Advertisement

Medicinal Chemistry Research

, Volume 28, Issue 1, pp 13–27 | Cite as

Synthesis, antimalarial, antiproliferative, and apoptotic activities of benzimidazole-5-carboxamide derivatives

  • Jesús A. Romero
  • María E. Acosta
  • Neira D. Gamboa
  • Michael R. Mijares
  • Juan B. De Sanctis
  • Ligia J. Llovera
  • Jaime E. CharrisEmail author
Original Research

Abstract

Twenty-eight compounds of the type N´-substituted-2-(5-nitroheterocyclic-2-yl)-3H-benzo[d]imidazole-5-carboxamide were obtained using as an oxidizing agent the nitrobenzene to obtain the benzimidazole scaffold, a modification of the Steglich esterification reaction was used to obtain the final compounds. The compounds were tested as potential inhibitors of the β-hematin formation in vitro, and in vivo were tested as antimalarial against mice infected by a strain of Plasmodium berghei ANKA sensitive to chloroquine. The survival time was increased by the compounds 3a and 4d to 17.00 ± 1.26 and 20.20 ± 1.95 days, while the progress of the infection was reduced to 4.02 ± 0.45 and 3.05 ± 0.09, respectively. The cytotoxic activity of all these compounds was assessed against Jurkat E6.1 and HL60 two human cancer cell line, and fresh human lymphocytes. Four compounds 4a, n and 5a, n showed enhanced cytotoxicity against Jurkat E6.1 and HL60 cell lines; fresh lymphocytes were not affected. Using flow cytometry, apoptotic cell death was observed at 24 h. The aforementioned compounds enhanced apoptosis both tumor cell lines decreasing cell survival by inhibiting autophagy.

Keywords

Benzimidazol Antimalarial P.berghei β-hematin Antiproliferative Apoptosis 

Notes

Acknowledgements

We thank the IIF and CDCH-UCV (grants IIF.02-2017, PG. 06-8627-2013/2) programs for financial support.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2018_2258_MOESM1_ESM.docx (22 kb)
Supplementary Information
44_2018_2258_MOESM2_ESM.docx (2.3 mb)
Supplementary Information

