Hepatotoxicity and antioxidant activity of some new N,N′-disubstituted benzimidazole-2-thiones, radical scavenging mechanism and structureactivity relationship

被引:31
作者
Anastassova, Neda O. [1 ]
Mavrova, Anelia Ts. [1 ]
Yancheva, Denitsa Y. [2 ]
Kondeva-Burdina, Magdalena S. [3 ]
Tzankova, Virginia I. [3 ]
Stoyanov, Simeon S. [2 ]
Shivachev, Boris L. [4 ]
Nikolova, Rositsa P. [4 ]
机构
[1] Univ Chem Technol & Met, 8 Kliment Ohridski Blvd, BU-1756 Sofia, Bulgaria
[2] Bulgarian Acad Sci, Inst Organ Chem, Ctr Phytochem, Acad G Bonchev Str,Bldg 9, BU-1113 Sofia, Bulgaria
[3] Med Univ Sofia, Fac Pharm, Drug Metab & Drug Tox Lab, Pharmacol Pharmacotherapy & Toxicol Dept, Sofia, Bulgaria
[4] Bulgarian Acad Sci, Acad Ivan Kostov Inst Mineral & Crystallog, Acad G Bonchev Str,Bldg 107, BU-1113 Sofia, Bulgaria
关键词
1,3-Disubstituted benzimidazole-2-thiones; Michael addition; Hepatotoxicity; Oxidative stress; Radical scavenging; DFT calculations; OXIDATIVE STRESS; LIPID-PEROXIDATION; INTERMOLECULAR INTERACTIONS; ANTIVIRAL ACTIVITY; DERIVATIVES; MELATONIN; INHIBITORS; ANALOGS; DAMAGE;
D O I
10.1016/j.arabjc.2016.12.003
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
A new method for the synthesis of 1,3-disubstituted benzimidazole derivatives was developed using aza-Michael addition. The target compounds were synthesized in good yields and purity and tested on isolated hepatocytes for their toxicity and antioxidant activity. The antioxidant properties of the substances with lowest toxicity were evaluated using oxidative stress induced by tertbutyl hydroperoxide (tert-BOOH). Some of them as methyl 3-[ 3-(3-methoxy-3-oxopropyl)-5-ben zoyl-2-thioxo-2,3-dihydro-1H-benzimidazol-1-yl] propanoate 10 and 1,3-bis[ 3-(hydrazinooxy)-3-oxo propyl]-5-benzoyl-1,3-dihydro-2H-benzimidazole-2-thione 15 exhibited statistically significant cytoprotective and antioxidant effects which were similar to those of quercetin. In order to estimate the influence of the structure on the biological properties, structural characterization of the studied compounds was performed by X-ray diffraction analysis and DFT methods. On the basis of the calculated reaction enthalpies of hydrogen atom abstraction (HAT mechanism) and single-electron transfer (SET mechanism) the mechanisms of the antioxidant action of the tested compounds were studied. Subsequently it was established that the HAT mechanism governs the radical scavenging of 10 and 15 in the lipid phase, while the SET mechanism is preferred in water medium for 10 and competitive to HAT for 15. (C) 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under theCCBY-NC-NDlicense.
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收藏
页码:353 / 369
页数:17
相关论文
共 83 条
  • [1] In-vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives
    Achar, Kavitha C. S.
    Hosamani, Kallappa M.
    Seetharamareddy, Harisha R.
    [J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2010, 45 (05) : 2048 - 2054
  • [2] AIKENS J, 1991, J BIOL CHEM, V266, P15091
  • [3] Synthesis and Evaluation of Selected Benzimidazole Derivatives as Potential Antimicrobial Agents
    Alasmary, Fatmah A. S.
    Snelling, Anna M.
    Zain, Mohammed E.
    Alafeefy, Ahmed M.
    Awaad, Amani S.
    Karodia, Nazira
    [J]. MOLECULES, 2015, 20 (08) : 15206 - 15223
  • [4] Novel coumarin benzimidazole derivatives as antioxidants and safer anti-inflammatory agents
    Arora, Radha Krishan
    Kaur, Navneet
    Bansal, Yogita
    Bansal, Gulshan
    [J]. ACTA PHARMACEUTICA SINICA B, 2014, 4 (05) : 368 - 375
  • [5] Identification of a Novel Series of N-Phenyl-5-[(2phenylbenzimidazol-1-yl)methyl]-1,3,4-oxadiazol-2-amines as Potent Antioxidants and Radical Scavengers
    Ayhan-Kilcigil, Gulgun
    Kus, Canan
    Coban, Tulay
    Ozdamar, Elcin D.
    Can-Eke, Benay
    [J]. ARCHIV DER PHARMAZIE, 2014, 347 (04) : 276 - 282
  • [6] Basu B., 2015, SUSTAINABLE SYNTHESI SUSTAINABLE SYNTHESI, P209
  • [7] DENSITY-FUNCTIONAL THERMOCHEMISTRY .3. THE ROLE OF EXACT EXCHANGE
    BECKE, AD
    [J]. JOURNAL OF CHEMICAL PHYSICS, 1993, 98 (07) : 5648 - 5652
  • [8] Alkylation and Aminomethylation of 1,3-Dihydro-2De-Benzimidazole-2-Thione
    Bespalov, A. Ya.
    Gorchakova, T. L.
    Ivanov, A. Yu.
    Kuznetsov, M. A.
    Kuznetsova, L. M.
    Pankova, A. S.
    Prokopenko, L. I.
    Avdontceva, M. S.
    [J]. CHEMISTRY OF HETEROCYCLIC COMPOUNDS, 2015, 50 (11) : 1547 - 1558
  • [9] BLAAUBOER BJ, 1994, ATLA-ALTERN LAB ANIM, V22, P231
  • [10] Synthesis of New Functionalized Indoles Based on Ethyl Indol-2-carboxylate
    Boraei, Ahmed T. A.
    El Ashry, El Sayed H.
    Barakat, Assem
    Ghabbour, Hazem A.
    [J]. MOLECULES, 2016, 21 (03):