Medicinal Chemistry Research

, Volume 26, Issue 10, pp 2243–2259 | Cite as

Synthesis, in vitro antiproliferative activity, antioxidant activity and molecular modeling studies of new carbazole Mannich bases

  • Pedavenkatagari Narayana Reddy
  • Pannala Padmaja
  • Bobbala Ramana Reddy
  • Surender Singh Jadav
Original Research


A new class of carbazole Mannich bases were synthesized from 4-hydroxycarbazole by reacting with aromatic aldehydes and cyclic amines under mild reaction conditions in good yields. The method does not require column chromatographic purification for isolation of the products. The synthetic potential of these carbazole Mannich bases is exemplified by the ortho-quinone methide formation and subsequent in situ trapping with active methylene compounds bearing a cyano group to construct biologically active pyrano[3,2-c]carbazoles. Further, all the synthesized Mannich bases were tested for their in vitro antiproliferative activity against three cancer cell lines (Hela, MDA-MB-231, and HepG2). The results indicated that these compounds showed selective cytotoxicity against Hela cells. In addition, the synthesized carbazole Mannich bases were also screened for their scavenging activity of the 2,2-diphenyl-1-picrylhydrazyl radical and most of the compounds showed very good antioxidant activity. In silico molecular docking study of synthesized carbazole Mannich bases against colchicine binding site of the tubulin polymer was investigated.


Mannich bases 4-Hydroxycarbazole Ortho-quinone methide Pyrano[3,2-c]carbazoles Antioxidant activity Molecular docking 



P. Narayana Reddy thanks to DST-SERB, India for a Start-Up Research Grant., P. Padmaja thankful to DST, India for Inspire Faculty Fellowship.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1927_MOESM1_ESM.docx (3 mb)
Supplementary Information


  1. Alden-Danforth E, Scerba MT, Lectka T (2008) Asymmetric cycloadditions of o-quinone methides employing chiral ammonium. Org Lett 10(21):4951–4953CrossRefPubMedPubMedCentralGoogle Scholar
  2. Amouri H, Bras JL (2002) Taming reactive phenol tautomers and o-quinone methides with transition metals: a structure-reactivity relationship. Acc Chem Res 35(7):501–510CrossRefPubMedGoogle Scholar
  3. Bai WJ, David JG, Feng ZG, Weaver MG, Wu K, Pettus TRR (2014) The domestication of ortho-quinone methides. Acc Chem Res 47(12):3655–3664CrossRefPubMedPubMedCentralGoogle Scholar
  4. Balasubramanian KK, Selvaraj S (1980) Novel reaction of o-phenolic mannich bases with alpha-chloroacrylonitrile. J Org Chem 45(18):3726–3727CrossRefGoogle Scholar
  5. Basaric N, Majerski KM, Kralj M (2014) Quinone methides: photochemical generation and its application in biomedicine. Curr Org Chem 18(1):3–18CrossRefGoogle Scholar
  6. Caruana L, Fochi M, Bernardi L (2015) The emergence of quinine methides in asymmetric organocatalysis. Molecules 20(7):11733–11764CrossRefPubMedGoogle Scholar
  7. Chao WR, Yean D, Amin K, Green C, Jong L (2007) Computer-aided rational drug design: a novel agent (SR13668) designed to mimic the unique anticancer mechanisms of dietary indole-3-carbinol to block akt signaling. J Med Chem 50(15):3412–3415CrossRefPubMedGoogle Scholar
  8. Cogan PS, Koch TH (2003) Rational design and synthesis of androgen receptor-targeted nonsteroidal anti-androgen ligands for the tumor-specific delivery of a doxorubicin-formaldehyde conjugate. J Med Chem 46(24):5258–5270CrossRefPubMedGoogle Scholar
  9. Cui CB, Yan SY, Cai B, Yao XS (2002) Carbazole alkaloids as new cell cycle inhibitor and apoptosis inducers from Clausena dunniana levl. J Asian Nat Prod Res 4(4):233–241CrossRefPubMedGoogle Scholar