References

  1. Akhtar W, Khan M, Verma G, Shaquiquzzaman M, Rizvi M, Mehdi S, Akhter M, Alam M (2017) Therapeutic evolution of benzimidazole derivatives in the last quinquennial period. Eur J Med Chem 126:705–753Google Scholar
  2. Baelmans R, Deharo E, Muñoz V, Sauvain M, Ginsburg H (2000) Experimental conditions for testing the inhibitory activity of chloroquine on the formation of β-hematin. Exp Parasitol 96:243–248Google Scholar
  3. Bansal Y, Silakari O (2012) The therapeutic journey of benzimidazoles: A review. Bioorg Med Chem 20:6208–6236Google Scholar
  4. Baran I, Ganea C, Scordino A, Musumeci F, Barresi V, Tudisco S, Privitera S, Grasso R, Condorelli D, Ursu I, Baran V, Katona E, Mocanu M-M, Gulino M, Ungureanu R, Surcel M, Ursaciuc C (2010) Effects of menadione, hydrogen peroxide, and quercetin on apoptosis and delayed luminescence of human leukemia Jurkat T-cells. Cell Biochem Biophys 58:169–179Google Scholar
  5. Berger T, Dieckmann D, Efferth T, Schultz E, Funk J, Baur A, Schuler G (2005) Artesunate in the treatment of metastatic uveal melanoma-first experiences. Oncol Rep 14:1599–1603Google Scholar
  6. Brain-Isasi S, Quezada C, Pessoa H, Morello A, Kogan M, Alvarez-Lueje A (2008) Determination and characterization of new benzimidazoles with activity against Trypanosoma cruzi by UV spectroscopy and HPLC. Bioorg Med Chem 16:7622–7630Google Scholar
  7. Camacho J, Barazarte A, Gamboa N, Rodrigues J, Rojas R, Vaisberg A, Gilman R, Charris J (2011) Synthesis and biological evaluation of benzimidazole-5-carbohydrazide derivatives as antimalarial, cytotoxic and antitubercular agents. Bioorg Med Chem 19:2023–2029Google Scholar
  8. Charris J, Camacho J, Ferrer R, Lobo G, Barazarte A, Gamboa N, Rodrigues J, López S (2006) A convenient route to 2-substituted benzothiazole-6-carboxylic acids using nitrobenzene as oxidant. J Chem Res 12:769–770Google Scholar
  9. Charris J, Lobo G, Camacho J, Ferrer R, Barazarte A, Domínguez J, Gamboa N, Rodrigues J, Ángel J (2007) Synthesis and antimalarial activity of (E) 2-(2´-Chloro-3´-quinolinylmethylidene)-5,7-dimethoxyindanones. Lett Drug Des Dis 4:49–54Google Scholar
  10. Chen D, Daniel K, Chen M, Kuhn D, Landis-Piwowar K, Dou Q (2005) Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. Biochem Pharmacol 69:1421–1432Google Scholar
  11. Chloroquine Phosphate Oral, 21 may 2018. http://nlm.nih.gov/medlineplus/druginfo/meds/a682318.html. Accessed 20 June 2018
  12. Cho Y, Ioerger T, Sacchettini J (2008) Discovery of novel nitrobenzothiazole inhibitors for Mycobacterium tuberculosis ATP phosphoribosyl transferase (HisG) through virtual screening. J Med Chem 51:5984–5992Google Scholar
  13. Choi E, Bae S, Ahn W (2008) Antiproliferative effects of quercetin through cell cycle arrest and apoptosis in human breast cancer MDA-MB-453 cells. Arch Pharm Res 31:1281–1285Google Scholar
  14. de Villiers K, Gildenhuys J, Roex T (2012) Iron(III) protoporphyrin IX complexes of the antimalarial cinchona alkaloids quinine and quinidine. ACS Chem Biol 7:666–671Google Scholar
  15. Dondorp A, Nosten F, Yi P, Das D, Phyo A, Tarning J, Lwin K, Ariey F, Hanpithakpong W, Lee S, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An S, Yeung S, Singhasivanon P, Day N, Lindegardh N, Socheat D, White N (2009) Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 361:455–467Google Scholar
  16. Dorn A, Stoffel R, Matile H, Bubendorf A, Ridley R (1995) Malarial haemozoin/beta-haematin supports haem polymerization in the absence of protein. Nat (Lond) 374:269–271Google Scholar
  17. Efferth T, Sauerbrey A, Olbrich A, Gebhart E, Rauch P, Weber H, Hengstler J, Halatsch M, Volm M, Tew K, Ross D, Funk J (2003) Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol 6:382–394Google Scholar
