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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Review Article

Medicinal Chemistry and Target Identification of Synthetic Clinical and Advanced Preclinical Antimalarial Candidates (2000 - 2022)

Author(s): Peter Mubanga Cheuka*, Dickson Mambwe and Godfrey Mayoka

Volume 23, Issue 3, 2023

Published on: 13 January, 2023

Page: [227 - 247] Pages: 21

DOI: 10.2174/1568026623666221220140526

Price: $65

Abstract

Background: The downward trend in malaria cases and deaths is steadily reversed - 627,000 deaths in 2020 compared to 405,000 deaths in 2018. Drug resistance has compromised the effectiveness of currently available treatment options, with some reports documenting molecular markers of resistance to artemisinins in African countries in addition to the Greater Mekong subregion, which was initially associated with this kind of resistance. Therefore, the development of novel drugs is crucial to replenishing the antimalarial drug arsenal toward malaria eradication. In this review, we summarize the progress made in antimalarial drug discovery in the period 2000 - 2022, focusing on drug candidates which have made it to advanced preclinical trials (drugs tested in rodent species and at least one higher species such as dog or monkey) and beyond.

Methods: We searched Google Scholar and selected studies meeting these defined criteria. We highlight the medicinal chemistry optimization of these compounds; the preclinical/clinical evaluation and the mechanisms of action.

Results and Conclusion: Although the pipeline seems promising, the prospect of having an antimalarial medicine that meets the current target product profiles (TPPs) towards the malaria eradication agenda is far from reality. Some of the key TPP attributes required include multistage activity, resistance- proof; ability to achieve a single dose cure and safety across a wide range of patient populations. Clinical trials are ongoing for some promising molecules, inspiring optimism toward identifying better drugs that meet these defined TPPs. Until then, concerted research efforts should continue to be mounted to populate the antimalarial drug discovery and development pipeline.

Keywords: Malaria, Clinical candidates, Preclinical candidates, Medicinal chemistry, Drug discovery, Target identification.

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[1]
World Health Organization. World Malaria Report 2021; World Health Organization: Geneva, Switzerland, 2021.
[2]
White, N.J. Antimalarial drug resistance. J. Clin. Invest., 2004, 113(8), 1084-1092.
[http://dx.doi.org/10.1172/JCI21682] [PMID: 15085184]
[3]
Sibley, C.H.; Hyde, J.E.; Sims, P.F.G.; Plowe, C.V.; Kublin, J.G.; Mberu, E.K.; Cowman, A.F.; Winstanley, P.A.; Watkins, W.M.; Nzila, A.M. Pyrimethamine–sulfadoxine resistance in Plasmodium falciparum: What next? Trends Parasitol., 2001, 17(12), 582-588.
[http://dx.doi.org/10.1016/S1471-4922(01)02085-2] [PMID: 11756042]
[4]
Terlouw, D.J.; Nahlen, B.L.; Courval, J.M.; Kariuki, S.K.; Rosenberg, O.S.; Oloo, A.J.; Kolczak, M.S.; Hawley, W.A.; Lal, A.A.; Kuile, F.O. Sulfadoxine-pyrimethamine in treatment of malaria in Western Kenya: Increasing resistance and underdosing. Antimicrob. Agents Chemother., 2003, 47(9), 2929-2932.
[http://dx.doi.org/10.1128/AAC.47.9.2929-2932.2003] [PMID: 12936996]
[5]
Warhurst, D.C. Resistance to antifolates in Plasmodium falciparum, the causative agent of tropical malaria. Sci. Prog., 2002, 85(1), 89-111.
[http://dx.doi.org/10.3184/003685002783238906] [PMID: 11969121]
[6]
Uwimana, A.; Legrand, E.; Stokes, B.H.; Ndikumana, J.L.M.; Warsame, M.; Umulisa, N.; Ngamije, D.; Munyaneza, T.; Mazarati, J.B.; Munguti, K.; Campagne, P.; Criscuolo, A.; Ariey, F.; Murindahabi, M.; Ringwald, P.; Fidock, D.A.; Mbituyumuremyi, A.; Menard, D. Author Correction: Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nat. Med., 2021, 27(6), 1113-1115.
[http://dx.doi.org/10.1038/s41591-021-01365-y] [PMID: 34045739]
[7]
Balikagala, B.; Fukuda, N.; Ikeda, M.; Katuro, O.T.; Tachibana, S.I.; Yamauchi, M.; Opio, W.; Emoto, S.; Anywar, D.A.; Kimura, E.; Palacpac, N.M.Q.; Odongo-Aginya, E.I.; Ogwang, M.; Horii, T.; Mita, T. Evidence of artemisinin-resistant malaria in Africa. N. Engl. J. Med., 2021, 385(13), 1163-1171.
[http://dx.doi.org/10.1056/NEJMoa2101746] [PMID: 34551228]
[8]
Lu, F.; Culleton, R.; Zhang, M.; Ramaprasad, A.; von Seidlein, L.; Zhou, H.; Zhu, G.; Tang, J.; Liu, Y.; Wang, W.; Cao, Y.; Xu, S.; Gu, Y.; Li, J.; Zhang, C.; Gao, Q.; Menard, D.; Pain, A.; Yang, H.; Zhang, Q.; Cao, J. Emergence of indigenous artemisinin-resistant Plasmodium falciparum in Africa. N. Engl. J. Med., 2017, 376(10), 991-993.
[http://dx.doi.org/10.1056/NEJMc1612765] [PMID: 28225668]
[9]
Hooft van Huijsduijnen, R.; Wells, T.N.C. The antimalarial pipeline. Curr. Opin. Pharmacol., 2018, 42, 1-6.
[http://dx.doi.org/10.1016/j.coph.2018.05.006] [PMID: 29860174]
[10]
Wells, T.N.C. New medicines to combat malaria: an overview of the global pipeline of therapeutics. In: Treatment and Prevention of Malaria; Staines, H.M.; Krishna, S., Eds.; Springer Basel: Basel, 2011; pp. 227-247.
[http://dx.doi.org/10.1007/978-3-0346-0480-2_12]
[11]
Bala, M.; Lahiry, S.; Choudhury, S.; Mukherjee, A.; Bhunya, P.K.; Chowdhury, K.; Sinha, R. Antimalarials: pre-clinical development update. Asian J. Med. Sci., 2017, 8(5), 1-3.
[http://dx.doi.org/10.3126/ajms.v8i5.17530]
[12]
Biamonte, M.A.; Wanner, J.; Le Roch, K.G. Recent advances in malaria drug discovery. Bioorg. Med. Chem. Lett., 2013, 23(10), 2829-2843.
[http://dx.doi.org/10.1016/j.bmcl.2013.03.067] [PMID: 23587422]
[13]
Calderón, F.; Wilson, D.M.; Gamo, F-J. Antimalarial Drug Discovery. In: Progress in Medicinal Chemistry; Elsevier, 2013; 52, pp. 97-151.
[http://dx.doi.org/10.1016/B978-0-444-62652-3.00003-X]
[14]
Held, J.; Jeyaraj, S.; Kreidenweiss, A. Antimalarial compounds in Phase II clinical development. Expert Opin. Investig. Drugs, 2015, 24(3), 363-382.
[http://dx.doi.org/10.1517/13543784.2015.1000483] [PMID: 25563531]
[15]
Madhav, H.; Hoda, N. An insight into the recent development of the clinical candidates for the treatment of malaria and their target proteins. Eur. J. Med. Chem., 2021, 210, 112955.
[http://dx.doi.org/10.1016/j.ejmech.2020.112955] [PMID: 33131885]
[16]
Ashley, E.A.; Phyo, A.P. Drugs in Development for Malaria. Drugs, 2018, 78(9), 861-879.
[http://dx.doi.org/10.1007/s40265-018-0911-9] [PMID: 29802605]
[17]
Belete, T.M. Recent progress in the development of new antimalarial drugs with novel targets. Drug Des. Devel. Ther., 2020, 14, 3875-3889.
[http://dx.doi.org/10.2147/DDDT.S265602] [PMID: 33061294]
[18]
Biot, C.; Dive, D. Bioorganometallic Chemistry and Malaria. In: Medicinal Organometallic Chemistry; Jaouen, G.; Metzler-Nolte, N., Eds.; Springer Berlin Heidelberg: Berlin, Heidelberg, 2010; 32, pp. 155-193.
