Novel Pyrazino[1,2-a]indole-1,3(2H,4H)-dione Derivatives Targeting the Replication of Flaviviridae Viruses: Structural and Mechanistic Insights

被引:1
|
作者
Giannakopoulou, Erofili [1 ]
Akrani, Ifigeneia [1 ]
Mpekoulis, George [2 ]
Frakolaki, Efseveia [2 ]
Dimitriou, Marios [2 ]
Myrianthopoulos, Vassilios [1 ]
Vassilaki, Niki [2 ]
Zoidis, Grigoris [1 ]
机构
[1] Natl & Kapodistrian Univ Athens, Fac Pharm, Sch Hlth Sci, Dept Pharmaceut Chem, GR-15771 Athens, Greece
[2] Hellenic Pasteur Inst, Mol Virol Lab, Vas Sofias Ave, GR-11521 Athens, Greece
来源
VIRUSES-BASEL | 2024年 / 16卷 / 08期
关键词
antivirals; novel heterocycles; HCV; DENV; YFV; metal chelators; high genetic barrier to resistance; drug design and synthesis; SAR; NMR; HEPATITIS-C VIRUS; OPEN READING FRAME; DENGUE VIRUS; DRUG-RESISTANCE; RNA-POLYMERASE; INHIBITION; IDENTIFICATION; THERAPIES; INFECTION; GENOTYPE;
D O I
10.3390/v16081238
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Infections with Flaviviridae viruses, such as hepatitis C (HCV), dengue (DENV), and yellow fever (YFV) viruses, are major public health problems worldwide. In the case of HCV, treatment is associated with drug resistance and high costs, while there is no clinically approved therapy for DENV and YFV. Consequently, there is still a need for new chemotherapies with alternative modes of action. We have previously identified novel 2-hydroxypyrazino[1,2-a]indole-1,3(2H,4H)-diones as metal-chelating inhibitors targeting HCV RNA replication. Here, by utilizing a structure-based approach, we rationally designed a second series of compounds by introducing various substituents at the indole core structure and at the imidic nitrogen, to improve specificity against the RNA-dependent RNA polymerase (RdRp). The resulting derivatives were evaluated for their potency against HCV genotype 1b, DENV2, and YFV-17D using stable replicon cell lines. The most favorable substitution was nitro at position 6 of the indole ring (compound 36), conferring EC50 1.6 mu M against HCV 1b and 2.57 mu Mu against HCV 1a, with a high selectivity index. Compound 52, carrying the acetohydroxamic acid functionality (-CH2CONHOH) on the imidic nitrogen, and compound 78, the methyl-substituted molecule at the position 4 indolediketopiperazine counterpart, were the most effective against DENV and YFV, respectively. Interestingly, compound 36 had a high genetic barrier to resistance and only one resistance mutation was detected, T181I in NS5B, suggesting that the compound target HCV RdRp is in accordance with our predicted model.
引用
收藏
页数:24
相关论文
共 33 条
  • [1] Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity
    Cai, Catherine W.
    Lomonosova, Elena
    Moran, Eileen A.
    Cheng, Xiaohong
    Patel, Kunjan B.
    Bailly, Fabrice
    Cotelle, Philippe
    Meyers, Marvin J.
    Tavis, John E.
    ANTIVIRAL RESEARCH, 2014, 108 : 48 - 55
  • [2] Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents
    Marcinkowska, Monika
    Kotanska, Magdalena
    Zagorska, Agnieszka
    Sniecikowska, Joanna
    Kubacka, Monika
    Siwek, Agata
    Bucki, Adam
    Pawlowski, Maciej
    Bednarski, Marek
    Sapa, Jacek
    Starek, Malgorzata
    Dabrowska, Monika
    Kolaczkowski, Marcin
    JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2018, 33 (01) : 536 - 545
  • [3] Design, synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon modulators
    Liu, Yilin
    Song, Yuming
    Xu, Yingju
    Jiang, Meixu
    Lu, Haibin
    JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2022, 37 (01) : 1715 - 1723
  • [4] Cascade Couplings of N-Alkyl-N-methacryloyl Benzamides with Ethers and Benzenesulfonohydrazides To Generate Isoquinoline-1,3(2H,4H)-dione Derivatives
    Zhang, Min
    Xie, Ping
    Zhao, Wannian
    Niu, Ben
    Wu, Wei
    Bian, Zhaogang
    Pittman, Charles U., Jr.
    Zhou, Aihua
    JOURNAL OF ORGANIC CHEMISTRY, 2015, 80 (08): : 4176 - 4183
  • [5] Synthesis and antimicrobial activity of derivatives of 1H-benzo[de]isoquinoline-1,3(2H)-dione
    Kuran, Bozena
    Krawiecka, Mariola
    Kossakowski, Jerzy
    Szymanek, Ksenia
    Kierzkowska, Marta
    Mlynarczyk, Grazyna
    HETEROCYCLIC COMMUNICATIONS, 2012, 18 (5-6) : 275 - 278
  • [6] Synthesis of isoquinoline-1,3(2H,4H)-dione derivatives via cascade reactions of N-alkyl-N-methacryloyl benzamide with aryl aldehydes
    Zhao, Wannian
    Xie, Ping
    Zhang, Min
    Niu, Ben
    Bian, Zhaogang
    Pittman, Charles, Jr.
    Zhou, Aihua
    ORGANIC & BIOMOLECULAR CHEMISTRY, 2014, 12 (39) : 7690 - 7693
  • [7] 2-Hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs), Novel Inhibitors of HIV Integrase with a High Barrier to Resistance
    Desimmie, Belete A.
    Demeulemeester, Jonas
    Suchaud, Virginie
    Taltynov, Oliver
    Billamboz, Muriel
    Lion, Cedric
    Bailly, Fabrice
    Strelkov, Sergei V.
    Debyser, Zeger
    Cotelle, Philippe
    Christ, Frauke
    ACS CHEMICAL BIOLOGY, 2013, 8 (06) : 1187 - 1194
  • [8] 6-Hydroxy-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Novel D-Amino Acid Oxidase Inhibitors
    Hin, Niyada
    Duvall, Bridget
    Ferraris, Dana
    Alt, Jesse
    Thomas, Ajit G.
    Rais, Rana
    Rojas, Camilo
    Wu, Ying
    Wozniak, Krystyna M.
    Slusher, Barbara S.
    Tsukamoto, Takashi
    JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (18) : 7258 - 7272
  • [9] An efficient and convenient protocol for the synthesis of novel 1′H-spiro[isoindoline-1,2′-quinazoline]-3,4′(3′H)-dione derivatives
    Dabiri, M.
    Mohammadi, Ali A.
    Qaraat, Hassan
    MONATSHEFTE FUR CHEMIE, 2009, 140 (04): : 401 - 404
  • [10] Structural stabilization of transthyretin by a new compound, 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione
    Yokoyama, Takeshi
    Takaki, Shun
    Chosa, Keisuke
    Sato, Takashi
    Suico, Mary Ann
    Teranishi, Yuriko
    Shuto, Tsuyoshi
    Mizuguchi, Mineyuki
    Kai, Hirofumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES, 2015, 129 (04) : 240 - 243