Halogenation as a Strategy to Improve Antiplasmodial Activity: A Report of New 3-Alkylpyridine Marine Alkaloid Analogs

Document Type : Original Article


1 Núcleo de Pesquisa em Química Biológica, Universidade Federal de São João Del-Rei, Campus Centro Oeste, Divinópolis, MG 35501-296, Brazil

2 Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG 30190-009, Brazil

3 Departamento Acadêmico de Química (DAQUI), Universidade Tecnológica Federal do Paraná, 86036-370 Londrina, Paraná, Brazil


Introduction: Due to the emergence of resistance to antimalarial drugs as well as the lack of vaccination for malaria, there is an urgent demand for the development of new antimalarial alternatives. Recently, our research group developed a new set of 3-alkylpyridine marine alkaloid analogs, of which a compound known as compound 5 was found to be inactive against Plasmodium falciparum.
Methods: Herein, we report a successful halogenation strategy to improve the antiplasmodial activity of compound 5 through the replacement of a hydroxyl group by chlorine (compound 6) and fluorine (compound 7) atoms.
Results: Compounds 6 and 7 showed improved antiplasmodial activities (IC50 = 7.2 and 8.3 μM, respectively) 20 times higher than that of their precursor, compound 5 (IC50 = 210.7 μM). Ultraviolet-visible titration experiments demonstrated that halogenation of compound 5 did not alter its ability to bind its target, hematin.
Conclusion: Halogenation can enhance the antiplasmodial activity of a compound without altering its mechanism of action.


  1. World Health Organization (WHO). World malaria report 2018. WHO; 2018.
  2. Pan American Health Organization (PAHO), World Health Organization (WHO). Epidemiological update increase of malaria in the Americas. PAHO, WHO; 2018.
  3. Cox-Singh J. Plasmodium knowlesi: experimental model, zoonotic pathogen and golden opportunity? Parasitology. 2018;145(1):1-5. doi:10.1017/S0031182017001858.
  4. Langlais D, Cencic R, Moradin N, et al. Rocaglates as dual-targeting agents for experimental cerebral malaria. Proc Natl Acad Sci U S A. 2018;115(10):E2366-E2375. doi:10.1073/pnas.1713000115.
  5. Zuber JA, Takala-Harrison S. Multidrug-resistant malaria and the impact of mass drug administration. Infect Drug Resist. 2018;11:299-306. doi:10.2147/IDR.S123887.
  6. Ashley EA, Phyo AP. Drugs in development for malaria. Drugs. 2018;78(9):861-879. doi:10.1007/s40265-018-0911-9.
  7. Hilário FF, de Paula RC, Silveira ML, et al. Synthesis and evaluation of antimalarial activity of oxygenated 3-alkylpyridine marine alkaloid analogues. Chem Biol Drug Des. 2011;78(3):477-482. doi:10.1111/j.1747-0285.2011.01154.x.
  8. Ribeiro-Viana RM, Butera AP, Santos ES, et al. Revealing the binding process of new 3-Alkylpyridine marine alkaloid analogue antimalarials and the heme group: an experimental and theoretical investigation. J Chem Inf Model. 2016;56(3):571-579. doi:10.1021/acs.jcim.5b00742.
  9. Nicolaou KC. Advancing the drug discovery and development process. Angew Chem Int Ed. 2014;53(35):9128-9140. doi:10.1002/anie.201404761.
  10. Trager W, Jensen JB. Human malaria parasites in continuous culture. Science. 1976;193(4254):673-675. doi:10.1126/science.781840.
  11. Lambros C, Vanderberg JP. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J Parasitol. 1979;65(3):418-420. doi:10.2307/3280287.
  12. Noedl H, Wernsdorfer WH, Miller RS, Wongsrichanalai C. Histidine-rich protein II: a novel approach to malaria drug sensitivity testing. Antimicrob Agents Chemother. 2002;46(6):1658-1664. doi:10.1128/AAC.46.6.1658-1664.2002.
  13. Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res. 1987;47(4):936-942.
  14. Gonçalves AM, de Lima AB, da Silva Barbosa MC, et al. Synthesis and biological evaluation of novel 3-alkylpyridine marine alkaloid analogs with promising anticancer activity. Mar Drugs. 2014;12(8):4361-4378. doi:10.3390/md12084361.
  15. Swallow S. Fluorine in medicinal chemistry. Prog Med Chem. 2015;54:65-133. doi:10.1016/bs.pmch.2014.11.001.
  16. Jia F, Zhang Y, Wang J, et al. The effect of halogenation on the antimicrobial activity, antibiofilm activity, cytotoxicity and proteolytic stability of the antimicrobial peptide Jelleine-I. Peptides. 2019;112:56-66. doi:10.1016/j.peptides.2018.11.006.
  17. Obach RS, Walker GS, Brodney MA. Biosynthesis of fluorinated analogs of drugs using human cytochrome P450 enzymes followed by deoxyfluorination and quantitative nuclear magnetic resonance spectroscopy to improve metabolic stability. Drug Metab Dispos. 2016;44(5):634-646. doi:10.1124/dmd.116.069310.
  18. Gerebtzoff G, Li-Blatter X, Fischer H, Frentzel A, Seelig A. Halogenation of drugs enhances membrane binding and permeation. Chembiochem. 2004;5(5):676-684. doi:10.1002/cbic.200400017.
  19. Hernandes MZ, Cavalcanti SM, Moreira DR, de Azevedo Junior WF, Leite AC. Halogen atoms in the modern medicinal chemistry: hints for the drug design. Curr Drug Targets. 2010;11(3):303-314. doi:10.2174/138945010790711996.
  20. Goldberg DE, Slater AF, Cerami A, Henderson GB. Hemoglobin degradation in the malaria parasite Plasmodium falciparum: an ordered process in a unique organelle. Proc Natl Acad Sci U S A. 1990;87(8):2931-2935. doi:10.1073/pnas.87.8.2931.
  21. Kumar G, Tanwar O, Kumar J, et al. Pyrazole-pyrazoline as promising novel antimalarial agents: a mechanistic study. Eur J Med Chem. 2018;149:139-147. doi:10.1016/j.ejmech.2018.01.082.
  22. Goyal M, Singh P, Alam A, et al. Aryl aryl methyl thio arenes prevent multidrug-resistant malaria in mouse by promoting oxidative stress in parasites. Free Radic Biol Med. 2012;53(1):129-142. doi:10.1016/j.freeradbiomed.2012.04.028.
  23. Katsuno K, Burrows JN, Duncan K, et al. Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat Rev Drug Discov. 2015;14(11):751-758. doi:10.1038/nrd4683.
Volume 7, Issue 4 - Serial Number 27
December 2019
Pages 129-134
  • Receive Date: 18 August 2019
  • Revise Date: 26 October 2019
  • Accept Date: 29 November 2019
  • First Publish Date: 01 December 2019