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Quinine Dimers Are Potent Inhibitors of the Plasmodium falciparum Chloroquine Resistance Transporter and Are Active against Quinoline-Resistant P. falciparum

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Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
Research School of Biology, The Australian National University, Canberra, Australian Capital Territory 0200, Australia
§ Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, United States
Department of Microbiology and Immunology, Columbia University, New York, New York 10027, United States
Division of Infectious Diseases, Department of Medicine, Columbia University, New York, New York 10027, United States
Cite this: ACS Chem. Biol. 2014, 9, 3, 722–730
Publication Date (Web):December 26, 2013
https://doi.org/10.1021/cb4008953
Copyright © 2013 American Chemical Society

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    Abstract

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    Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the “chloroquine resistance transporter” (PfCRT). The resistance-conferring form of PfCRT (PfCRTCQR) mediates CQ resistance by effluxing the drug from the parasite’s digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRTCQR can also decrease the parasite’s susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRTCQR and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H+ ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRTCQR reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRTCQR from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRTCQR. This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.

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    6. Sarah Heckmatt Shafik, Sashika Natasha Richards, Ben Corry, Rowena Elizabeth Martin, . Mechanistic basis for multidrug resistance and collateral drug sensitivity conferred to the malaria parasite by polymorphisms in PfMDR1 and PfCRT. PLOS Biology 2022, 20 (5) , e3001616. https://doi.org/10.1371/journal.pbio.3001616
    7. Abraham Nudelman. Dimeric Drugs. Current Medicinal Chemistry 2022, 29 (16) , 2751-2845. https://doi.org/10.2174/0929867328666210810124159
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    10. Sarah H. Shafik, Simon A. Cobbold, Kawthar Barkat, Sashika N. Richards, Nicole S. Lancaster, Manuel Llinás, Simon J. Hogg, Robert L. Summers, Malcolm J. McConville, Rowena E. Martin. The natural function of the malaria parasite’s chloroquine resistance transporter. Nature Communications 2020, 11 (1) https://doi.org/10.1038/s41467-020-17781-6
    11. Lian‐Shun Feng, Zhi Xu, Le Chang, Chuan Li, Xiao‐Fei Yan, Chuan Gao, Chao Ding, Feng Zhao, Feng Shi, Xiang Wu. Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum. Medicinal Research Reviews 2020, 40 (3) , 931-971. https://doi.org/10.1002/med.21643
    12. Zhiping Che, Jinming Yang, Di Sun, Yuee Tian, Shengming Liu, Xiaomin Lin, Jia Jiang, Genqiang Chen. Combinatorial Synthesis of Novel 9R-Acyloxyquinine Derivatives as Insecticidal Agents. Combinatorial Chemistry & High Throughput Screening 2020, 23 (2) , 111-118. https://doi.org/10.2174/1386207323666200120112714
    13. Zhiping Che, Jinming Yang, Di Sun, Yuee Tian, Shengming Liu, Xiaomin Lin, Jia Jiang, Genqiang Chen. Synthesis of Novel (9 S )‐Acyloxy Derivatives of Quinidine and Dihydroquinidine as Insecticidal Agents. Chemistry & Biodiversity 2020, 17 (4) https://doi.org/10.1002/cbdv.201900696
    14. Abdul Hafiz, Mahmood A. Alam, Othman A. Alghamdi, Arif Mohammed. Combination therapy and multidrug resistance in malaria parasite. 2020, 141-156. https://doi.org/10.1016/B978-0-12-820576-1.00008-4
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    17. . Bibliography. 2019, 385-525. https://doi.org/10.1016/B978-0-12-812131-3.00018-5