[http://dx.doi.org/10.1007/978-3-642-13185-1_7]
[19]
Beagley, P.; Blackie, M.A.L.; Chibale, K.; Clarkson, C.; Meijboom, R.; Moss, J.R.; Smith, P.J.; Su, H. Synthesis and antiplasmodial activity in vitro of new ferrocene–chloroquine analogues. Dalton Trans., 2003, (15), 3046-3051.
[http://dx.doi.org/10.1039/B303335J]
[20]
Biot, C.; Daher, W.; Chavain, N.; Fandeur, T.; Khalife, J.; Dive, D.; De Clercq, E. Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities. J. Med. Chem., 2006, 49(9), 2845-2849.
[http://dx.doi.org/10.1021/jm0601856] [PMID: 16640347]
[21]
Delhaes, L.; Abessolo, H.; Berry, L.; Delcourt, P.; Maciejewski, L.; Brocard, J.; Camus, D.; Dive, D.; Biot, C. In vitro and in vivo antimalarial activity of ferrochloroquine, a ferrocenyl analogue of chloroquine against chloroquine-resistant malaria parasites. Parasitol. Res., 2001, 87(3), 239-244.
[http://dx.doi.org/10.1007/s004360000317] [PMID: 11293573]
[22]
Biot, C.; Chavain, N.; Dubar, F.; Pradines, B.; Trivelli, X.; Brocard, J.; Forfar, I.; Dive, D. Structure–activity relationships of 4-N-substituted ferroquine analogues: Time to re-evaluate the mechanism of action of ferroquine. J. Organomet. Chem., 2009, 694(6), 845-854.
[http://dx.doi.org/10.1016/j.jorganchem.2008.09.033]
[23]
Atteke, C.; Ndong, J.M.; Aubouy, A.; Maciejewski, L.; Brocard, J.; Lébibi, J.; Deloron, P. In vitro susceptibility to a new antimalarial organometallic analogue, ferroquine, of Plasmodium falciparum isolates from the Haut-Ogooue region of Gabon. J. Antimicrob. Chemother., 2003, 51(4), 1021-1024.
[http://dx.doi.org/10.1093/jac/dkg161] [PMID: 12654770]
[24]
Pradines, B.; Tall, A.; Rogier, C.; Spiegel, A.; Mosnier, J.; Marrama, L.; Fusai, T.; Millet, P.; Panconi, E.; Trape, J.F.; Parzy, D. In vitro activities of ferrochloroquine against 55 Senegalese isolates of Plasmodium falciparum in comparison with those of standard antimalarial drugs. Trop. Med. Int. Health, 2002, 7(3), 265-270.
[http://dx.doi.org/10.1046/j.1365-3156.2002.00848.x] [PMID: 11903989]
[25]
Pradines, B.; Fusai, T.; Daries, W.; Laloge, V.; Rogier, C.; Millet, P.; Panconi, E.; Kombila, M.; Parzy, D. Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum. J. Antimicrob. Chemother., 2001, 48(2), 179-184.
[http://dx.doi.org/10.1093/jac/48.2.179] [PMID: 11481286]
[26]
Chim, P.; Lim, P.; Sem, R.; Nhem, S.; Maciejewski, L.; Fandeur, T. The in-vitro antimalarial activity of ferrochloroquine, measured against Cambodian isolates of Plasmodium falciparum. Ann. Trop. Med. Parasitol., 2004, 98(4), 419-424.
[http://dx.doi.org/10.1179/000349804225003361] [PMID: 15228723]
[27]
Kreidenweiss, A.; Mordmüller, B.; Dietz, K.; Kremsner, P.G. In vitro activity of ferroquine (SAR97193) is independent of chloroquine resistance in Plasmodium falciparum. Am. J. Trop. Med. Hyg., 2006, 75(6), 1178-1181.
[http://dx.doi.org/10.4269/ajtmh.2006.75.1178] [PMID: 17172389]
[28]
Barends, M.; Jaidee, A.; Khaohirun, N.; Singhasivanon, P.; Nosten, F. In vitro activity of ferroquine (SSR 97193) against Plasmodium falciparum isolates from the Thai-Burmese border. Malar. J., 2007, 6(1), 81.
[http://dx.doi.org/10.1186/1475-2875-6-81] [PMID: 17597537]
[29]
McCarthy, J.S.; Rückle, T.; Djeriou, E.; Cantalloube, C.; Ter-Minassian, D.; Baker, M.; O’Rourke, P.; Griffin, P.; Marquart, L.; Hooft van Huijsduijnen, R.; Möhrle, J.J. A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study. Malar. J., 2016, 15(1), 469.
[http://dx.doi.org/10.1186/s12936-016-1511-3] [PMID: 27624471]
[30]
Adoke, Y.; Zoleko-Manego, R.; Ouoba, S.; Tiono, A.B.; Kaguthi, G.; Bonzela, J.E.; Duong, T.T.; Nahum, A.; Bouyou-Akotet, M.; Ogutu, B.; Ouedraogo, A.; Macintyre, F.; Jessel, A.; Laurijssens, B.; Cherkaoui-Rbati, M.H.; Cantalloube, C.; Marrast, A.C.; Bejuit, R.; White, D.; Wells, T.N.C.; Wartha, F.; Leroy, D.; Kibuuka, A.; Mombo-Ngoma, G.; Ouattara, D.; Mugenya, I.; Phuc, B.Q.; Bohissou, F.; Mawili-Mboumba, D.P.; Olewe, F.; Soulama, I.; Tinto, H.; Ramharter, M.; Nahum, D.; Zohou, H.; Nzwili, I.; Ongecha, J.M.; Thompson, R.; Kiwalabye, J.; Diarra, A.; Coulibaly, A.S.; Bougouma, E.C.; Kargougou, D.G.; Tegneri, M.; Castin Vuillerme, C.; Djeriou, E.; Ansary, A.F. A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria. Malar. J., 2021, 20(1), 222.
[http://dx.doi.org/10.1186/s12936-021-03749-4] [PMID: 34011358]
[31]
Held, J.; Supan, C.; Salazar, C.L.O.; Tinto, H.; Bonkian, L.N.; Nahum, A.; Moulero, B.; Sié, A.; Coulibaly, B.; Sirima, S.B.; Siribie, M.; Otsyula, N.; Otieno, L.; Abdallah, A.M.; Kimutai, R.; Bouyou-Akotet, M.; Kombila, M.; Koiwai, K.; Cantalloube, C.; Din-Bell, C.; Djeriou, E.; Waitumbi, J.; Mordmüller, B.; Ter-Minassian, D.; Lell, B.; Kremsner, P.G. Ferroquine and artesunate in African adults and children with Plasmodium falciparum malaria: A phase 2, multicentre, randomised, double-blind, dose-ranging, non-inferiority study. Lancet Infect. Dis., 2015, 15(12), 1409-1419.
[http://dx.doi.org/10.1016/S1473-3099(15)00079-1] [PMID: 26342427]
[32]
Supan, C.; Walsh, D.S.; Lell, B.; Kombila, M.; Polhemus, M.E.; Ospina Salazar, C.L.; Kremsner, P.G.; Cantalloube, C.; Otsula, N.; Djeriou, E.; Apollo, D.; Waitumbi, J.; Ogutu, B.; Mombo-Ngoma, G.; Held, J. Phase 2a, open-label, 4-escalating-dose, randomized multicenter study evaluating the safety and activity of ferroquine (SSR97193) plus artesunate, versus amodiaquine plus artesunate, in african adult men with uncomplicated Plasmodium falciparum malaria. Am. J. Trop. Med. Hyg., 2017, 97(2), 514-525.
[http://dx.doi.org/10.4269/ajtmh.16-0731] [PMID: 28722611]
[33]
Taylor, N.P. Sanofi Punts 38 R&D Projects to Narrow Pipeline Focus., 2019. Available from: https://www.Fiercebiotech.Com/Biotech/Sanofi-Punts-38-r-d-Projects-to-Narrow-Pipeline-Focus
[34]
Ré, D.B.; Nafia, I.; Nieoullon, A.; Le Goff, L.K.; Had-Aissouni, L. Stress oxydatif cérébral: Les astrocytes sont-ils vulnérables aux faibles concentrations intracellulaires de glutamate? Implications sur la survie neuronale. Ann. Fr. Anesth. Reanim., 2005, 24(5), 502-509.
