzymatic inhibitory effects. The results demonstrated that both the quinoxalinone (series I and II) and 1,4-dithia-7-azaspiro[4,4]nonane-based hydrazide peptidomimetics (series III) displayed remarkably selectivity towards gelatinase A as compared to APN, with IC50 values in the micromole range. Structure-activity relationships were herein briefly discussed. Given evidences have validated that gelatinase inhibition may be contributable to the therapy of HIV-1 infection, all the target compounds were also submitted to the preliminary in vitro anti-HIV-1 evaluation. It resulted that gelatinase inhibition really has positive correlation with anti-HIV-1 activity, especially compounds 4m and 7h, which gave enhanced gelatinase inhibition in comparison with the positive control LY52, and also decent anti-HIV-1 potencies. The FlexX docking results provided a straightforward insight into the binding pattern between inhibitors and gelatinase, as well as the selective inhibition towards gelatinase over APN. Collectively, our research encouraged potent gelatinase inhibitors might be used in the development of anti-HIV-1 agents. And else, compounds 4m and 7h might be promising candidates to be considered for further chemical optimization.
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong 250012, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Institute of Criminal Science and Technology, Ji'nan Public Security Bureau, Ji'nan 250100, China.
authors.forename: Ji-Feng
authors.initials: JF
authors.lastname: Wu
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
authors.forename: Liu-Meng
authors.initials: LM
authors.lastname: Yang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
authors.forename: Rui-Rui
authors.initials: RR
authors.lastname: Wang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Pang
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong 250012, China.
authors.forename: Yong-Gang
authors.initials: YG
authors.lastname: Li
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong 250012, China.
authors.forename: Yue-Mao
authors.initials: YM
authors.lastname: Shen
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China. Electronic address: zhengyt@mail.kiz.ac.cn.
authors.forename: Yong-Tang
authors.initials: YT
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong 250012, China. Electronic address: tjulx2004@sdu.edu.cn.
authors.forename: Xun
authors.initials: X
authors.lastname: Li
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001386:Azides / Q000494:pharmacology*; D015195:Drug Design; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D057786:Peptidomimetics
chemical_list: D019380:Anti-HIV Agents; D001386:Azides; D057786:Peptidomimetics; D018093:Gelatinases
keywords: Anti-HIV activity; Hydrazide derivatives; Peptidomimetics; Quinoxalinone; Selective gelatinase inhibitors