  18. Efferth T (2007) Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin-from bench to bedside. Planta Med 73:299–309Google Scholar
  19. Egan T, Ncokazi K (2005) Quinoline antimalarials decrease the rate of β-hematin formation. J Inorg Biochem 99:1532–1539Google Scholar
  20. Gaba M, Mohan C (2016) Development of drugs based on imidazole and benzimidazole bioactive heterocycles: recent advances and future directions. Med Chem Res 25:173–210Google Scholar
  21. Gaba M, Singh S, Mohan C (2014) Benzimidazole: An emerging scaffold for analgesic and anti-inflammatory agents. Eur J Med Chem 76:494–505Google Scholar
  22. Graph Pad Prism Software Inc. 4.02 for windows. May 17th. La Jolla, CA, 92037 USA (1992–2004)Google Scholar
  23. Gupta S, Sung B, Prasad S, Webb L, Aggarwal B (2013) Cancer drug discovery by repurposing: teaching new tricks to old dogs. Trends Pharmacol Sci 34:508–517Google Scholar
  24. Handrick R, Ontikatze T, Bauer K, Freier F, Rübel A, Dürig J, Belka C, Jendrossek V (2010) Dihydroartemisinin induces apoptosis by a bak-dependent intrinsic pathway. Mol Cancer Ther 9:2497–2510Google Scholar
  25. Hooft van Huijsduijnen R, Guy R, Chibale K, Haynes R, Peitz I, Kelter G, Phillips M, Vennerstrom J, Yuthavong Y, Wells T (2013) Anticancer properties of distinct antimalarial drug classes. PLoS ONE 8:e82962Google Scholar
  26. Hosseinzadeh N, Hasani M, Foroumadi A, Nadri H, Emami S, Samadi N, Faramarzi M, Saniee P, Siavoshi F, Abadian N, Mahmoudjanlou Y, Sakhteman A, Moradi A, Shafiee A (2013) 5-Nitro-heteroarylidene analogs of 2-thiazolylimino-4-thiazolidinones as a novel series of antibacterial agents. Med Chem Res 22:2293–2302Google Scholar
  27. Joshi A, Viswanathan C (2006) Recent developments in antimalarial drug discovery. Anti-Infec Agents Med Chem 5:105–122Google Scholar
  28. Kangwan N, Park J, Kim E, Hahm K (2014) Chemoquiesence for ideal cancer treatment and prevention: where are we now? J Cancer Prev 19:89–96Google Scholar
  29. Kim P, Kang S, Boshoff H, Jiricek J, Collins M, Singh R, Manjunatha U, Niyomrattanakit P, Zhang L, Goodwin M, Dick T, Keller T, Dowd C, Barry C (2009) Structure-activity relationships of antitubercular nitroimidazoles. 2. Determinants of aerobic activity and quantitative structure-activity relationships. J Med Chem 52:1329–1344Google Scholar
  30. Kim E, Stenberg R, Ru bsam A, Schmitz-Salue C, Warnecke G, Bücker E, Pettkus N, Speidel D, Rohde V, Schulz-Schaeffer W, Deppert W, Giese A (2010) Chloroquine activates the p53 pathway and induces apoptosis in humanglioma cells. Neuro-Oncol 12:389–400Google Scholar
  31. Kundu C, Das S, Nayak A, Satapathy S, Das D, Siddharth S (2015) Anti-malarials are anti-cancers and vice versa – One arrow two sparrows. Acta Trop1 49:113–127Google Scholar
  32. Lai H, Singh N (2006) Oral artemisinin prevents and delays the development of 7,12 dimethylbenz[a]anthracene (DMBA)-induced breast cancer in the rat. Cancer Lett 231:43–48Google Scholar
  33. Lan P, Romero F, Wodka D, Kassick A, Dang Q, Gibson T, Cashion D, Zhou G, Chen Y, Zhang X, Zhang A, Li Y, Trujillo M, Shao Q, Wu M, Xu S, He H, MacKenna D, Staunton J, Chapman K, Weber A, Sebhat I, Makara G (2017) Hit-to-lead optimization and discovery of 5-((5-([1,1’-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (MK-3903): A novel class of benzimidazole based activators of AMP-activated protein kinase. J Med Chem 60:9040–9052Google Scholar
  34. Li Y, Zeng X, Wang S, Fan J, Wang Z, Song P, Mei X, Ju D (2016) Blocking autophagy enhanced leukemia cell death induced by recombinant human arginase. Tumour Biol 37:6627–6635Google Scholar
  35. Manic G, Obrist F, Kroemer G, Vitale L, Galluzzi L (2014) Chloroquine and hydroxychloroquine for cancer therapy. Mol Cell Oncol 1:e29911Google Scholar