[http://dx.doi.org/10.1016/j.annfar.2005.03.004] [PMID: 15885966]
[35]
Kannan, R.; Kumar, K.; Sahal, D.; Kukreti, S.; Chauhan, V.S. Reaction of artemisinin with haemoglobin: Implications for antimalarial activity. Biochem. J., 2005, 385(2), 409-418.
[http://dx.doi.org/10.1042/BJ20041170] [PMID: 15361062]
[36]
Chavain, N.; Vezin, H.; Dive, D.; Touati, N.; Paul, J.F.; Buisine, E.; Biot, C. Investigation of the redox behavior of ferroquine, a new antimalarial. Mol. Pharm., 2008, 5(5), 710-716.
[http://dx.doi.org/10.1021/mp800007x] [PMID: 18563912]
[37]
Dubar, F.; Egan, T.J.; Pradines, B.; Kuter, D.; Ncokazi, K.K.; Forge, D.; Paul, J.F.; Pierrot, C.; Kalamou, H.; Khalife, J.; Buisine, E.; Rogier, C.; Vezin, H.; Forfar, I.; Slomianny, C.; Trivelli, X.; Kapishnikov, S.; Leiserowitz, L.; Dive, D.; Biot, C. The antimalarial ferroquine: Role of the metal and intramolecular hydrogen bond in activity and resistance. ACS Chem. Biol., 2011, 6(3), 275-287.
[http://dx.doi.org/10.1021/cb100322v] [PMID: 21162558]
[38]
Biot, C.; Taramelli, D.; Forfar-Bares, I.; Maciejewski, L.A.; Boyce, M.; Nowogrocki, G.; Brocard, J.S.; Basilico, N.; Olliaro, P.; Egan, T.J. Insights into the mechanism of action of ferroquine. Relationship between physicochemical properties and antiplasmodial activity. Mol. Pharm., 2005, 2(3), 185-193.
[http://dx.doi.org/10.1021/mp0500061] [PMID: 15934779]
[39]
Plouffe, D.; Brinker, A.; McNamara, C.; Henson, K.; Kato, N.; Kuhen, K.; Nagle, A.; Adrián, F.; Matzen, J.T.; Anderson, P.; Nam, T.; Gray, N.S.; Chatterjee, A.; Janes, J.; Yan, S.F.; Trager, R.; Caldwell, J.S.; Schultz, P.G.; Zhou, Y.; Winzeler, E.A. In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen. Proc. Natl. Acad. Sci. USA, 2008, 105(26), 9059-9064.
[http://dx.doi.org/10.1073/pnas.0802982105] [PMID: 18579783]
[40]
Smilkstein, M.; Sriwilaijaroen, N.; Kelly, J.X.; Wilairat, P.; Riscoe, M. Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening. Antimicrob. Agents Chemother., 2004, 48(5), 1803-1806.
[http://dx.doi.org/10.1128/AAC.48.5.1803-1806.2004] [PMID: 15105138]
[41]
Bennett, T.N.; Paguio, M.; Gligorijevic, B.; Seudieu, C.; Kosar, A.D.; Davidson, E.; Roepe, P.D. Novel, rapid, and inexpensive cell-based quantification of antimalarial drug efficacy. Antimicrob. Agents Chemother., 2004, 48(5), 1807-1810.
[http://dx.doi.org/10.1128/AAC.48.5.1807-1810.2004] [PMID: 15105139]
[42]
Russell, B.M.; Udomsangpetch, R.; Rieckmann, K.H.; Kotecka, B.M.; Coleman, R.E.; Sattabongkot, J. Simple in vitro assay for determining the sensitivity of Plasmodium vivax isolates from fresh human blood to antimalarials in areas where P. vivax is endemic. Antimicrob. Agents Chemother., 2003, 47(1), 170-173.
[http://dx.doi.org/10.1128/AAC.47.1.170-173.2003] [PMID: 12499187]
[43]
White, N.J. Antimalarial drug resistance: The pace quickens. J. Antimicrob. Chemother., 1992, 30(5), 571-585.
[http://dx.doi.org/10.1093/jac/30.5.571] [PMID: 1493976]
[44]
Upton, L.M.; Brock, P.M.; Churcher, T.S.; Ghani, A.C.; Gething, P.W.; Delves, M.J.; Sala, K.A.; Leroy, D.; Sinden, R.E.; Blagborough, A.M. Lead clinical and preclinical antimalarial drugs can significantly reduce sporozoite transmission to vertebrate populations. Antimicrob. Agents Chemother., 2015, 59(1), 490-497.
[http://dx.doi.org/10.1128/AAC.03942-14] [PMID: 25385107]
[45]
van Pelt-Koops, J.C.; Pett, H.E.; Graumans, W.; van der Vegte-Bolmer, M.; van Gemert, G.J.; Rottmann, M.; Yeung, B.K.S.; Diagana, T.T.; Sauerwein, R.W. The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector. Antimicrob. Agents Chemother., 2012, 56(7), 3544-3548.
[http://dx.doi.org/10.1128/AAC.06377-11] [PMID: 22508309]
[46]
Huskey, S.E.W.; Zhu, C.; Fredenhagen, A.; Kühnöl, J.; Luneau, A.; Jian, Z.; Yang, Z.; Miao, Z.; Yang, F.; Jain, J.P.; Sunkara, G.; Mangold, J.B.; Stein, D.S. KAE609 (Cipargamin), a new spiroindolone agent for the treatment of malaria: evaluation of the absorption, distribution, metabolism, and excretion of a single oral 300-mg dose of [14C]KAE609 in healthy male subjects. Drug Metab. Dispos., 2016, 44(5), 672-682.
[http://dx.doi.org/10.1124/dmd.115.069187] [PMID: 26921387]
[47]
White, N.J.; Pukrittayakamee, S.; Phyo, A.P.; Rueangweerayut, R.; Nosten, F.; Jittamala, P.; Jeeyapant, A.; Jain, J.P.; Lefèvre, G.; Li, R.; Magnusson, B.; Diagana, T.T.; Leong, F.J. Spiroindolone KAE609 for falciparum and vivax malaria. N. Engl. J. Med., 2014, 371(5), 403-410.
[http://dx.doi.org/10.1056/NEJMoa1315860] [PMID: 25075833]
[48]
Hien, T.T.; White, N.J.; Thuy-Nhien, N.T.; Hoa, N.T.; Thuan, P.D.; Tarning, J.; Nosten, F.; Magnusson, B.; Jain, J.P.; Hamed, K. Estimation of the in vivo mic of cipargamin in uncomplicated Plasmodium falciparum malaria. Antimicrob. Agents Chemother., 2017, 61(2), e01940-16.
[http://dx.doi.org/10.1128/AAC.01940-16] [PMID: 27872070]
[49]
Leong, F.J.; Li, R.; Jain, J.P.; Lefèvre, G.; Magnusson, B.; Diagana, T.T.; Pertel, P. A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel antimalarial Spiroindolone KAE609 (Cipargamin) to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers. Antimicrob. Agents Chemother., 2014, 58(10), 6209-6214.
[http://dx.doi.org/10.1128/AAC.03393-14] [PMID: 25114127]
[50]
Novartis. Novartis Clinical Trials Results CKAE609X2202. An Open Label, Single Dose Study to Assess Efficacy, Safety, Tolerability and Pharmacokinetics of KAE609 in Adult Patients with Acute, Uncomplicated Plasmodium falciparum Malaria Mono- Infection. Available from: https://www.novctrd.com/ctrdweb/displaypdf.nov?trialresultid=14013
[51]
Novartis. Novartis Clinical Trials Results CKAE609A2109. A Phase 1 Interventional, Sequential, Single-Site Study to Characterize the Effectiveness of Oral KAE609 in Reducing Asexual and Sexual Blood-Stage P. Falciparum Following Inoculation in Healthy Volunteers and Subsequent Infectivity to Mosquitoes. Available from: https://www.novctrd.com/ctrdweb/displaypdf.nov?trialresultid=17484
[52]
Chughlay, M.F.; Akakpo, S.; Odedra, A.; Csermak-Renner, K.; Djeriou, E.; Winnips, C.; Leboulleux, D.; Gaur, A.H.; Shanks, G.D.; McCarthy, J.; Chalon, S. Liver Enzyme Elevations in Plasmodium falciparum Volunteer Infection Studies: Findings and Recommendations. Am. J. Trop. Med. Hyg., 2020, 103(1), 378-393.
