Design, Synthesis and Anti-HIV-1 Activity of (E)-N′-Arylmethylene-4-(4-Phenylpyrimidin-2-ylamino) benzohydrazide Derivatives as CDK9 Inhibitors
ZHU Ke-yu1, ZHAO Sheng-xian2, HE Feng-ming3, ZHENG Xiao-xiang1,4*, YANG Xue-wen2, ZHANG Zhao-lin1, HU Hong-yu1*
1. Xingzhi College, Zhejiang Normal University, Lanxi 321100, China; 2. Zhejiang Apeloa Tospo Pharmaceutical Co.,Ltd., Dongyang 322118, China; 3. School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; 4. College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China
Abstract：OBJECTIVE To design and synthesize(E)-N′-arylmethylene-4-(4-phenylpyrimidin-2-ylamino) benzohydrazide derivatives and investigate their anti-HIV-1 activities. METHODS The target compound was synthesized by five step reactions using ethyl aminobenzoate as starting material. The transcriptional inhibitory activities of the synthetic compounds against HIV-1 were detected by luciferase reporter gene. RESULTS The target compounds showed certain inhibitory activities on HIV-1 transcription, among which compound 7P had the best inhibitory activity, with inhibitory rate of (73±0.05)% at 2 μmol·L-1 and (90±0.01)% at 20 μmol·L-1, respectively. Further study showed that compound 7P inhibited HIV-1 transcriptional activity and down-regulated RNA polymerase Ⅱ CTD serine 2 phosphorylation in a concentration-dependent manner in NH1 and NH2 cells. Finally, molecular docking showed that compound 7P had a strong binding effect with CDK9. CONCLUSION This series of compounds have good anti-HIV-1 activities, which has significant research value for further study.
GAO D, ZOU Z, DONG B, et al. Secular trends in HIV/AIDS mortality in China from 1990 to 2016: Gender disparities[J]. PLoS One, 2019, 14(7): e0219689. Doi:10.1371/journal.pone.0219689.
DEEKS S G, AUTRAN B,BERKHOUT B, et al. Towards an HIV cure: a global scientific strategy[J]. Nat Rev Immunol, 2012, 12(8): 607-614.
WANGY Y, JIN Y, CHEN C, et al. Meta-analysis of adherence to highly active antiretroviral therapy in patients with HIV infection in China[J]. Aids Care,2019,31(8):913-922.
SHI J, VAKOC C. The mechanisms behind the therapeutic activity of BET bromodomain inhibition[J]. Mol Cell,2014,54(5):728-736.
FILIPPAKOPOULOS P, KNAPP S. Targeting bromodomains: epigenetic readers of lysine acetylation[J]. Nat Rev Drug Discov,2014, 13(5):337-356.
PINGW, GARBER M E, FANG S M, et al. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA[J]. Cell,1998, 92(4):451-462.
BACON C W, IVAN D O. CDK9: a signaling hub for transcriptional control[J]. Transcription,2018,10(2):57-75.
SOBHIAN B, LAGUETTE N, YATIM A, et al. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP[J]. Mol Cell, 2010, 38(3):439-451.
HE N, LIU M, HSU J, et al. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription[J]. Mol Cell,2010, 38(3): 428-438.
CHEN R, WIERDA W G, CHUBB S, et al. Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia[J]. Blood,2009,113(19): 4637-4645.
CHAO S H, FUJINAGA K, MARION, et al. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication[J]. J Biol Chem, 2000,275(37): 28345-28348.
MANCEBO H S, LEE G, FLYGARE J, et al. P-TEFb kinase is required for HIV Tat transcriptional activation in vivo and in vitro[J]. Gen Dev,1997, 11(20):2633-2644.
HU H Y, WU J, YUAN J F, et al. Synthesis and cytotoxic activity of 4-substitued-1-(2-methyl-6-(pyridin-3-yl)-nicotinoyl) semicarbazides[J]. Chin J Org Chem(有机化学), 2019,39(9):2507-2514.
