SYNTHESIS, CHARACTERIZATION, AND IN VITRO ANTIMALARIAL ACTIVITY OF DIHYDROXYLATION DERIVATIVES OF TRICLOSAN
DOI:
https://doi.org/10.22159/ijap.2020.v12s1.FF007Keywords:
Triclosan, Synthetic analogs, Plasmodium falciparum, AntimalarialAbstract
Objective: The emergence of malaria as a global health problem over the past few decades, accompanied by the rise of chemoresistant strains of
Plasmodium falciparum, has emphasized the need for the discovery of new therapeutic drugs against this disease. In this study, enantiomerically
enriched (enantioenriched) analogs of triclosan were synthesized and evaluated for antimalarial activity against P. falciparum cultures.
Methods: Enantioselective dihydroxylation of the olefin in amide seven was performed efficiently using chiral quinine ligand (DHQ)2PHAL to yield
enantioenriched dihydroxy propionamide derivative (+)-1 in moderate yields. In a similar way, the chiral quinidine ligand (DHQD)2PHAL was used as
stereoselectivity agent yielded the desired enantioenriched (−)-1. The enantioenriched products were used for further in vitro assay, and accordingly the
percent enantiomeric excess (% ee) was not determined. The structures of compounds were proven by spectral data (1H NMR, 13C NMR, and mass spectra).
Results: The phenol moiety at the C1 position of triclosan was chemically substituted with a methoxy group, in conjunction with an introduced
stereocenter in a 2,3-dihydroxy-propionamide group at C2’ position. Unmodified triclosan inhibited the P. falciparum cultures with an IC50 value of
27.2 μM. By contrast, the triclosan analogs, compounds (+)-1 and (−)-1, inhibited the P. falciparum cultures with IC50 values of 0.034 and 0.028 μM,
respectively.
Conclusion: Collectively, our preliminary in vitro results suggest that these triclosan analogs have potent antimalarial activity and represent a
promising new treatment strategy on further development.
Downloads
References
Efficacy and Drug Resistance: 2000-2010. Geneva: World Health
Organization; 2010. p. 18.
2. Stratton L, O’Neill MS, Kruk ME, Bell ML. The persistent problem of
malaria: Addressing the fundamental causes of a global killer. Soc Sci
Med 2008;67:854-62.
3. Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI. The global
distribution of clinical episodes of Plasmodium falciparum malaria.
Nature 2005;434:214-7.
4. Breman JG. The ears of the hippopotamus: Manifestations, determinants,
and estimates of the malaria burden. Am J Trop Med Hyg 2001;64:1-1.
5. Sachs J, Malaney P. The economic and social burden of malaria. Nature
2002;415:680-5.
6. Clark IA, Cowden WB. The pathophysiology of falciparum malaria.
Pharmacol Ther 2003;99:221-60.
7. Ridley RG. Medical need, scientific opportunity and the drive for
antimalarial drugs. Nature 2002;415:686-93.
8. Jones RD, Jampani HB, Newman JL, Lee AS. Triclosan: A review of
effectiveness and safety in health care settings. Am J Infect Control
2000;28:184-96.
9. McMurry LM, Oethinger M, Levy SB. Triclosan targets lipid synthesis.
Nature 1998;394:531-2.
10. Levy CW, Roujeinikova A, Sedelnikova S, Baker PJ, Stuitje AR, Slabas AR,
et al. Molecular basis of triclosan activity. Nature 1999;398:383-4.
11. Heath RJ, Rock CO. A triclosan-resistant bacterial enzyme. Nature
2000;406:145-6.
12. Surolia N, Surolia A. Triclosan offers protection against blood stages of
malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum.
Nat Med 2001;7:167-73.
13. Sharma S, Ramya TN, Surolia A, Surolia N. Triclosan as a systemic
antibacterial agent in a mouse model of acute bacterial challenge.
Antimicrob Agents Chemother 2003;47:3859-66.
14. Chhibber M, Kumar G, Parasuraman P, Ramya TN, Surolia N,
Surolia A. Novel diphenyl ethers: Design, docking studies, synthesis
and inhibition of enoyl ACP reductase of Plasmodium falciparum and
Escherichia coli. Bioorg Med Chem 2006;14:8086-98.
15. Mishra S, Karmodiya K, Parasuraman P, Surolia A, Surolia N. Design,
synthesis, and application of novel triclosan prodrugs as potential
antimalarial and antibacterial agents. Bioorg Med Chem 2008;16:5536-46.
16. Perozzo R, Kuo M, Sidhu Ab, Valiyaveettil JT, Bittman R, Jacobs WR Jr.,
et al. Structural elucidation of the specificity of the antibacterial agent
triclosan for malarial enoyl acyl carrier protein reductase. J Biol Chem
2002;277:13106-14.
17. Freundlich JS, Yu M, Lucumi E, Kuo M, Tsai HC, Valderramos JC,
et al. Synthesis and biological activity of diaryl ether inhibitors of
malarial enoyl acyl carrier protein reductase. Part 2: 2’-substituted
triclosan derivatives. Bioorg Med Chem Lett 2006;16:2163-9.
18. Kapoor N, Banerjee T, Babu P, Maity K, Surolia N, Surolia A. Design,
development, synthesis, and docking analysis of 2’-substituted triclosan
analogs as inhibitors for Plasmodium falciparum enoyl-ACP reductase.
IUBMB Life 2009;61:1083-91.
19. Rifai EA, Hayun H, Yanuar A. In silico screening of antimalarial from
Indonesian medicinal plants database to plasmepsin target. Asian J
Pharm Clin Res 2017;10:130-3.
20. Pamudi BF, Azizahwati A, Yanuar A. In-silico screening against
antimalarial target Plasmodium falciparum enoyl-acyl carrier protein
reductase. Asian J Pharm Clin Res 2017;10:127-9.
21. Budimulja AS, Syafruddin, Tapchaisri P, Wilairat P, Marzuki S. The
sensitivity of Plasmodium protein synthesis to prokaryotic ribosomal
inhibitors. Mol Biochem Parasitol 1997;84:137-41.
22. Sharpless KB, Amberg W, Bennani YL, Crispino GL, Hartung J, Jeong K,
et al. The osmium catalyzed asymmetric dihydroxylation: A new ligand
class and a process improvement. J Org Chem 1992;57:2768-71.
23. Corey EJ, Noe MC. A critical analysis of the mechanistic basis
of enantioselectivity in the bis-Cinchona alkaloid catalyzed
dihydroxylation of olefins. J Am Chem Soc 1996;118:11038-35.
Published
How to Cite
Issue
Section