[http://dx.doi.org/10.4269/ajtmh.19-0846] [PMID: 32314694]
[53]
Ndayisaba, G.; Yeka, A.; Asante, K.P.; Grobusch, M.P.; Karita, E.; Mugerwa, H.; Asiimwe, S.; Oduro, A.; Fofana, B.; Doumbia, S.; Jain, J.P.; Barsainya, S.; Kullak-Ublick, G.A.; Su, G.; Schmitt, E.K.; Csermak, K.; Gandhi, P.; Hughes, D. Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: A randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa. Malar. J., 2021, 20(1), 478.
[http://dx.doi.org/10.1186/s12936-021-04009-1] [PMID: 34930267]
[54]
Stein, D.S.; Jain, J.P.; Kangas, M.; Lefèvre, G.; Machineni, S.; Griffin, P.; Lickliter, J. Open-label, single-dose, parallel-group study in healthy volunteers to determine the drug-drug interaction potential between KAE609 (cipargamin) and piperaquine. Antimicrob. Agents Chemother., 2015, 59(6), 3493-3500.
[http://dx.doi.org/10.1128/AAC.00340-15] [PMID: 25845867]
[55]
Spillman, N.J.; Allen, R.J.W.; Kirk, K. Na+ extrusion imposes an acid load on the intraerythrocytic malaria parasite. Mol. Biochem. Parasitol., 2013, 189(1-2), 1-4.
[http://dx.doi.org/10.1016/j.molbiopara.2013.04.004] [PMID: 23623918]
[56]
Dennis, A.S.M.; Lehane, A.M.; Ridgway, M.C.; Holleran, J.P.; Kirk, K. Cell Swelling Induced by the Antimalarial KAE609 (Cipargamin) and Other PfATP4-Associated Antimalarials. Antimicrob. Agents Chemother., 2018, 62(6), e00087-18.
[http://dx.doi.org/10.1128/AAC.00087-18] [PMID: 29555632]
[57]
Spillman, N.J.; Allen, R.J.W.; McNamara, C.W.; Yeung, B.K.S.; Winzeler, E.A.; Diagana, T.T.; Kirk, K. Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host Microbe, 2013, 13(2), 227-237.
[http://dx.doi.org/10.1016/j.chom.2012.12.006] [PMID: 23414762]
[58]
Das, S.; Bhatanagar, S.; Morrisey, J.M.; Daly, T.M.; Burns, J.M., Jr; Coppens, I.; Vaidya, A.B. Na+ influx induced by new antimalarials causes rapid alterations in the cholesterol content and morphology of Plasmodium falciparum. PLoS Pathog., 2016, 12(5), e1005647.
[http://dx.doi.org/10.1371/journal.ppat.1005647] [PMID: 27227970]
[59]
U.S. National Library of Medicine. 2022. Available from: https://www.clinicaltrials.gov/ct2/results?cond=malaria&term=KAF156&cntry=&state=&city=&dist=
[60]
Wu, T.; Nagle, A.; Kuhen, K.; Gagaring, K.; Borboa, R.; Francek, C.; Chen, Z.; Plouffe, D.; Goh, A.; Lakshminarayana, S.B.; Wu, J.; Ang, H.Q.; Zeng, P.; Kang, M.L.; Tan, W.; Tan, M.; Ye, N.; Lin, X.; Caldwell, C.; Ek, J.; Skolnik, S.; Liu, F.; Wang, J.; Chang, J.; Li, C.; Hollenbeck, T.; Tuntland, T.; Isbell, J.; Fischli, C.; Brun, R.; Rottmann, M.; Dartois, V.; Keller, T.; Diagana, T.; Winzeler, E.; Glynne, R.; Tully, D.C.; Chatterjee, A.K. Imidazolopiperazines: Hit to lead optimization of new antimalarial agents. J. Med. Chem., 2011, 54(14), 5116-5130.
[http://dx.doi.org/10.1021/jm2003359] [PMID: 21644570]
[61]
Nagle, A.; Wu, T.; Kuhen, K.; Gagaring, K.; Borboa, R.; Francek, C.; Chen, Z.; Plouffe, D.; Lin, X.; Caldwell, C.; Ek, J.; Skolnik, S.; Liu, F.; Wang, J.; Chang, J.; Li, C.; Liu, B.; Hollenbeck, T.; Tuntland, T.; Isbell, J.; Chuan, T.; Alper, P.B.; Fischli, C.; Brun, R.; Lakshminarayana, S.B.; Rottmann, M.; Diagana, T.T.; Winzeler, E.A.; Glynne, R.; Tully, D.C.; Chatterjee, A.K. Imidazolopiperazines: Lead optimization of the second-generation antimalarial agents. J. Med. Chem., 2012, 55(9), 4244-4273.
[http://dx.doi.org/10.1021/jm300041e] [PMID: 22524250]
[62]
Leong, F.J.; Zhao, R.; Zeng, S.; Magnusson, B.; Diagana, T.T.; Pertel, P. A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel Imidazolopiperazine KAF156 to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers. Antimicrob. Agents Chemother., 2014, 58(11), 6437-6443.
[http://dx.doi.org/10.1128/AAC.03478-14] [PMID: 25136017]
[63]
Leong, F.J.; Jain, J.P.; Feng, Y.; Goswami, B.; Stein, D.S. A phase 1 evaluation of the pharmacokinetic/pharmacodynamic interaction of the anti-malarial agents KAF156 and piperaquine. Malar. J., 2018, 17(1), 7.
[http://dx.doi.org/10.1186/s12936-017-2162-8] [PMID: 29304859]
[64]
White, N.J.; Duong, T.T.; Uthaisin, C.; Nosten, F.; Phyo, A.P.; Hanboonkunupakarn, B.; Pukrittayakamee, S.; Jittamala, P.; Chuthasmit, K.; Cheung, M.S.; Feng, Y.; Li, R.; Magnusson, B.; Sultan, M.; Wieser, D.; Xun, X.; Zhao, R.; Diagana, T.T.; Pertel, P.; Leong, F.J. Antimalarial activity of KAF156 in falciparum and vivax malaria. N. Engl. J. Med., 2016, 375(12), 1152-1160.
[http://dx.doi.org/10.1056/NEJMoa1602250] [PMID: 27653565]
[65]
U. S. National Library of Medicine. Efficacy, Safety and Tolerability of KAF156 in Combination With Lumefantrine Solid Dispersion Formulation (LUM-SDF) in Pediatric Population With Uncomplicated Plasmodium Falciparum Malaria., 2022. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04546633?Term=KAF156&cond=Malaria&draw=2&rank=3
[66]
Novartis Pharmaceuticals. Drug-Drug Interaction Study of Ganaplacide and Lumefantrine With Itraconazole., 2021. Available from: https://www.clinicaltrials.gov/Ct2/Show/NCT05084651?Term=KAF156&cond=Malaria&draw=2&rank=5
[67]
Novartis Pharmaceuticals. Drug-Drug Interaction Study of Ganaplacide and Lumefantrine With Midazolam, Repaglinide, Dextromethorphan, Metformin, Rosuvastatin and Dolutegravir. 2022. Available from: https://www.clinicaltrials.gov/ct2/show/NCT05236530?Term=KAF156&cond=Malaria&draw=2&rank=6
[68]
Meister, S.; Plouffe, D.M.; Kuhen, K.L.; Bonamy, G.M.C.; Wu, T.; Barnes, S.W.; Bopp, S.E.; Borboa, R.; Bright, A.T.; Che, J.; Cohen, S.; Dharia, N.V.; Gagaring, K.; Gettayacamin, M.; Gordon, P.; Groessl, T.; Kato, N.; Lee, M.C.S.; McNamara, C.W.; Fidock, D.A.; Nagle, A.; Nam, T.; Richmond, W.; Roland, J.; Rottmann, M.; Zhou, B.; Froissard, P.; Glynne, R.J.; Mazier, D.; Sattabongkot, J.; Schultz, P.G.; Tuntland, T.; Walker, J.R.; Zhou, Y.; Chatterjee, A.; Diagana, T.T.; Winzeler, E.A. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science, 2011, 334(6061), 1372-1377.