  10. Dimmock JR, Erciyas E, Kumar P, Hetherington M, Quail JW, Pugazhenthi U, Arpin SA, Hayes SJ, Allen TM, Halleran S, Clercq ED, Balzarini J, Stables JB (1997) Mannich bases of phenolic azobenzenes possessing cytotoxic activity. Eur J Med Chem 32:583–594CrossRefGoogle Scholar
  11. Dimmock JR, Jonnalagadda SS, Phillips OA, Erciyas E, Shyam K, Semple HA (1992) Anticonvulsant properties of some mannich bases of conjugated arylidene ketones. J Pharm Sci 81(5):436–440CrossRefPubMedGoogle Scholar
  12. Doria F, Nadai M, Folini M, Antonio MD, Germani L, Percivalle C, Sissi C, Zaffaroni N, Alcaro S, Artese A, Richter SN, Freccero M (2012) Hybrid ligand-alkylating agents targeting telomeric G-quadruplex structures. Org Biomol Chem 10:2798–2806CrossRefPubMedGoogle Scholar
  13. Doria F, Nadai M, Folini M, Scalabrin M, Germani L, Sattin G, Mella M, Palumbo M, Zaffaroni N, Fabris D, Freccero M, Richter SN (2013) Targeting loop adenines in G-quadruplex by a selective oxirane. Chem Eur J 19(1):78–81CrossRefPubMedGoogle Scholar
  14. Edwards ML, Ritter HW, Stemerick DM, Stewart KT (1983) Mannich bases of 4-phenyl-3-butene-2-one. A new class of antiherpes agent. J Med Chem 26:431–436CrossRefPubMedGoogle Scholar
  15. Erciyas E, Erkaleli HI, Cosar G (1994) Antimicrobial evaluation of some styryl ketone derivatives and related thiol adducts. J Pharm Sci 83(4):545–548CrossRefPubMedGoogle Scholar
  16. Ferreira SB, Da Silva FC, Pinto AC, Gonzaga DTG, Ferreira VF (2009) Syntheses of chromenes and chromanes via o-quinone methide intermediates. Heterocycl Chem 46(6):1080–1097CrossRefGoogle Scholar
  17. Friebolin W, Jannack B, Wenzel N, Furrer J, Oeser T, Sanchez CP, Lanzer M, Yardley V, Becker K, Davioud-Charvet E (2008) Antimalarial dual drugs based on potent inhibitors of glutathione reductase from Plasmodium falciparum. J Med Chem 51(5):1260–1277CrossRefPubMedGoogle Scholar
  18. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein–ligand complex. J Med Chem 49(21):6177–6196CrossRefPubMedGoogle Scholar
  19. Gul HI, Gul M, Erciyas E (2002) Syntheses and stability studies of some mannich bases of acetophenonnes and evaluation of their cytotoxicity against jurkat cells. Arzneim Forsch 52:628–635Google Scholar
  20. Gul M, Mete E, Atalay E, Arik M, Gul HI (2009) Cytotoxicity of 1-aryl-3-buttylamino-1-propanone hydrochlorides against jurkat and L6 cells. Arzneim Forsch 59:364–369Google Scholar
  21. Hsiao CC, Raja S, Liao HH, Atodiresei I, Rueping M (2015) Ortho-quinone methides as reactive intermediates in asymmetric bronsted acid catalyzed cycloadditions with unactivated alkenes by exclusive activation of the electrophile. Angew Chem Int Ed 54(19):5762–5765CrossRefGoogle Scholar
  22. Hu H, Liu Y, Guo J, Lin L, Xu Y, Liu X, Feng X (2015) Enantioselective synthesis of dihydrocoumarin derivatives by chiral scandium(III)-complex catalyzed inverse-electron-demand hetero-diels-alder reaction. Chem Commun 51:3835–3837CrossRefGoogle Scholar
  23. Indumathi T, Ahamed VSJ, Moon S, Fronczek FR, Prasad KJR (2011) l-Proline anchored multicomponent synthesis of novel pyrido[2,3-a]carbazoles: investigation of in vitro antimicrobial, antioxidant, cytotoxicity and structure–activity relationship studies. Eur J Med Chem 46(11):5580–5590CrossRefPubMedGoogle Scholar
  24. Indumathi T, Fronczek FR, Prasad KJR (2012) Synthesis of 2-amino-8-chloro-4-phenyl-5,11-dihydro-6H-pyrido[2,3-a]carbazole-3-carbonitrile: structural and biological evaluation. J Mol Struct 1016:134–139CrossRefGoogle Scholar
  25. Ito C, Itoigawa M, Sato A, Hasan CM, Rashid MA, Tokuda H, Mukainaka T, Nishino H, Furukawa H (2004) Chemical constituents of Glycosmis arborea: three new carbazole alkaloids and their biological activity. J Nat Prod 67(9):1488–1491CrossRefPubMedGoogle Scholar