  36. Martínez A, Rajapakse C, Sánchez-Delgado R, Varela-Ramírez A, Lema C, Aguilera R (2010) Arene-Ru(II)-chloroquine complexes interact with DNA, induce apoptosis on human lymphoid cell lines and display low toxicity to normal mammalian cells. J Inorg Biochem 104:967–977Google Scholar
  37. Maso V, Calgarotto A, Franchi Jr G, Nowill A, Filho P, Vassallo J, Olalla S (2014) Multitarget effects of quercetin in leukemia. Cancer Prev Res (Phila) 12:1240–1250Google Scholar
  38. Meshnick S, Thomas A, Ranz A, Xu C, Pan H (1991) Artemisinin (qinghaosu): the role of intracellular hemin in its mechanism of antimalarial action. Mol Biochem Parasitol 49:181–189Google Scholar
  39. Mijares M, Ochoa M, Barroeta A, Martínez G, Suárez A, Compagnone R, Chirinos P, Avila R, De Sanctis J (2013) Cytotoxic effets of fisturalin-3 and 11-deoxyfisturalin-3 on jurkat and U937 cell lines. Biomed Pap 157:222–226Google Scholar
  40. Mital A (2009) Synthetic nitroimidazoles: Biological activities and mutagenicity relationships. Sci Pharm 77:497–520Google Scholar
  41. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63Google Scholar
  42. Mushtaque S (2015) Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: a review. Eur J Med Chem 90:280–295Google Scholar
  43. Neises B, Steglich W (1978) Simple method for the esterification of carboxylic acids. Angew Chem Int Ed Engl 17:522–524Google Scholar
  44. Njaria P, Okombo J, Njuguna N, Chibale K (2015) Chloroquine-containing compounds: a patent review (2010-2014). Expert Opin Ther Pat 25:1003–1024Google Scholar
  45. Noedl H, Se Y, Schaecher K, Smith B, Socheat D, Fukuda M (2008) Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 359:2619–2620Google Scholar
  46. Noedl H, Socheat D, Satimai W (2009) Artemisinin-resistant malaria in Asia. N Engl J Med 361:540–541Google Scholar
  47. Nordstrøm L, Sironi J, Aranda E, Maisonet J, Perez-Soler R, Wu P, Schwartz E (2015) Discovery of autophagy inhibitors with antiproliferative activity in lung and pancreatic cancer cells. ACS Med Chem Lett 6:134–139Google Scholar
  48. O’Neill P, Barton V, Ward S (2010) The molecular mechanism of action of artemisinin-the debate continues. Molecules 15:1705–1721Google Scholar
  49. Peters W, Robinson B (1999) Parasitic infection models. In: Zak O, Sande M (eds) Handbook of antimalarial models of infection. Academic Press, London, p 757Google Scholar
  50. Phillips M, Burrows J, Manyando C, van Huijsduijnen R, van Voorhis W, Wells T (2017) Malaria. Nat Rev Dis Prim 3:17050Google Scholar
  51. Posner G, McRiner A, Paik I, Sur S, Borstnik K, Xie S, Shapiro T, Alagbala A, Foster B (2004) Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents. J Med Chem 47:1299–1301Google Scholar
  52. Rodrigues J, Charris J, Ferrer R, Gamboa N, Ángel J, Nitzsche B, Hoepfner M, Lein M, Jung K, Abramjuk C (2012) Effect of quinolinyl acrylate derivatives on prostate cancer in vitro and in vivo. Invest New Drugs 30:1426–1433Google Scholar
  53. Romero J, Acosta M, Gamboa N, Mijares M, De Sanctis J, Charris J (2018) Optimization of antimalarial, and anticancer activities of (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate. Bioorg Med Chem 26:815–823Google Scholar
  54. Santos G, Almeida M, Antunes L, Bianchi M (2016) Effect of bixin on DNA damage and cell death induced by doxorubicin in HL60 cell line. Hum Exp Toxicol 35:1319–1327Google Scholar
  55. Singh B, Kim Sung L, Matusop A, Radhakrishnan A, Shamsul S, Cox-Singh J, Thomas A, Conway D (2004) A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet 363:1017–1024Google Scholar
  56. Singh N, Panwar V (2006) Case report of a pituitary macroadenoma treated with artemether. Integr Cancer Ther 5:391–394Google Scholar