[http://dx.doi.org/10.1126/science.1211936] [PMID: 22096101]
[69]
Kuhen, K.L.; Chatterjee, A.K.; Rottmann, M.; Gagaring, K.; Borboa, R.; Buenviaje, J.; Chen, Z.; Francek, C.; Wu, T.; Nagle, A.; Barnes, S.W.; Plouffe, D.; Lee, M.C.S.; Fidock, D.A.; Graumans, W.; van de Vegte-Bolmer, M.; van Gemert, G.J.; Wirjanata, G.; Sebayang, B.; Marfurt, J.; Russell, B.; Suwanarusk, R.; Price, R.N.; Nosten, F.; Tungtaeng, A.; Gettayacamin, M.; Sattabongkot, J.; Taylor, J.; Walker, J.R.; Tully, D.; Patra, K.P.; Flannery, E.L.; Vinetz, J.M.; Renia, L.; Sauerwein, R.W.; Winzeler, E.A.; Glynne, R.J.; Diagana, T.T. KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission. Antimicrob. Agents Chemother., 2014, 58(9), 5060-5067.
[http://dx.doi.org/10.1128/AAC.02727-13] [PMID: 24913172]
[70]
Lim, M.Y.X.; LaMonte, G.; Lee, M.C.S.; Reimer, C.; Tan, B.H.; Corey, V.; Tjahjadi, B.F.; Chua, A.; Nachon, M.; Wintjens, R.; Gedeck, P.; Malleret, B.; Renia, L.; Bonamy, G.M.C.; Ho, P.C.L.; Yeung, B.K.S.; Chow, E.D.; Lim, L.; Fidock, D.A.; Diagana, T.T.; Winzeler, E.A.; Bifani, P. UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes. Nat. Microbiol., 2016, 1(12), 16166.
[http://dx.doi.org/10.1038/nmicrobiol.2016.166] [PMID: 27642791]
[71]
Gujjar, R.; Marwaha, A.; El Mazouni, F.; White, J.; White, K.L.; Creason, S.; Shackleford, D.M.; Baldwin, J.; Charman, W.N.; Buckner, F.S.; Charman, S.; Rathod, P.K.; Phillips, M.A. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J. Med. Chem., 2009, 52(7), 1864-1872.
[http://dx.doi.org/10.1021/jm801343r] [PMID: 19296651]
[72]
McCarthy, J.S.; Lotharius, J.; Rückle, T.; Chalon, S.; Phillips, M.A.; Elliott, S.; Sekuloski, S.; Griffin, P.; Ng, C.L.; Fidock, D.A.; Marquart, L.; Williams, N.S.; Gobeau, N.; Bebrevska, L.; Rosario, M.; Marsh, K.; Möhrle, J.J. Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: A two-part first-in-human phase 1a/1b randomised study. Lancet Infect. Dis., 2017, 17(6), 626-635.
[http://dx.doi.org/10.1016/S1473-3099(17)30171-8] [PMID: 28363636]
[73]
Sulyok, M.; Rückle, T.; Roth, A.; Mürbeth, R.E.; Chalon, S.; Kerr, N.; Samec, S.S.; Gobeau, N.; Calle, C.L.; Ibáñez, J.; Sulyok, Z.; Held, J.; Gebru, T.; Granados, P.; Brückner, S.; Nguetse, C.; Mengue, J.; Lalremruata, A.; Sim, B.K.L.; Hoffman, S.L.; Möhrle, J.J.; Kremsner, P.G.; Mordmüller, B. DSM265 for Plasmodium falciparum chemoprophylaxis: A randomised, double blinded, phase 1 trial with controlled human malaria infection. Lancet Infect. Dis., 2017, 17(6), 636-644.
[http://dx.doi.org/10.1016/S1473-3099(17)30139-1] [PMID: 28363637]
[74]
Murphy, S.C.; Duke, E.R.; Shipman, K.J.; Jensen, R.L.; Fong, Y.; Ferguson, S.; Janes, H.E.; Gillespie, K.; Seilie, A.M.; Hanron, A.E.; Rinn, L.; Fishbaugher, M.; VonGoedert, T.; Fritzen, E.; Kappe, S.H.; Chang, M.; Sousa, J.C.; Marcsisin, S.R.; Chalon, S.; Duparc, S.; Kerr, N.; Möhrle, J.J.; Andenmatten, N.; Rueckle, T.; Kublin, J.G. A randomized trial evaluating the prophylactic activity of dsm265 against preerythrocytic Plasmodium falciparum infection during controlled human malarial infection by mosquito bites and direct venous inoculation. J. Infect. Dis., 2018, 217(5), 693-702.
[http://dx.doi.org/10.1093/infdis/jix613] [PMID: 29216395]
[75]
Collins, K.A.; Rückle, T.; Elliott, S.; Marquart, L.; Ballard, E.; Chalon, S.; Griffin, P.; Möhrle, J.J.; McCarthy, J.S. DSM265 at 400 Milligrams Clears Asexual Stage Parasites but Not Mature Gametocytes from the Blood of Healthy Subjects Experimentally Infected with Plasmodium falciparum. Antimicrob. Agents Chemother., 2019, 63(4), e01837-18.
[http://dx.doi.org/10.1128/AAC.01837-18] [PMID: 30858218]
[76]
McCarthy, J.S.; Rückle, T.; Elliott, S.L.; Ballard, E.; Collins, K.A.; Marquart, L.; Griffin, P.; Chalon, S.; Möhrle, J.J. A single-dose combination study with the experimental antimalarials artefenomel and DSM265 to determine safety and antimalarial activity against blood-stage Plasmodium falciparum in healthy volunteers. Antimicrob. Agents Chemother., 2019, 64(1), e01371-19.
[http://dx.doi.org/10.1128/AAC.01371-19] [PMID: 31685476]
[77]
Llanos-Cuentas, A.; Casapia, M.; Chuquiyauri, R.; Hinojosa, J.C.; Kerr, N.; Rosario, M.; Toovey, S.; Arch, R.H.; Phillips, M.A.; Rozenberg, F.D.; Bath, J.; Ng, C.L.; Cowell, A.N.; Winzeler, E.A.; Fidock, D.A.; Baker, M.; Möhrle, J.J.; Hooft van Huijsduijnen, R.; Gobeau, N.; Araeipour, N.; Andenmatten, N.; Rückle, T.; Duparc, S. Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: A proof-of-concept, open-label, phase 2a study. Lancet Infect. Dis., 2018, 18(8), 874-883.
[http://dx.doi.org/10.1016/S1473-3099(18)30309-8] [PMID: 29909069]
[78]
Younis, Y.; Douelle, F.; Feng, T.S.; Cabrera, D.G.; Manach, C.L.; Nchinda, A.T.; Duffy, S.; White, K.L.; Shackleford, D.M.; Morizzi, J.; Mannila, J.; Katneni, K.; Bhamidipati, R.; Zabiulla, K.M.; Joseph, J.T.; Bashyam, S.; Waterson, D.; Witty, M.J.; Hardick, D.; Wittlin, S.; Avery, V.; Charman, S.A.; Chibale, K. 3,5-Diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential. J. Med. Chem., 2012, 55(7), 3479-3487.
[http://dx.doi.org/10.1021/jm3001373] [PMID: 22390538]
[79]
Cheuka, P.M.; Mayoka, G.; Okombo, J.; Chibale, K. Medicinal chemistry progression of antimalarial hits from phenotypic whole cell screening of softfocus libraries. In: Annual Reports in Medicinal Chemistry; Elsevier, 2019; Vol. 53, pp. 25-71.
[http://dx.doi.org/10.1016/bs.armc.2019.04.001]
[80]
Paquet, T.; Le Manach, C.; Cabrera, D.G.; Younis, Y.; Henrich, P.P.; Abraham, T.S.; Lee, M.C.S.; Basak, R.; Ghidelli-Disse, S.; Lafuente-Monasterio, M.J.; Bantscheff, M.; Ruecker, A.; Blagborough, A.M.; Zakutansky, S.E.; Zeeman, A.M.; White, K.L.; Shackleford, D.M.; Mannila, J.; Morizzi, J.; Scheurer, C.; Angulo-Barturen, I.; Martínez, M.S.; Ferrer, S.; Sanz, L.M.; Gamo, F.J.; Reader, J.; Botha, M.; Dechering, K.J.; Sauerwein, R.W.; Tungtaeng, A.; Vanachayangkul, P.; Lim, C.S.; Burrows, J.; Witty, M.J.; Marsh, K.C.; Bodenreider, C.; Rochford, R.; Solapure, S.M.; Jiménez-Díaz, M.B.; Wittlin, S.; Charman, S.A.; Donini, C.; Campo, B.; Birkholtz, L.M.; Hanson, K.K.; Drewes, G.; Kocken, C.H.M.; Delves, M.J.; Leroy, D.; Fidock, D.A.; Waterson, D.; Street, L.J.; Chibale, K. Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci. Transl. Med., 2017, 9(387), eaad9735.
