Advertisement

Medicinal Chemistry Research

, Volume 24, Issue 4, pp 1558–1567 | Cite as

Synthesis and antitumor activity of 4-cyclohexyl/aryl-5-(pyridin-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones

  • Mashooq Ahmad BhatEmail author
  • Mohamed A. Al-Omar
  • Ahmed M. Naglah
  • Mohamed M. Abdulla
  • Hoong-Kun Fun
Original Research

Abstract

The reaction of 2-isonicotinoyl-N-cyclohexyl/arylhydrazinecarbothioamide (2ar) with sodium hydroxide, in each case, a single product was obtained. The structures of the compounds were confirmed on the basis of their elemental analysis and spectral data. The single crystal X-ray analysis confirmed the structure of these products as N-4-cyclohexyl/aryl-5-(pyridine-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones (3ar). The in vitro antitumor activity of compounds was screened against three cell lines; BEL-7402, HUH-7 and HepG2 human hepatoma using MTT assay. Sorafenib (50 µM) was used as a positive control. The results of the MTT-dye reduction assay indicated that most of the compounds exert potent cytotoxic/antiproliferative effect in a time and dose-dependent manner via induced apoptosis of HepG2 cells. Results also showed that the tested compounds could significantly enhance the activity of caspase-3 which plays a very important role as the central effecter during apoptosis. The effect of different substitutions on the aromatic portion on the activity was found to be in the following order CH3 > OCH3 > I > SO2NH2 > OC2H5 > C2H5 > NO2 > Cl > CH3CONH.

Keywords

Isoniazid 1,2,4-Triazole-3-thione Cytotoxic activity MTT assay 

Notes

Acknowledgments

The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for funding this research group No. (RG 1435-006).

Supplementary material

44_2014_1216_MOESM1_ESM.docx (473 kb)
Supplementary material 1 (DOCX 472 kb)

