Primaquine-NSAID twin drugs: Synthesis, radical scavenging, antioxidant and Fe2+ chelating activity

Zrinka Rajić 1 , Marijana Končić 1 , Kristina Miloloža 1 , Ivana Perković 1 , Ivan Butula 1 , Franz Bucar 2 ,  and Branka Zorc 1
  • 1 Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
  • 2 Institut für Pharmazeutische Wissenschaften, Bereich Pharmakognosie Graz, Austria

Primaquine-NSAID twin drugs: Synthesis, radical scavenging, antioxidant and Fe2+ chelating activity

Novel primaquine conjugates with non-steroidal anti-inlammatory drugs (PQ-NSAIDs, 4a-h) were prepared, fully chemically characterized and screened for radical scavenging and antioxidant activities. The synthetic procedure leading to twin drugs 4a-h involved two steps: i) preparation of NSAID benzotriazolides 3a-h from the corresponding NSAID (ibuprofen, ketoprofen, fenoprofen, ketoprofen hydroxy and methylene analogues, diclofenac or indomethacin) and benzotriazole carboxylic acid chloride (BtCOCl, 1), ii) reaction of intermediates 3a-h with PQ. The prepared PQ-NSAIDs exerted moderate activities in the DPPH free radical test and β-carotene-linoleic acid assay. Moreover, ketoprofen derivatives 4d and 4b demonstrated a notable Fe2+ chelating ability as well. On the other hand, negligible antiproliferative and antituberculotic effects of conjugates 4a-h were observed.

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  • A. Paboón, J. Carmona, L. C. Burgos and S. Blair, Oxidative stress in patients with non-complicated malaria, Clin. Biochem. 36 (2003) 71-78; DOI: 10.1016/S0009-9120(02)00423-X.

  • D. V. Ratnam, D. D. Ankola, V. Bhardwaj, D. K. Sahana and M. N. V. Ravi Kumar, Role of antioxidants in prophylaxis and therapy: A pharmaceutical perspective, J. Control. Rel. 113 (2006) 189-207; DOI: 10.1016/j.jconrel.2006.04.015.

  • O. M. Akanbi, A. B. Odaibo, R. Olatoregun and A. B. Ademowo, Role of malaria induced oxidative stress on anaemia in pregnancy, Asian Pac. J. Trop. Med. 3 (2010) 211-214.

  • L. M. Veggi, L. Pretto, E. J. Ochoa, V. A. Catania, M. G. Luquita, D. R. Taborda, E. J. Sánchez Pozzi, S. Ikushiro, M. D. Coleman, M. G. Roma and A. D. Mottino, Dapsone induces oxidative stress and impairs antioxidant defenses in rat liver, Life Sci. 83 (2008) 155-163; DOI: 10.1016/j.lfs.2008.05.016.

  • N. Vale, R. Moreira and P. Gomes, Primaquine revisited six decades after its discovery, Eur. J. Med. Chem. 44 (2009) 937-953; DOI: 10.1016/j.ejmech.2008.08.011.

  • M. Jain, S. Vangapandu, S. Sachdeva and R. Jain, Synthesis and blood-schizontocidal antimalarial activities of 2-substituted/2,5-disubstituted-8-quinolinamines and some of their amino acid conjugates, Bioorg. Med. Chem. 12 (2004) 1003-1010; DOI: 10.1016/j.bmc.2003.12.029.

  • M. Šimunović, I. Perković, B. Zorc, K. Ester, M. Kralj, D. Hadjipavlou-Litina and E. Pontiki, Urea and carbamate derivatives of primaquine: Synthesis, cytostatic and antioxidant activities, Bioorg. Med. Chem. 17 (2009) 5605-5613; DOI: 10.1016/j.bmc.2009.06.030.

  • M. Zovko Končić, Z. Rajić, N. Petrić and B. Zorc, Antioxidant activity of NSAID hydroxamic acids, Acta Pharm. 59 (2009) 235-242; DOI: 10.2478/v10007-009-0017-8.

  • G. F. Mabeza, M. Loyevsky, V. R. Gordeuk and G. Weiss, Iron chelation therapy for malaria: A review, Pharmacol. Ther. 81 (1999) 53-75.

  • M. J. Thun, S. J. Henley and C. Patrono, Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues, J. Natl. Cancer Inst. 94 (2002) 252-266; DOI: 10.1093/jnci/94.4.267.

  • B. Zorc, S. Antolić and I. Butula, Macromolecular prodrugs. I. Synthesis of some non-steroidal anti-inflammatory drug esters, Acta Pharm. 43 (1993) 127-133.

  • Z. Rajić, D. Hadjipavlou-Litina, E. Pontiki, M. Kralj, L. Šuman and B. Zorc, The novel ketoprofen amides - Synthesis and biological evaluation as antioxidants, lipoxygenase inhibitors and cytostatic agents, Chem. Biol. Drug Des. 75 (2010) 641-652; DOI: 10.1111/j.1747-0285.2010. 00963.x.

  • G. C. Yen and H. Y. Chen, Antioxidant activity of various tea extracts in relation to their antimutagenicity, J. Agric. Food Chem. 43 (1995) 27-32; DOI: 10.1021/jf00049a007.

  • R. Amarowicz, R. B. Pegg, P. Rahimi-Moghaddam, B. Barl and J. A. Weil, Free-radical scavenging capacity and antioxidant activity of selected plant species from the Canadian prairies, Food Chem. 84 (2004) 551-562; DOI: 10.1016/S0308-8146(03)00278-4.

  • M. S. Al-Saikhan, L. R. Howard and J. C. Miller, Jr., Antioxidant activity and total phenolics in different genotypes of potato (Solanum tuberosum, L.), J. Food Sci. 60 (1995) 341-343.

  • E. A. Decker and B. Welch, Role of ferritin as lipid oxidation catalyst in muscle food, J. Agric. Food Chem. 38 (1990) 674-677; DOI: 10.1021/jf00093a018.

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