[http://dx.doi.org/10.1126/scitranslmed.aad9735] [PMID: 28446690]
[81]
Medicines for Malaria Venture. MMV390048 against early Plasmodium falciparum blood stage infection in healthy participants. 2014. Available from: https://clinicaltrials.gov/ct2/show/NCT02281344?term=MMV+390048&cond=Malaria&draw=2&rank=3
[82]
Sinxadi, P.; Donini, C.; Johnstone, H.; Langdon, G.; Wiesner, L.; Allen, E.; Duparc, S.; Chalon, S.; McCarthy, J.S.; Lorch, U.; Chibale, K.; Möhrle, J.; Barnes, K.I. Safety, tolerability, pharmacokinetics, and antimalarial activity of the novel plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048 in healthy volunteers. Antimicrob. Agents Chemother., 2020, 64(4), e01896-19.
[http://dx.doi.org/10.1128/AAC.01896-19] [PMID: 31932368]
[83]
Medicines for Malaria Venture. MMV390048 POC in patients with P. vivax and P. falciparum malaria., 2016. Available from: https://clinicaltrials.gov/ct2/show/NCT02880241?term=MMV+390048&cond=Malaria&draw=2&rank=2
[84]
Annual Report; Medicines for Malaria Venture: Geneva, Switzerland, 2020, p. 16.
[85]
Le Manach, C.; Nchinda, A.T.; Paquet, T.; Gonzàlez Cabrera, D.; Younis, Y.; Han, Z.; Bashyam, S.; Zabiulla, M.; Taylor, D.; Lawrence, N.; White, K.L.; Charman, S.A.; Waterson, D.; Witty, M.J.; Wittlin, S.; Botha, M.E.; Nondaba, S.H.; Reader, J.; Birkholtz, L.M.; Jiménez-Díaz, M.B.; Martínez, M.S.; Ferrer, S.; Angulo-Barturen, I.; Meister, S.; Antonova-Koch, Y.; Winzeler, E.A.; Street, L.J.; Chibale, K. Identification of a potential antimalarial drug candidate from a series of 2-aminopyrazines by optimization of aqueous solubility and potency across the parasite life cycle. J. Med. Chem., 2016, 59(21), 9890-9905.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01265] [PMID: 27748596]
[86]
Brunschwig, C.; Lawrence, N.; Taylor, D.; Abay, E.; Njoroge, M.; Basarab, G.S.; Le Manach, C.; Paquet, T.; Cabrera, D.G.; Nchinda, A.T.; de Kock, C.; Wiesner, L.; Denti, P.; Waterson, D.; Blasco, B.; Leroy, D.; Witty, M.J.; Donini, C.; Duffy, J.; Wittlin, S.; White, K.L.; Charman, S.A.; Jiménez-Díaz, M.B.; Angulo-Barturen, I.; Herreros, E.; Gamo, F.J.; Rochford, R.; Mancama, D.; Coetzer, T.L.; van der Watt, M.E.; Reader, J.; Birkholtz, L.M.; Marsh, K.C.; Solapure, S.M.; Burke, J.E.; McPhail, J.A.; Vanaerschot, M.; Fidock, D.A.; Fish, P.V.; Siegl, P.; Smith, D.A.; Wirjanata, G.; Noviyanti, R.; Price, R.N.; Marfurt, J.; Silue, K.D.; Street, L.J.; Chibale, K. UCT943, a Next-generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria. Antimicrob. Agents Chemother., 2018, 62(9), e00012-18.
[http://dx.doi.org/10.1128/AAC.00012-18] [PMID: 29941635]
[87]
De, D.; Cogswell, F.B.; Krogstad, D.J.; Krogstad, F.M. Aminoquinolines that circumvent resistance in Plasmodium falciparumin vitro. Am. J. Trop. Med. Hyg., 1996, 55(6), 579-583.
[http://dx.doi.org/10.4269/ajtmh.1996.55.579] [PMID: 9025680]
[88]
Hocart, S.J.; Liu, H.; Deng, H.; De, D.; Krogstad, F.M.; Krogstad, D.J. 4-aminoquinolines active against chloroquine-resistant Plasmodium falciparum: Basis of antiparasite activity and quantitative structure-activity relationship analyses. Antimicrob. Agents Chemother., 2011, 55(5), 2233-2244.
[http://dx.doi.org/10.1128/AAC.00675-10] [PMID: 21383099]
[89]
De, D.; Krogstad, F.M.; Byers, L.D.; Krogstad, D.J. Structure-activity relationships for antiplasmodial activity among 7-substituted 4-aminoquinolines. J. Med. Chem., 1998, 41(25), 4918-4926.
[http://dx.doi.org/10.1021/jm980146x] [PMID: 9836608]
[90]
Ramanathan-Girish, S.; Catz, P.; Creek, M.R.; Wu, B.; Thomas, D.; Krogstad, D.J.; De, D.; Mirsalis, J.C.; Green, C.E. Pharmacokinetics of the antimalarial drug, AQ-13, in rats and cynomolgus macaques. Int. J. Toxicol., 2004, 23(3), 179-189.
[http://dx.doi.org/10.1080/10915810490471352] [PMID: 15204721]
[91]
Koita, O.A.; Sangaré, L.; Miller, H.D.; Sissako, A.; Coulibaly, M.; Thompson, T.A.; Fongoro, S.; Diarra, Y.; Ba, M.; Maiga, A.; Diallo, B.; Mushatt, D.M.; Mather, F.J.; Shaffer, J.G.; Anwar, A.H.; Krogstad, D.J. AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: A randomised, phase 2, non-inferiority clinical trial. Lancet Infect. Dis., 2017, 17(12), 1266-1275.
[http://dx.doi.org/10.1016/S1473-3099(17)30365-1] [PMID: 28916443]
[92]
Mzayek, F.; Deng, H.; Mather, F.J.; Wasilevich, E.C.; Liu, H.; Hadi, C.M.; Chansolme, D.H.; Murphy, H.A.; Melek, B.H.; Tenaglia, A.N.; Mushatt, D.M.; Dreisbach, A.W.; Lertora, J.J.L.; Krogstad, D.J. Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers. PLoS Clin. Trials, 2007, 2(1), e6.
[http://dx.doi.org/10.1371/journal.pctr.0020006] [PMID: 17213921]
[93]
Hameed P, S.; Solapure, S.; Patil, V.; Henrich, P.P.; Magistrado, P.A.; Bharath, S.; Murugan, K.; Viswanath, P.; Puttur, J.; Srivastava, A.; Bellale, E.; Panduga, V.; Shanbag, G.; Awasthy, D.; Landge, S.; Morayya, S.; Koushik, K.; Saralaya, R.; Raichurkar, A.; Rautela, N.; Roy Choudhury, N.; Ambady, A.; Nandishaiah, R.; Reddy, J.; Prabhakar, K.R.; Menasinakai, S.; Rudrapatna, S.; Chatterji, M.; Jiménez-Díaz, M.B.; Martínez, M.S.; Sanz, L.M.; Coburn-Flynn, O.; Fidock, D.A.; Lukens, A.K.; Wirth, D.F.; Bandodkar, B.; Mukherjee, K.; McLaughlin, R.E.; Waterson, D.; Rosenbrier-Ribeiro, L.; Hickling, K.; Balasubramanian, V.; Warner, P.; Hosagrahara, V.; Dudley, A.; Iyer, P.S.; Narayanan, S.; Kavanagh, S.; Sambandamurthy, V.K. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat. Commun., 2015, 6(1), 6715.
[http://dx.doi.org/10.1038/ncomms7715]
[94]
Ghoghari, A.M.; Patel, H.V.; Nayak, N.N.; Mansuri, T.H.; Pillai, S.M.; Jain, M.R.; Patel, H.B.; Kansagra, K.; Resta, I.D.; Möhrle, J.; Parmar, D.V. Simultaneous estimation of ZY-19489 and its active metabolite ZY-20486 in human plasma using LC–MS/MS, a novel antimalarial compound. Bioanalysis, 2021, 13(23), 1761-1777.
