Synthesis and antiplasmodial activity of novel phenanthroline derivatives: An in vivo study

Document Type : Original Article

Authors

1 Malaria and Vector Research Group (MVRG), Biotechnology Research Center (BRC), Pasteur Institute of Iran, Tehran, Iran

2 Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran

Abstract

Objective(s): Due to the rapid increased drug resistance to Plasmodium parasites, an urgent need to achieve new antiplasmodial drugs is felt. Therefore, in this study, the new synthetic phenanthroline derivatives were synthesized with antiplasmodial activity.
Materials and Methods: A series of 1,10-phenanthroline derivatives containing amino-alcohol and amino-ether substituents were synthesized via facile procedures, starting with 5,6-epoxy-1,10-phenanthroline. Their antiplasmodial activity was then evaluated using Peter's 4-day suppressive test against Plasmodium berghei-infected mice (ANKA strain). Furthermore, the mean survival time of the mice treated with synthetic compounds was compared with the negative control group.
Results: The results demonstrated that the compounds 6-(3-(dibutylamino)propylamino)-5,6-dihydro-1,10-phenanthroline-5-ol (7b) at the dose of 150 mg/kg/day and 4-(1,10-phenanthroline-5-yloxy)-N,N-dipropylbutan-1-amine (8b) at the dose of 15 mg/kg/day have 90.58% and 88.32% suppression, respectively. All synthetic compounds prolonged the mean survival time of treated mice in comparison with negative control groups, indicating the in vivo antiplasmodial activity of these new compounds.
Conclusion: The present study is the first attempt to achieve new, effective synthetic compounds based on phenanthroline scaffold with the antiplasmodial activity. However, more research is needed to optimize their antimalarial activity.