  26. Itoigawa M, Kashiwada Y, Ito C, Furukawa H, Tochibana Y, Bastow KF, Lee LH (2000) Antitumor agents. 203. Carbazole alkaloid murrayaquinone A and related synthetic carbazolequinones as cytotoxic agents. J Nat Prod 63(7):893–897CrossRefPubMedGoogle Scholar
  27. Janosik T, Wahlstrom N, Bergman J (2008) Recent progress in the chemistry and applications of indolocarbazoles. Tetrahedron 64(39):9159–9180CrossRefGoogle Scholar
  28. Jaworski AA, Scheidt KA (2016) Emerging roles of in situ generated quinine methides in metal-free catalysis. J Org Chem 81(21):10145–10153CrossRefPubMedGoogle Scholar
  29. Kaim LE, Grimaud L, Oble J (2006) New ortho-quinone methide formation: application to three-component coupling of isocyanides, aldehydes and phenols. Org Biomol Chem 4:3410–3413CrossRefPubMedGoogle Scholar
  30. Kato S, Kawasaki T, Urata T, Mochizuki J (1993) In vitro and ex vivo free radical scavenging activities of caraostatin, carbazomycin B and their derivatives. J Antibiot 46(12):1859–1865CrossRefPubMedGoogle Scholar
  31. Knolker HJ (2004) Transition metal complexed in organic synthesis, part 70. Syntehsis of biologically active carbazole alkaloids using organometallic chemistry. Curr Org Synth 1(4):309–331CrossRefGoogle Scholar
  32. Knolker HJ, Reddy KR (2002) Isolation and synthesis of biologically active carbazole alkaloids. Chem Rev 102(11):4304–4327CrossRefGoogle Scholar
  33. Knolker HJ, Reddy KR (2008) The Alkaloids. In: Cordell GA (ed) Chemistry and biology. Academica Press, Amsterdam, voi. 65, p 1–430Google Scholar
  34. Kucukoglu K, Gul M, Atalay M, Mete E, Kazaz C, Hanninen O, Gul HI (2011) Synthesis of some Mannich bases with dimethylamine and their hydrazones and evaluation of their cytotoxicity against jurkat cells. Arzneim Forsch 61(6):366–371CrossRefGoogle Scholar
  35. Lai Z, Wang Z, Sun J (2015) Organocatalytic asymmetric nucleophilic addition to o-quinone methides by alcohols. Org Lett 17(24):6058–6061CrossRefPubMedGoogle Scholar
  36. Lee CM, Plattner JJ, Ours CW, Horrom BW, Smital JR, Martin YC, Pernet AG, Bunnell PR, El Masry SE, Dodge PW (1984) [[(Aminomethyl)aryl]oxy]acetic acid esters. A new class of high ceiling diuretics. 1. Effects of nitrogen and aromatic nuclear substitution. J Med Chem 27(12):1579–1587CrossRefPubMedGoogle Scholar
  37. Lv H, Jia WQ, Sun LH, Ye S (2013) N-heterocyclic carbine catalyzed [4 + 3] annulations of enals and o-quinone methides:highly enantioselective synthesis of benzo-ε-lactones. Angew Chem Int Ed 52(33):8607–8610CrossRefGoogle Scholar
  38. Maneerat W, Ritthiwigrom T, Cheenpracha S, Promgool T, Yossathera K, Deachathai S, Phakhodee W, Laphookhieo S (2012) Bioactive carbazole alkaloids from clausena wallichii roots. J Nat Prod 75(4):741–746CrossRefPubMedGoogle Scholar
  39. Mester I, Reisch J (1977) Ingredients from Clausena Anisata (Willd.) Oliv, (Rutaceae), II. Isolation and structure of Mupamins, a new carbazolalkaloids. Ann Chem 10:1725–1729CrossRefGoogle Scholar
  40. Miroshnikova OV, Hudson TH, Gerena L, Kyle DE, Lin AJ (2007) Synthesis and antimalarial activity of new isotebuquine analogues. J Med Chem 50(4):889–896CrossRefPubMedGoogle Scholar
  41. Muthumani P, Neckmohammed MR, Venkataraman S, Chidambaranathan N, Devi P, Suresh Kumar CA (2010) Synthesis and evaluation of anticonvulsant and antimicrobial activities of some mannich bases of substituted aminophenol and acetophenone. Int J Pharm Biomed Res 1(3):78–86Google Scholar