    18. Xue-Mei Chu, Cong Wang, Wen Liu, Li-Li Liang, Kai-Kai Gong, Cheng-Ying Zhao, Kun-Lai Sun. Quinoline and quinolone dimers and their biological activities: An overview. European Journal of Medicinal Chemistry 2019, 161 , 101-117. https://doi.org/10.1016/j.ejmech.2018.10.035
    19. Rowena E Martin, Sarah H Shafik, Sashika N Richards. Mechanisms of resistance to the partner drugs of artemisinin in the malaria parasite. Current Opinion in Pharmacology 2018, 42 , 71-80. https://doi.org/10.1016/j.coph.2018.07.010
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    24. Sashika N. Richards, Megan N. Nash, Eileen S. Baker, Michael W. Webster, Adele M. Lehane, Sarah H. Shafik, Rowena E. Martin, . Molecular Mechanisms for Drug Hypersensitivity Induced by the Malaria Parasite’s Chloroquine Resistance Transporter. PLOS Pathogens 2016, 12 (7) , e1005725. https://doi.org/10.1371/journal.ppat.1005725
    25. Sonia Edaye, Dagobert Tazoo, D. Scott Bohle, Elias Georges. 3-Iodo-4-aminoquinoline derivative sensitises resistant strains of Plasmodium falciparum to chloroquine. International Journal of Antimicrobial Agents 2016, 47 (6) , 482-485. https://doi.org/10.1016/j.ijantimicag.2016.03.016
    26. Bianca K. Verlinden, Abraham Louw, Lyn-Marié Birkholtz. Resisting resistance: is there a solution for malaria?. Expert Opinion on Drug Discovery 2016, 11 (4) , 395-406. https://doi.org/10.1517/17460441.2016.1154037
    27. Sonia Edaye, Dagobert Tazoo, D. Scott Bohle, Elias Georges. 3-Halo Chloroquine Derivatives Overcome Plasmodium falciparum Chloroquine Resistance Transporter-Mediated Drug Resistance in P. falciparum. Antimicrobial Agents and Chemotherapy 2015, 59 (12) , 7891-7893. https://doi.org/10.1128/AAC.01139-15
    28. Ines Petersen, Stanislaw J. Gabryszewski, Geoffrey L. Johnston, Satish K. Dhingra, Andrea Ecker, Rebecca E. Lewis, Mariana Justino de Almeida, Judith Straimer, Philipp P. Henrich, Eugene Palatulan, David J. Johnson, Olivia Coburn‐Flynn, Cecilia Sanchez, Adele M. Lehane, Michael Lanzer, David A. Fidock. Balancing drug resistance and growth rates via compensatory mutations in the P lasmodium falciparum chloroquine resistance transporter. Molecular Microbiology 2015, 97 (2) , 381-395. https://doi.org/10.1111/mmi.13035
    29. Rachel A. Jones, Siva S. Panda, C. Dennis Hall. Quinine conjugates and quinine analogues as potential antimalarial agents. European Journal of Medicinal Chemistry 2015, 97 , 335-355. https://doi.org/10.1016/j.ejmech.2015.02.002
    30. Sushil Kumar, Renu Kumari, Richa Pandey. New insight-guided approaches to detect, cure, prevent and eliminate malaria. Protoplasma 2015, 252 (3) , 717-753. https://doi.org/10.1007/s00709-014-0697-x
    31. Przemysław J. Boratyński. Dimeric Cinchona alkaloids. Molecular Diversity 2015, 19 (2) , 385-422. https://doi.org/10.1007/s11030-014-9563-1
    32. Narinobu Juge, Sawako Moriyama, Takaaki Miyaji, Mamiyo Kawakami, Haruka Iwai, Tomoya Fukui, Nathan Nelson, Hiroshi Omote, Yoshinori Moriyama. Plasmodium falciparum chloroquine resistance transporter is a H + -coupled polyspecific nutrient and drug exporter. Proceedings of the National Academy of Sciences 2015, 112 (11) , 3356-3361. https://doi.org/10.1073/pnas.1417102112
    33. Sebastiano Bellanca, Robert L. Summers, Max Meyrath, Anurag Dave, Megan N. Nash, Martin Dittmer, Cecilia P. Sanchez, Wilfred D. Stein, Rowena E. Martin, Michael Lanzer. Multiple Drugs Compete for Transport via the Plasmodium falciparum Chloroquine Resistance Transporter at Distinct but Interdependent Sites. Journal of Biological Chemistry 2014, 289 (52) , 36336-36351. https://doi.org/10.1074/jbc.M114.614206

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