Keywords

Main Subjects

References

1.World Health Organization. World Malaria Report 2015. Geneva 2015. Available at: http://www.who.int/malaria/ publications/world-malaria-report-2015/.
2.Golan DE, Tashjian AH, Armstrong EJ. Principles of pharmacology: the pathophysiologic basis of drug therapy, 4st ed. Lippincott Williams & Wilkins; 2011.
3.Enserink M. Malaria's drug miracle in danger. Science 2010; 328:844-846.
4.Kappe SH, Vaughan AM, Boddey JA, Cowman AF. That was then but this is now: malaria research in the time of an eradication agenda. Science 2010; 328:862-866.
5.Nosten F, Van Vugt M, Price R, Luxemburger C, Thway KL, Brockman A, McGready R, ter Kuile F, Looareesuwan S, White NJ. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet 2000; 356:297-302.
6.Beshir K, Sutherland CJ, Merinopoulos I, Durrani N, Leslie T, Rowland M, Hallett L. Amodiaquine resistance in Plasmodium falciparum malaria in Afghanistan is associated with the pfcrt SVMNT allele at codons 72 to 76. Antimicrob Agents Chemother 2010; 54:3714-3716.
7.Smrkovski LL, Buck RL, Alcantara AK, Rodriguez CS, Uylangco CV. Studies of resistance to chloroquine, quinine, amodiaquine and mefloquine among Philippine strains of Plasmodium falciparum. Transa R Soc Trop Med Hyg 1985; 79:37-41.
8.Croft AM. A lesson learnt: the rise and fall of Lariam and Halfan. J R Soc Med2007; 100:170–174.
9.ter Kuile FO, Dolan G, Nosten F, Edstein MD, Luxemburger C, Phaipun L, Chongsuphajaisiddhi T, Webster HK, White NJ. Halofantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria. Lancet 1993; 341:1044-1049.
10.Cui L, Su XZ. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev Anti Infect Ther 2009; 7:999-1013.
11.Lim P, Alker AP, Khim N, Shah NK, Incardona S, Doung S, Yi P, Bouth DM, Bouchier C, Puijalon OM, Meshnick SR, Wongsrichanalai C, Fandeur T, Le Bras J, Ringwald P, Ariey F. Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia. Malar J 2009; 8:11.
12.Sunjic V, Parnham MJ. Signposts to chiral drugs: organic synthesis in action. Springer Science & Business Media; 2011.
13.Biamonte MA, Wanner J, Le Roch KG. Recent advances in malaria drug discovery. Bioorg Med Chem Lett 2013; 23:2829-2843.
14.Hadanu R, Mastjeh S, Jumina J, Mustofa M, Widjayanti MA, Sholikhah EN. Synthesis and antiplasmodial activity testing of(1)-N-(4-methoxybenzyl)-1,10-phenanthrolinium bromide. Indones J Chemistry 2010; 7: 197-201.
15.Hadanu R, Matsjeh S, Jumina M, Widjayanti MA, Sholikhah EN. Synthesis and antiplasmodial activity testing of (1)-N-(4-methoxybenzyl)-1, 10-phenanthrolinium bromide compound. Proceeding of ICCS 2007; 24-26.
16.Sholikhah EN, Supargiyono S, Jumina J, Wijayanti MA, Tahir I, Hadanu R, Mustofa. In vitro antiplasmodial activity and cytotoxicity of newly synthesized N-alkyl and N-benzyl-1, 10-phenanthroline derivatives.Southeast Asian J Trop Med Public Health 2006; 37:1072-1077.
17.Wijayanti MA, Sholikhah EN, Hadanu R, Jumina J, Supargiyono S, Mustofa M. Additive in vitro anti-plasmodial effect of N-alkyl and N-benzyl-1, 10-phenanthroline derivatives and cysteine protease inhibitor E64. Malar Res Treat 2010; 2010:540786.
18.Wijayanti MA, Sholikhah EN, Tahir I, Hadanu R, Jumina J, Supargiyono S, Mustafa M. Antiplasmodial activity and acute toxicity of  N-alkyl and N-benzyl-1, 10-phenanthroline derivatives in mouse malaria model. J Health Sci 2006; 52:794-799.
19.Fitriastuti D, Mardjan MID, Jumina J, Mustofa M. Synthesis and heme polymerization inhibitory activity (HPIA) assay of antiplasmodium of (1)-N-(3, 4-dimethoxybenzyl)-1, 10-phenanthrolinium bromide from vanillin. Indones J Chem 2014; 14:1-6.
20.Egan TJ, Koch KR, Swan PL, Clarkson C, Van Schalkwyk DA, Smith PJ. In vitro antimalarial activity of a series of cationic 2,2′-bipyridyl- and 1,10-phenanthrolineplatinum(II) benzoylthiourea complexes. J Med Chem 2004; 47:2926 -2934.
21.Shahroosvand H, Abbasi P, Notash B, Najafi L. Separation of functionalized 5, 6-disubstituted-1, 10-phenanthroline for dye-sensitized solar cell applications. J Chem 2013; 2013: Article ID 475843.
22.Howell BA, Dumitrascu A. Thermal stability of bidendate nitrogen ligands tethered to multiwall carbon nanotubes. J Therm Anal Calorim 2010; 102: 505-512.
23.Knight DJ, Peters W. The anti-malarial activity of N-benzyloxydihydrotriazines. I. The activity of clociguanil (BRL 50216) against rodent malaria, and studies on its mode of action. Ann Trop Med Parasitol 1980; 74:393-404.
24.Shen Y, Sullivan BP. A Versatile Preparative Route to 5-Substituted-1,10-Phenanthroline Ligands via 1,10-Phenanthroline 5,6-Epoxide. Inorg Chem 1995; 34:6235–6236.
25.Sullivan DJ, Gluzman IY, Russell DG, Goldberg DE. On the molecular mechanism of chloroquine's antimalarial action. Proc Natl Acad Sci USA 1996; 93:11865-11870.
26.Kumar S, Guha M, Choubey V, Maity P, Bandyopadhyay U. Antimalarial drugs inhibiting hemozoin (β-hematin) formation: a mechanistic update. Life Sci 2007; 80:813-828.
27.Coronado LM, Nadovich CT, Spadafora C. Malarial hemozoin: from target to tool. Biochim Biophys Acta 2014; 1840:2032-2041.
28.Weissbuch I, Leiserowitz L . Interplay between malaria, crystalline hemozoin formation, and antimalarial drug action and design. Chem Rev 2008; 108:4899-4914.
Iranian Journal of Basic Medical Sciences
Volume 21, Issue 2
February 2018
Pages 202-211

Files

Share

How to cite

Statistics