  42. Nadai M, Doria F, Antonio MD, Sattin G, Germani L, Percivalle C, Palumbo M, Richter SN, Freccero M (2011) Napthalene dimide scaffolds with dual reversible and covalent interaction properties towards G-quadruplex. Biochimie 93(8):1328–1340CrossRefPubMedGoogle Scholar
  43. Nakatani K, Higashida N, Saito I (1997) Highly efficient photochemical generation of o-quinone methide from mannich bases of phenol derivatives. Tetrahedron Lett 38(28):5005–5008CrossRefGoogle Scholar
  44. Padmaja P, Rao GK, Indrasena A, Reddy BVS, Patel N, Shaik AB, Reddy N, Dubey PK, Bhadra MP (2015) Synthesis and biological evaluation of novel pyrano[3,2-c]carbazole derivatrives as anti-tumor agents including apoptosis via tubulin polymerization inhibition. Org Biomol Chem 13(5):1404–1414CrossRefPubMedGoogle Scholar
  45. Padmaja P, Reddy BVS, Nishant J, Rao MS, Priyanka B, Sowjanya P, Rambabu G, Reddy PN (2016) Synthesis, molecular docking and in vitro antiproliferative activity of novel pyrano[3,2-c]carbazole derivatives. N J Chem 40:8305–8315CrossRefGoogle Scholar
  46. Pathak TP, Sigman MS (2011) Applications of ortho-quinone methide intermediates in catalysis and asymmetric synthesis. J Org Chem 76(22):9210–9215CrossRefPubMedPubMedCentralGoogle Scholar
  47. Pettigrew JD, Wilson PD (2006) Synthesis of xyloketal A, B, C, D and G analogues. J Org Chem 71(4):1620–1625CrossRefPubMedGoogle Scholar
  48. Pieper AA, McKnight SL, Ready JM (2014) P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases. Chem Soc Rev 43:6716–6726CrossRefPubMedPubMedCentralGoogle Scholar
  49. Prasad P, Shuhendler A, Cai P, Rauth AM, Wu XY (2013) Doxorubicin and mitomycin C co-loaded polymer–lipid hybrid nanoparticles inhibit growth of sensitive and multridrug resistant human mammary tumor xenografts. Cancer Lett 334(2):263–273CrossRefPubMedGoogle Scholar
  50. Ramsewak RS, Nair MG, Strasburg GM, Dawitt DL, Nitiss JL (1999) Biologically active carbazole alkaloids from murraya koenigii. J Agric Food Chem 47(2):444–447CrossRefPubMedGoogle Scholar
  51. Reddy PN, Padmaja P, Reddy BR, Rambabu G, Kumar MP (2016) Synthesis, molecular docking, antriproliferative and antimicrobial activity of novel pyrano[3,2-c]carbazole derivatives. Med Chem Res 25:2093–2103CrossRefGoogle Scholar
  52. Rokita SE (2009)  Quinone Methides. Reactive Intermediates in Chemistry and Biology, Vol. 1, Wiley: Hoboken, NJGoogle Scholar
  53. Romagnoli R, Baraldi PG, Brancale A, Ricci A, Hamel E, Bortolozzi R, Basso G, Viola G (2011) Convergent synthesis and biological evaluation of 2-amino-4-3′,4′,5′-trimethoxyphenyl)-5-aryl-thiazoles as microtubule targeting agents. J Med Chem 54(14):5144–5153CrossRefPubMedPubMedCentralGoogle Scholar
  54. Romans AM, Boulven M, Lemaire M, Popowycz F (2016) 3-Methylene-2,4-chromandione in situ trapping: introducing molecular diversity on 4-hydroxycoumarin. RSC Adv 6:4540–4544CrossRefGoogle Scholar
  55. Schmidt AW, Reddy KR, Knolker HJ (2012) Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids. Chem Rev 112(6):3193–3328CrossRefPubMedGoogle Scholar
  56. Scott MK, Martin GE, DiStefano DL, Fedde CL, Kukla MJ, Barrett DL, Baldy WJ, Elgin Jr RJ, Kesslick JM (1992) Pyrrole Mannich bases as potential antipsychotic agents. J Med Chem 35:552–558CrossRefPubMedGoogle Scholar
  57. Selvakumar V, Duraipandi S, Devdas S (2011) Synthesis and psychorpharmacological activities of some succinimide mannich bases. J Pharm Res 4:3168–3170Google Scholar
  58. Shiozawa A, Narita K, Izumi G, Kurashige S, Sakitama K, Ishikawa M (1995) Synthesis and activity of 2-methyl-3-aminopropiophenones as centrally acting muscle relaxants. Eur J Med Chem 30(1):85–94CrossRefGoogle Scholar