[http://dx.doi.org/10.4155/bio-2021-0194] [PMID: 34779650]
[95]
SINDOFO. What Is SINDOFO?, 2022. Available from: https://www.sindofo.net/about
[96]
Kuhlmann, F.M.; Fleckenstein, J.M. Antiparasitic agents. In: Infectious Diseases; Elsevier, 2017; pp. 1345-1372.e2.
[http://dx.doi.org/10.1016/B978-0-7020-6285-8.00157-X]
[97]
O’Neill, P.M.; Mukhtar, A.; Stocks, P.A.; Randle, L.E.; Hindley, S.; Ward, S.A.; Storr, R.C.; Bickley, J.F.; O’Neil, I.A.; Maggs, J.L.; Hughes, R.H.; Winstanley, P.A.; Bray, P.G.; Park, B.K. Isoquine and related amodiaquine analogues: A new generation of improved 4-aminoquinoline antimalarials. J. Med. Chem., 2003, 46(23), 4933-4945.
[http://dx.doi.org/10.1021/jm030796n] [PMID: 14584944]
[98]
O’Neill, P.M.; Park, B.K.; Shone, A.E.; Maggs, J.L.; Roberts, P.; Stocks, P.A.; Biagini, G.A.; Bray, P.G.; Gibbons, P.; Berry, N.; Winstanley, P.A.; Mukhtar, A.; Bonar-Law, R.; Hindley, S.; Bambal, R.B.; Davis, C.B.; Bates, M.; Hart, T.K.; Gresham, S.L.; Lawrence, R.M.; Brigandi, R.A.; Gomez-delas-Heras, F.M.; Gargallo, D.V.; Ward, S.A. Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century. J. Med. Chem., 2009, 52(5), 1408-1415.
[http://dx.doi.org/10.1021/jm8012618] [PMID: 19222165]
[99]
Tse, E.G.; Korsik, M.; Todd, M.H. The past, present and future of anti-malarial medicines. Malar. J., 2019, 18(1), 93.
[http://dx.doi.org/10.1186/s12936-019-2724-z] [PMID: 30902052]
[100]
O’Neill, P.M.; Shone, A.E.; Stanford, D.; Nixon, G.; Asadollahy, E.; Park, B.K.; Maggs, J.L.; Roberts, P.; Stocks, P.A.; Biagini, G.; Bray, P.G.; Davies, J.; Berry, N.; Hall, C.; Rimmer, K.; Winstanley, P.A.; Hindley, S.; Bambal, R.B.; Davis, C.B.; Bates, M.; Gresham, S.L.; Brigandi, R.A.; Gomez-de-las-Heras, F.M.; Gargallo, D.V.; Parapini, S.; Vivas, L.; Lander, H.; Taramelli, D.; Ward, S.A. Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4′-fluoro and 4′-chloro analogues of amodiaquine. Identification of a suitable “back-up” compound for N-tert-butyl isoquine. J. Med. Chem., 2009, 52(7), 1828-1844.
[http://dx.doi.org/10.1021/jm8012757] [PMID: 19284751]
[101]
Taft, B.R.; Yokokawa, F.; Kirrane, T.; Mata, A.C.; Huang, R.; Blaquiere, N.; Waldron, G.; Zou, B.; Simon, O.; Vankadara, S.; Chan, W.L.; Ding, M.; Sim, S.; Straimer, J.; Guiguemde, A.; Lakshminarayana, S.B.; Jain, J.P.; Bodenreider, C.; Thompson, C.; Lanshoeft, C.; Shu, W.; Fang, E.; Qumber, J.; Chan, K.; Pei, L.; Chen, Y.L.; Schulz, H.; Lim, J.; Abas, S.N.; Ang, X.; Liu, Y.; Angulo-Barturen, I.; Jiménez-Díaz, M.B.; Gamo, F.J.; Crespo-Fernandez, B.; Rosenthal, P.J.; Cooper, R.A.; Tumwebaze, P.; Aguiar, A.C.C.; Campo, B.; Campbell, S.; Wagner, J.; Diagana, T.T.; Sarko, C. Discovery and preclinical pharmacology of INE963, a potent and fast-acting blood-stage antimalarial with a high barrier to resistance and potential for single-dose cures in uncomplicated malaria. J. Med. Chem., 2022, 65(5), 3798-3813.
[http://dx.doi.org/10.1021/acs.jmedchem.1c01995] [PMID: 35229610]
[102]
Baragaña, B.; Hallyburton, I.; Lee, M.C.S.; Norcross, N.R.; Grimaldi, R.; Otto, T.D.; Proto, W.R.; Blagborough, A.M.; Meister, S.; Wirjanata, G.; Ruecker, A.; Upton, L.M.; Abraham, T.S.; Almeida, M.J.; Pradhan, A.; Porzelle, A.; Martínez, M.S.; Bolscher, J.M.; Woodland, A.; Luksch, T.; Norval, S.; Zuccotto, F.; Thomas, J.; Simeons, F.; Stojanovski, L.; Osuna-Cabello, M.; Brock, P.M.; Churcher, T.S.; Sala, K.A.; Zakutansky, S.E.; Jiménez-Díaz, M.B.; Sanz, L.M.; Riley, J.; Basak, R.; Campbell, M.; Avery, V.M.; Sauerwein, R.W.; Dechering, K.J.; Noviyanti, R.; Campo, B.; Frearson, J.A.; Angulo-Barturen, I.; Ferrer-Bazaga, S.; Gamo, F.J.; Wyatt, P.G.; Leroy, D.; Siegl, P.; Delves, M.J.; Kyle, D.E.; Wittlin, S.; Marfurt, J.; Price, R.N.; Sinden, R.E.; Winzeler, E.A.; Charman, S.A.; Bebrevska, L.; Gray, D.W.; Campbell, S.; Fairlamb, A.H.; Willis, P.A.; Rayner, J.C.; Fidock, D.A.; Read, K.D.; Gilbert, I.H.; Gilbert, I.H. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature, 2015, 522(7556), 315-320.
[http://dx.doi.org/10.1038/nature14451] [PMID: 26085270]
[103]
Baragaña, B.; Norcross, N.R.; Wilson, C.; Porzelle, A.; Hallyburton, I.; Grimaldi, R.; Osuna-Cabello, M.; Norval, S.; Riley, J.; Stojanovski, L.; Simeons, F.R.C.; Wyatt, P.G.; Delves, M.J.; Meister, S.; Duffy, S.; Avery, V.M.; Winzeler, E.A.; Sinden, R.E.; Wittlin, S.; Frearson, J.A.; Gray, D.W.; Fairlamb, A.H.; Waterson, D.; Campbell, S.F.; Willis, P.; Read, K.D.; Gilbert, I.H. Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy. J. Med. Chem., 2016, 59(21), 9672-9685.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00723] [PMID: 27631715]
[104]
Hewitt, P.; Abla, N.; Lignet, F.; Oeuvray, C.; Bagchus, W.; Bebrevska, L. An innovative study design with intermittent dosing to generate a GLP-regulatory package in preclinical species for long lasting molecule M5717, inhibitor of Plasmodium eukaryotic translation elongation factor 2. Toxicol. Appl. Pharmacol., 2022, 443, 116006.
[http://dx.doi.org/10.1016/j.taap.2022.116006] [PMID: 35367236]
[105]
McCarthy, J.S.; Yalkinoglu, Ö.; Odedra, A.; Webster, R.; Oeuvray, C.; Tappert, A.; Bezuidenhout, D.; Giddins, M.J.; Dhingra, S.K.; Fidock, D.A.; Marquart, L.; Webb, L.; Yin, X.; Khandelwal, A.; Bagchus, W.M. Safety, pharmacokinetics, and antimalarial activity of the novel plasmodium eukaryotic translation elongation factor 2 inhibitor M5717: A first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection study. Lancet Infect. Dis., 2021, 21(12), 1713-1724.
