6465-01-6Relevant articles and documents
Ligand-based optimization to identify novel 2-aminobenzo[d]thiazole derivatives as potent sEH inhibitors with anti-inflammatory effects
Han, Yufei,Huang, Desheng,Xu, Sicong,Li, Lingling,Tian, Ye,Li, Shuo,Chen, Cong,Li, Yingxiu,Sun, Yanping,Hou, Yunlei,Sun, Yongjun,Qin, Mingze,Gong, Ping,Gao, Zibin,Zhao, Yanfang
, (2020/12/07)
Inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapeutic approach in the treatment of inflammation. Driven by the in-house database product lead 1, a hybridization strategy was utilized for the design of a series of novel benzo [d]thiazol derivatives. To our delight, D016, a byproduct of compound 9, was obtained with an extraordinarily low IC50 value of 0.1 nM but poor physical and chemical properties. After removal of a non-essential urea moiety or replacement of the urea group by an amide group, compounds 15a, 17p, and 18d were identified as promising sEH inhibitors, and their molecular binding modes to sEH were constructed. Furthermore, compounds 15a and 18d exhibited more effective in vivo anti-inflammatory effect than t-AUCB in carrageenan-induced mouse paw edema. Compound 15a also showed moderate metabolic stability with a half-time of 34.7 min. Although 18d was unstable in rat liver microsomes, it might be a “prodrug”. In conclusion, this study could provide valuable insights into discovery of new sEH inhibitors, and compounds 15a and 18d were worthy of further development as potential drug candidates to treat inflammation.
Azobenzene-Semicarbazone Enables Optical Control of Insect Sodium Channels and Behavior
Chen, Ruijia,Fu, Wen,Li, Zhong,Qiao, Zhi,Shao, Xusheng,Xu, Zhiping,Zhang, Yongchao
, p. 15554 - 15561 (2021/12/27)
Photopharmacology uses molecular photoswitches to establish control over the action of bioactive molecules. The application of photopharmacology in the research of invertebrate sodium channels has not been investigated. Here we report several photochromic ligands of metaflumizone. One ligand, termed ABM04, underwent reversible trans-cis isomerization under ultraviolet or blue light irradiation. cis-ABM04 had excellent larvicidal activity against mosquito larvae with an LC50 value of 4.39 μM and showed insecticidal activity against Mythimna separata with an LC50 value of 7.19 μM. However, trans-ABM04 was not found to have biological activity. ABM04 (10 μM) can induce depolarization of dorsal unpaired median neurons and enable the real-time photoregulation of mosquito larval behavior. The precise regulation of invertebrate sodium channels is realized for the first time, which provides a new strategy for the basic and accurate research of invertebrate sodium channels.
Discovery of 4-piperazinyl-2-aminopyrimidine derivatives as dual inhibitors of JAK2 and FLT3
Li, Yingxiu,Ye, Tianyu,Xu, Le,Dong, Yuhong,Luo, Yong,Wang, Chu,Han, Yufei,Chen, Ke,Qin, Mingze,Liu, Yajing,Zhao, Yanfang
, (2019/08/12)
Hybridization strategy is an effective strategy to obtain multi-target inhibitors in drug design. In this study, we assembled the pharmacophores of momelotinib and tandutinib to get a series of 4-piperazinyl-2-aminopyrimidine derivatives. All compounds were tested for the inhibition of JAK2 and FLT3 enzymes, of which, compounds with potent enzyme activities were assayed for antiproliferative activities against three cancer cell lines (HEL, MV4-11, and HL60). The structure-activity relationship studies were conducted through variations in two regions, the “A” phenyl ring and “B” phenyl ring. Compound 14j showed the most balanced in vitro inhibitory activity against JAK2 and FLT3 (JAK2 IC50 = 27 nM, FLT3 IC50 = 30 nM), and it also showed potent inhibition against the above tested cell lines. In the cellular context, 14j strongly induced apoptosis by arresting cell cycle in the G1/S phase, and was selected as a promising JAK2/FLT3 dual inhibitor.