References

  1. Almasirad A, Tabatabai A, Shafiee A (2004) Synthesis and anticonvulsant activity of new 2-substituted-5-[2-(2-fluorophenoxy) phenyl]-1,3,4-oxadiazoles and 1,2,4-triazoles. Bioorg Med Chem Lett 14(11):6057–6059CrossRefPubMedGoogle Scholar
  2. Banik B, Sasmal PK, Roy S, Majumdar R, Dighe RR, Chakravarty AR (2011) Terpyridine oxovanadium (IV) complexes of phenanthroline bases for cellular imaging and photocytotoxicity in HeLa cells. Eur J Inorg Chem 9:1425–1435CrossRefGoogle Scholar
  3. Bayrak H, Demirbas A, Karaoglu SA, Demirbas N (2009) Synthesis of some new 1,2,4-triazoles, their mannich and Schiff bases and evaluation of their antimicrobial activities. Eur J Med Chem 44(3):1057–1066CrossRefPubMedGoogle Scholar
  4. Bhat MA, Khan AA, Khan S, Al-Omar MA, Parvez MK, Al-Dosari MS, Al-Dhfyan A (2014) Synthesis and anti-candidal activity of N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl-carbonyl) hydrazinecarbothioamide. Bioorg Med Chem Lett 24:1299–1302CrossRefPubMedGoogle Scholar
  5. Duan M, Kazmierski WM, Chong PY, Deanda F, Edelstein M, Ferris R, Peckham J, Wheelan P, Xiong Z, Zhang H, Nishizawa R, Takaoka Y (2011) Discovery of novel pyridyl carboxamides as potent CCR5 antagonists and optimization of their pharmacokinetic profile in rats. Bioorg Med Chem Lett 21(21):6470–6475CrossRefPubMedGoogle Scholar
  6. Ebrahimi S (2010) Synthesis of some pyridyl cyclohexyl substituted 1,2,4-triazole, 1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives. Eur J Chem 1(4):322–324CrossRefGoogle Scholar
  7. Grossi G, Braccio M, Roma G, Ballabeni V, Toglonini M, Calcina F, Barocelli E (2002) 1,5-Benzodiazepines. Part XIII. Substituted 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amines and 4H-imidazo[1,2-a][1,5]benzodiazepin-5-amines as analgesic, anti-inflammatory and/or antipyretic agents with low acute toxicity. Eur J Med Chem 37:933–944CrossRefPubMedGoogle Scholar
  8. Haber J (2001) Present status and perspectives on antimycoties with systematic effects. Cas Lek Cesk 140:596–604PubMedGoogle Scholar
  9. Holla BS, Poojary KN, Rao BS, Shivananda MK (2002) New bis-aminomercaptotriazoles and bis-triazolothiadiazoles as possible anticancer agents. Eur J Med Chem 37(6):511–517CrossRefPubMedGoogle Scholar
  10. Johnstone RW, Ruefli AA, Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108:153–164CrossRefPubMedGoogle Scholar
  11. Kaplancikli ZA, Turan-Zitouni G, Ozdemir A, Revial G (2008) New triazole and triazolothiadiazine derivatives as possible antimicrobial agents. Eur J Med Chem 43(1):155–159CrossRefPubMedGoogle Scholar
  12. Kucukguzel I, Tatar E, Kucukguzel SG, Rollas S, De Clercq E (2008) Synthesis of some novel thiourea derivatives obtained from 5-[(4-amino phenoxy) methyl]-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones and evaluation as antiviral/anti-HIV and anti-tuberculosis agents. Eur J Med Chem 43(2):381–392CrossRefPubMedGoogle Scholar
  13. Labanauskas L, Udrenaite E, Brukstus A (2004) Synthesis of 5-(2,3 and 4-methoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives exhibiting anti-inflammatory activity. IL Farmaco 59(4):255–259CrossRefPubMedGoogle Scholar
  14. Lebouvier N, Pagniez F, Duflas M, Le Pape P, Na YM, Le Bault G, Le Borgne M (2007) Synthesis and antifungal activities of new fluconazole analogues with azaheterocycle moiety. Bioorg Med Chem Lett 17(13):3686–3689CrossRefPubMedGoogle Scholar
  15. Liu P, Zhu S, Xie P, Xie W, Jiang Y, Zhang D (2008) Synthesis and SAR studies of biaryloxy-substituted triazoles as antifungal agents. Bioorg Med Chem Lett 18:3261–3265CrossRefPubMedGoogle Scholar
  16. Luedtke GR, Schinzel K, Tan X, Tester RW, Nashashibi I, Xu YJ, Dugar S, Levy DE, Jung J (2010) Amide-based inhibitors of p38alpha MAP kinase. Part 1: discovery of novel N-pyridyl amide lead molecules. Bioorg Med Chem Lett 20(8):2556–2559CrossRefPubMedGoogle Scholar
  17. Mathew V, Keshavayya J, Vaidya VP (2006) Heterocyclic system containing bridgehead nitrogen atom: synthesis and pharmacological activities of some substituted 1,2,4-triazolo [3,4-b]-1,3,4-thiadiazoles. Eur J Med Chem 41(9):1048–1058CrossRefPubMedGoogle Scholar
  18. Packiarajan M, Coate H, Desai M, Jimenez HN, Reinhard EJ, Jubian VJ, Marzabadi MR, Chandrasena G, Wolinski TC, Walker MW, Andersen K (2011) 5-(2′-Pyridyl)-2-aminothiazoles: alkyl amino sulfonamides and sulfamides as potent NPY (5) antagonists. Bioorg Med Chem Lett 21(21):6500–6504CrossRefPubMedGoogle Scholar
  19. Prakash OP, Bhardwaj V, Kumar R, Aneja KR (2004) Organoiodine (III) mediated synthesis of 3-aryl/hetryl-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidines as antibacterial agents. Eur J Med Chem 39(12):1073–1077CrossRefPubMedGoogle Scholar
  20. Siddiqui SM, Azam SA (2012) Synthesis, characterization and antimicrobial activity of some hydrazone and azole derivatives bearing pyridyl moiety as promising heterocyclic scaffold. Eur J Med Chem 49:411–416CrossRefPubMedGoogle Scholar
  21. Sonntag R, Gassler N, Bangen J-M, Trautwein C, Liedtke C (2014) Pro-apoptotic sorafenib signaling in murine hepatocytes depends on malignancy and is associated with PUMA expression in vitro and in vivo. Cell Death Dis 5:e1030. doi: 10.1038/cddis.2013.557 CrossRefPubMedCentralPubMedGoogle Scholar
  22. Sriram D, Yogeeswari P, Priya DY (2009) Antimycobacterial activity of novel N-(substituted)-2-isoniconinoylhydrazono-carbothioamide endowed with high activity towards isoniazid resistant tuberculosis. Biomed Pharmacother 63:36–39CrossRefPubMedGoogle Scholar
  23. Sztanke R, Pasternak K, Jozwiak K (2006) Synthesis of imidazoline and imidazo[2,1-c][1,2,4]triazole aryl derivatives containing the methylthio group as possible antibacterial agents. Bioorg Med Chem 14(2):3635–3642CrossRefPubMedGoogle Scholar
  24. Sztanke K, Tuzimski T, Rzymowska J, Pasternak K, Szerszen MK (2008) Synthesis, determination of the lipophilicity, anticancer and antimicrobial properties of some fused 1,2,4-triazole derivatives. Eur J Med Chem 43:404–419CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Mashooq Ahmad Bhat
    • 1
    Email author
  • Mohamed A. Al-Omar
    • 1
  • Ahmed M. Naglah
    • 2
    • 3
  • Mohamed M. Abdulla
    • 4
  • Hoong-Kun Fun
    • 1
  1. 1.Department of Pharmaceutical Chemistry, College of PharmacyKing Saud UniversityRiyadhKingdom of Saudi Arabia
  2. 2.Pharmaceutical Chemistry Department, Drug Exploration & Development Chair, College of PharmacyKing Saud UniversityRiyadhKingdom of Saudi Arabia
  3. 3.Peptide Chemistry Department, Chemical Industries Research DivisionNational Research CentreCairoEgypt
  4. 4.Research Unit6th October CityEgypt

Personalised recommendations