  57. Siriram D, Yogeeswari P, Dhakla P, Senthilkumar P, Banerjee D, Manjashetty T (2009) 5-Nitrofuran-2-yl derivatives: Synthesis and inhibitory activities against growing and dormant mycobacterium species. Bioorg Med Chem Lett 19:1152–1154Google Scholar
  58. Siriram D, Yogeeswari P, Kumar D, Senthilkumar P, Bhat P, Srividya M (2010) 5-Nitro-2-furoic acid hydrazones: Design, synthesis and in vitro antimycobacterial evaluation against log and starved phase cultures. Bioorg Med Chem Lett 20:4313–4316Google Scholar
  59. Suárez A, Chávez K, Mateu E, Compagnone R, Muñoz A, Sojo F, Arvelo F, Mijares M, De Sanctis J (2009) Cytotoxic activity of seco-entkaurenes from Croton caracasana on human cancer cell lines. Nat Prod Commun 4:1547–1550Google Scholar
  60. US Centers for Disease Control and Prevention. Atlanta, GA: CDC; (2016) http://www.cdc.gov/malaria/history/index.htm. (Accessed 02. 19. 2018)
  61. Van Huijsduijnen R, Guy R, Chibale K, Haynes R, Peitz I, Kelter G, Phillips M, Vennerstrom J, Yuthavong Y, Wells T (2013) Anticancer properties of distinct antimalarial drug classes. PLoS ONE 8:e82962Google Scholar
  62. Wei Y, Zhao X, Kariya Y, Fukata H, Teshigawara K, Uchida A (1994) Induction of apoptosis by quercetin: involvement of heat shock protein. Cancer Res 54:4952–4957Google Scholar
  63. Wicht K, Combrinck J, Smith P, Hunter R, Egan T (2016) Identification and SAR evaluation of hemozoin-inhibiting benzamides active against Plasmodium falciparum. J Med Chem 59:6512–6530Google Scholar
  64. World Health Organization, Media centre Cancer february (2018a) http://www.who.int/mediacentre/factsheets/fs094/en/. (Accessed 02.05.2018)
  65. World Health Organization, Media centre Cancer february (2018b) http://www.who.int/mediacentre/factsheets/fs297/en/.(Accessed 02.05.2018)
  66. World Health Organization, welcomes global health funding for malaria vaccine (2016)http://www.who.int/mediacentre/news/releases/2016/malaria-control-africa/en/. (Accessed 02. 19. 2018)
  67. Xu Q, Li Z, Peng H, Sun Z, Cheng R, Ye Z, Li W (2011) Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo. J Zhejiang Univ Sci B 12:247–255Google Scholar
  68. Yadav G, Ganguly S (2015) Structure activity relationship (SAR) study of benzimidazole scaffold for different biological activities: A mini-review. Eur J Med Chem 97:419–443Google Scholar
  69. Zeng Q, Zhang P (2011) Artesunate mitigates proliferation of tumor cells by alkylating heme-harboring nitric oxide synthase. Nitric Oxide 24:110–112Google Scholar
  70. Zhang S, Chen H, Webster J, Gerhard G (2013) Targeting heme for the identification of cytotoxic agents. Anti-Cancer Agents Med Chem 13:515–522Google Scholar
  71. Zhang S, Gerhard G (2009) Heme mediates cytotoxicity from artemisinin and serves as a general anti-proliferation target. PLoS ONE 4:e7472Google Scholar
  72. Zhou C, Pan W, Wang X, Chen T (2012) Artesunate induces apoptosis via a Bak-mediated caspase-independent intrinsic pathway in human lung adenocarcinoma cells. J Cell Physiol 227:3778–3786Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jesús A. Romero
    • 1
  • María E. Acosta
    • 1
  • Neira D. Gamboa
    • 1
  • Michael R. Mijares
    • 2
    • 3
  • Juan B. De Sanctis
    • 2
  • Ligia J. Llovera
    • 4
  • Jaime E. Charris
    • 1
    Email author return OK on get
  1. 1.Laboratorio de Síntesis Orgánica, Unidad de Bioquímica, Facultad de FarmaciaUniversidad Central de VenezuelaCaracasVenezuela
  2. 2.Instituto de inmunología, Facultad de MedicinaUniversidad Central de VenezuelaCaracasVenezuela
  3. 3.Unidad de Biotecnología, Facultad de FarmaciaUniversidad Central de VenezuelaCaracasVenezuela
  4. 4.Laboratorio de Resonancia Magnética Nuclear, Centro de QuímicaInstituto Venezolano de Investigaciones CientíficasCaracasVenezuela

Personalised recommendations