CLAUDIO V J,AMAND D,VANDERLAN S B,et al. Molecular hybridization: auseful tool in the design of new drug prototypes[J].Curr Med Chem, 2007, 14(17):1829-1852.
FANG Z Y, ZHENG S C, CHAN K F, et al. Design, synthesis and antibacterial evaluation of 2,4-disubstituted-6-thiophenyl-pyrimidines[J]. Eur J Med Chem, 2019,161(1):141-153.
ZHANG Y, ZHANG L Y, WANG J K, et al. Design,synthesis and antitumor activity evaluation of 2,4,6-substitute pyrimidine derivatives[J]. Chin J Org Chem(有机化学), 2020,40(10): 3050-3054.
HOLYA, VOTRUBA I, MASOJIDKOVA M, et al. 6-[2-(Phosphonomethoxy) alkoxy]pyrimidines with Antiviral Activity[J]. J Med Chem, 2002,45(9):1918-1929.
UNNISA A, ABOUZIED A S, BARATAM A, et al. Design, synthesis, characterization, computational study and in-vitro antioxidant and anti-inflammatory activities of few novel 6-aryl substituted pyrimidine azo dye[J]. Arab J Chem, 2021,14(1):141-153.
AMATO G, ROELOFFS R, RIGDONGC, et al. N-Pyridyl and pyrimidine benzamides as KCNQ2/Q3 potassium channel openers for the treatment of epilepsy[J]. ACS Med Chem Lett, 2011,2(6):481-484.
LANG D K, KAUR R, ARORA R, et al. Nitrogen-containing heterocycles as anticancer agents: an overview[J]. Anticancer Agents Med Chem, 2020, 20(18):2150-2168.
WANG Z W, JIANG Y, LIU F, et al. Microwave-induced rapid preparation of N,N′-disalicylhydrazine and its anti-HIV activity[J].Fine Chem Intermed(精细化工中间体), 2014,44(3):33-36.
El-SADEK M E, ABOUKULL M E, EI-SABBAGH O I, et al. Design, synthesis and cytotoxic activity of novel 1-aroyl-4-(2-chloroethyl)semicarbazides[J]. Pharm Chem J, 2007,41(4):188-192.
YUY Y, LVY F, YANGM, et al. The synthesis and anti-inflammatory activity of N-bromoacetyl salicylhydrazide[J]. Fine Spec Chem (精细与专用化学品), 2016,24(10):38-40.
HU H Y, WU J, AO M T, et al. Synthesis, structure-activity relationship studies and biological evaluation of novel 2,5-disubstituted indole derivatives as anticancer agents[J].Chem Biol Drug Des, 2016, 88(5):766-778.
HU H Y, WU J,AO MT, et al. Design, synthesis and biological evaluation of methylenehydrazine-1-carboxamide derivatives with(5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1 H-indole scaffold: Novel potential CDK9 inhibitors[J]. Bioorg Chem, 2020, 102,104064. Doi:10.1016/j.bioorg.2020.104064.
HU H Y, ZHANG W D, WU J F, et al. Synthesis and antitumor activity of pyridine biphenylsemicarbazide derivatives[J]. Chin Pharm J (中国药学杂志), 2019, 54(6):948-952.
WU J, AO M T, SHAO R, et al. A chalcone derivative reactivates latent HIV-1 transcription through activating P-TEFb and promoting Tat-SEC interaction on viral promoter[J]. Sci Rep, 2017, 7(1):10657. Doi:10.1038/s41598-017-10728-w.
SHERMAN W, DAY T, JACOBSON M P, et al. Novel procedure for modeling ligand/receptor induced fit effects[J]. J Med Chem, 2006, 49(2): 534-553.
SHERMAN W, BEARD H S, FARID R,et al. Use of an induced fit receptor structure in virtual screening[J]. Chem Biol Drug Des, 2006, 67(1): 83-84.