  59. Shuhendler AJ, Cheung RY, Manias J, Connor A, Rauth AM, Wu XY (2010) A novel doxorubicin-mitomycin C co-encapsulated nanoparticle formulation exhibits anti-cancer synergy in multidrug resistant human breast cancer cells. Breast Cancer Res Treat 119(2):255–269CrossRefPubMedGoogle Scholar
  60. Syam S, Abdul AB, Sukari MA, Mohan S, Abdelwahab SI, Wah TS (2011) The growth suppressing effects of Girinimbine on Hepg2 involve induction of apoptosis and cell cycle arrest. Molecules 16(8):7155–7170CrossRefPubMedGoogle Scholar
  61. Tachibana Y, Kikuzaki H, Lajis LH, Nakatani N (2003) Comparison of antioxidative properties of carbazole alkaloids from Murraya Koenigii leaves. J Agric Food Chem 51(22):6461–6467CrossRefPubMedGoogle Scholar
  62. Taj T, Kamble RR, Gireesh TM, Hunnur RK, Margankop SB (2011) One-pot synthesis of pyrazoline derivatised carbazoles as antitubercular, anticancer agents, their DNA cleavage and antioxidant activities. Eur J Med Chem 46(9):4366–4373CrossRefPubMedGoogle Scholar
  63. Takeuchi T, Oishi S, Watanabe T, Ohno H, Sawada J, Matsuno K, Asai A, Asada N, Kitaura K, Fujii N (2011) Structure–activity relationships of carboline and carbazole derivatives as a novel class of ATP-competitive kinesin spindle protein inhibitors. J Med Chem 54(13):4839–4846CrossRefPubMedGoogle Scholar
  64. Tomasz M, Das A, Tang KS, Ford MGJ, Minnock A, Musser SM, Waring MJ (1998) The purine-2-amino group as the critical recognition element for sequence-specific alkylation and cross-linking of DNA by mitomycin C. J Am Chem Soc 120:11581–11593CrossRefGoogle Scholar
  65. Vashishtha SC, Zello GA, Nienaber KH, Balzarini J, Clercq ED, Stables JP, Dimmock JR (2004) Cytotoxic and anticonvulsant aryloxyary Mannich bases and related compounds. Eur J Med Chem 39(1):27–35CrossRefPubMedGoogle Scholar
  66. Wang Z, Sun J (2015) Recent advances in catalytic asymmetric reactions of o-quinone methides. Synthesis 47(23):3629–3644CrossRefGoogle Scholar
  67. Water RWVD, Pettus TRR (2002) o-Quinone methides: intermediates underdeveloped and underutilized in organic synthesis. Tetrahedron 58(27):5367–5405CrossRefGoogle Scholar
  68. Weng X, Ren L, Weng L, Huang J, Zhu S, Zhou X, Weng L (2007) Synthesis and biological studies of inducible DNA cross-linking agents. Angew Chem Int Ed 46(42):8020–8023CrossRefGoogle Scholar
  69. Wen-Shyong L, McChesney JD, El-Feraly FS (1991) Carbazole alkaloids from clausena lansium. Phytochemistry 30(1):343–346CrossRefGoogle Scholar
  70. Willis NJ, Bray CD (2012) ortho-quinone methides in natural product synthesis. Chem Eur J 18(30):9160–9173CrossRefPubMedGoogle Scholar
  71. Willis NJ, Bray CD (2015) An ortho-quinone methide based strategy towards the rubromycin spiroketal family. RSC Adv 5:80212–80215CrossRefGoogle Scholar
  72. Xu Z, Li Y, Xiang Q, Pei Z, Liu X, Lu B, Chen L, Wang G, Pang J, Lin Y (2010) Design and synthesis of novel xyloketal derivatives and their vasorelaxing activities in rat thoracic aorta and angiogenic activities in zebrafish angiogenesis screen. J Med Chem 53(12):4642–4653CrossRefPubMedGoogle Scholar
  73. Yu X, Chen J, Wei Q, Cheng H, Liu Z, Xiao W (2016) Catalytic asymmetric cycloaddition of in situ-generated ortho-quinone methides and azalactones by a triple bronsted acid activation strategy. Chem Eur J 22(20):6774–6778CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Pedavenkatagari Narayana Reddy
    • 1
  • Pannala Padmaja
    • 2
  • Bobbala Ramana Reddy
    • 1
  • Surender Singh Jadav
    • 3
  1. 1.Department of Chemistry, Gitam School of TechnologyGitam UniversityHyderabadIndia
  2. 2.Department of ChemistryJNTUH College of EngineeringHyderabadIndia
  3. 3.Department of Pharmaceutical Sciences & TechnologyBirla Institute of TechnologyRanchiIndia

Personalised recommendations