[http://dx.doi.org/10.1016/S1473-3099(21)00252-8] [PMID: 34715032]
[106]
Guiguemde, W.A.; Shelat, A.A.; Bouck, D.; Duffy, S.; Crowther, G.J.; Davis, P.H.; Smithson, D.C.; Connelly, M.; Clark, J.; Zhu, F.; Jiménez-Díaz, M.B.; Martinez, M.S.; Wilson, E.B.; Tripathi, A.K.; Gut, J.; Sharlow, E.R.; Bathurst, I.; Mazouni, F.E.; Fowble, J.W.; Forquer, I.; McGinley, P.L.; Castro, S.; Angulo-Barturen, I.; Ferrer, S.; Rosenthal, P.J.; DeRisi, J.L.; Sullivan, D.J.; Lazo, J.S.; Roos, D.S.; Riscoe, M.K.; Phillips, M.A.; Rathod, P.K.; Van Voorhis, W.C.; Avery, V.M.; Guy, R.K. Chemical genetics of Plasmodium falciparum. Nature, 2010, 465(7296), 311-315.
[http://dx.doi.org/10.1038/nature09099] [PMID: 20485428]
[107]
Jiménez-Díaz, M.B.; Ebert, D.; Salinas, Y.; Pradhan, A.; Lehane, A.M.; Myrand-Lapierre, M.E.; O’Loughlin, K.G.; Shackleford, D.M.; Justino de Almeida, M.; Carrillo, A.K.; Clark, J.A.; Dennis, A.S.M.; Diep, J.; Deng, X.; Duffy, S.; Endsley, A.N.; Fedewa, G.; Guiguemde, W.A.; Gómez, M.G.; Holbrook, G.; Horst, J.; Kim, C.C.; Liu, J.; Lee, M.C.S.; Matheny, A.; Martínez, M.S.; Miller, G.; Rodríguez-Alejandre, A.; Sanz, L.; Sigal, M.; Spillman, N.J.; Stein, P.D.; Wang, Z.; Zhu, F.; Waterson, D.; Knapp, S.; Shelat, A.; Avery, V.M.; Fidock, D.A.; Gamo, F.J.; Charman, S.A.; Mirsalis, J.C.; Ma, H.; Ferrer, S.; Kirk, K.; Angulo-Barturen, I.; Kyle, D.E.; DeRisi, J.L.; Floyd, D.M.; Guy, R.K. (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. Proc. Natl. Acad. Sci. USA, 2014, 111(50), E5455-E5462.
[http://dx.doi.org/10.1073/pnas.1414221111] [PMID: 25453091]
[108]
Floyd, D.M.; Stein, P.; Wang, Z.; Liu, J.; Castro, S.; Clark, J.A.; Connelly, M.; Zhu, F.; Holbrook, G.; Matheny, A.; Sigal, M.S.; Min, J.; Dhinakaran, R.; Krishnan, S.; Bashyum, S.; Knapp, S.; Guy, R.K. Hit-to-lead studies for the antimalarial tetrahydroisoquinolone carboxanilides. J. Med. Chem., 2016, 59(17), 7950-7962.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00752] [PMID: 27505686]
[109]
Gaur, A.H.; McCarthy, J.S.; Panetta, J.C.; Dallas, R.H.; Woodford, J.; Tang, L.; Smith, A.M.; Stewart, T.B.; Branum, K.C.; Freeman, B.B., III; Patel, N.D.; John, E.; Chalon, S.; Ost, S.; Heine, R.N.; Richardson, J.L.; Christensen, R.; Flynn, P.M.; Van Gessel, Y.; Mitasev, B.; Möhrle, J.J.; Gusovsky, F.; Bebrevska, L.; Guy, R.K. Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: A first-inhuman and induced blood-stage malaria phase 1a/b trial. Lancet Infect. Dis., 2020, 20(8), 964-975.
[http://dx.doi.org/10.1016/S1473-3099(19)30611-5] [PMID: 32275867]
[110]
Gaur, A.H.; Panetta, J.C.; Smith, A.M.; Dallas, R.H.; Freeman, B.B., III; Stewart, T.B.; Tang, L.; John, E.; Branum, K.C.; Patel, N.D.; Ost, S.; Heine, R.N.; Richardson, J.L.; Hammill, J.T.; Bebrevska, L.; Gusovsky, F.; Maki, N.; Yanagi, T.; Flynn, P.M.; McCarthy, J.S.; Chalon, S.; Guy, R.K. Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the pharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drug development. EBioMedicine, 2022, 80, 104065.
[http://dx.doi.org/10.1016/j.ebiom.2022.104065] [PMID: 35598441]
[111]
Boss, C.; Aissaoui, H.; Amaral, N.; Bauer, A.; Bazire, S.; Binkert, C.; Brun, R.; Bürki, C.; Ciana, C.L.; Corminboeuf, O.; Delahaye, S.; Dollinger, C.; Fischli, C.; Fischli, W.; Flock, A.; Frantz, M.C.; Girault, M.; Grisostomi, C.; Friedli, A.; Heidmann, B.; Hinder, C.; Jacob, G.; Le Bihan, A.; Malrieu, S.; Mamzed, S.; Merot, A.; Meyer, S.; Peixoto, S.; Petit, N.; Siegrist, R.; Trollux, J.; Weller, T.; Wittlin, S. Discovery and characterization of ACT-451840: an antimalarial drug with a novel mechanism of action. ChemMedChem, 2016, 11(18), 1995-2014.
[http://dx.doi.org/10.1002/cmdc.201600298] [PMID: 27471138]
[112]
Le Bihan, A.; de Kanter, R.; Angulo-Barturen, I.; Binkert, C.; Boss, C.; Brun, R.; Brunner, R.; Buchmann, S.; Burrows, J.; Dechering, K.J.; Delves, M.; Ewerling, S.; Ferrer, S.; Fischli, C.; Gamo-Benito, F.J.; Gnädig, N.F.; Heidmann, B.; Jiménez-Díaz, M.B.; Leroy, D.; Martínez, M.S.; Meyer, S.; Moehrle, J.J.; Ng, C.L.; Noviyanti, R.; Ruecker, A.; Sanz, L.M.; Sauerwein, R.W.; Scheurer, C.; Schleiferboeck, S.; Sinden, R.; Snyder, C.; Straimer, J.; Wirjanata, G.; Marfurt, J.; Price, R.N.; Weller, T.; Fischli, W.; Fidock, D.A.; Clozel, M.; Wittlin, S. Characterization of novel antimalarial compound ACT-451840: preclinical assessment of activity and dose-efficacy modeling. PLoS Med., 2016, 13(10), e1002138.
[http://dx.doi.org/10.1371/journal.pmed.1002138] [PMID: 27701420]
[113]
Bruderer, S.; Hurst, N.; de Kanter, R.; Miraval, T.; Pfeifer, T.; Donazzolo, Y.; Dingemanse, J. First-in-humans study of the safety, tolerability, and pharmacokinetics of ACT-451840, a new chemical entity with antimalarial activity. Antimicrob. Agents Chemother., 2015, 59(2), 935-942.
[http://dx.doi.org/10.1128/AAC.04125-14] [PMID: 25421475]
[114]
Krause, A.; Dingemanse, J.; Mathis, A.; Marquart, L.; Möhrle, J.J.; McCarthy, J.S. Pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of Actelion‐451840 in an induced blood stage malaria study in healthy subjects. Br. J. Clin. Pharmacol., 2016, 82(2), 412-421.
[http://dx.doi.org/10.1111/bcp.12962] [PMID: 27062080]
[115]
Edstein, M.D.; Kotecka, B.M.; Ager, A.L.; Smith, K.S.; DiTusa, C.A.; Diaz, D.S.; Kyle, D.E.; Schiehser, G.A.; Jacobus, D.P.; Rieckmann, K.H.; O’Neil, M.T. Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate JPC2056 in cynomolgus monkeys using an in vivo in vitro model. J. Antimicrob. Chemother., 2007, 60(4), 811-818.
[http://dx.doi.org/10.1093/jac/dkm280] [PMID: 17646199]
[116]
Rieckmann, K. Chemotherapy of malaria and resistance to antimalarials; world health organization world health organization technical report 529. In: The in Vitro Activity of Experimental Antimalarial Compounds against Strains of Plasmodium Falciparum with Varying Degrees of Sensitivity to Pyrimethamine and Chloroquine; World Health Organization: Geneva, Switzerland, 1973.
[117]
Canfield, C.; Bruce-Chwatt, L. Chemotherapy of Malaria; Monograph 27. In: New Antimalarials under Development; World Health Organization: Geneva, Switzerland, 1986; pp. 99-100.
[118]
Canfield, C.J.; Sweeney, T.R.; Jacobus, D.P.; Rossan, R.N.; Milhous, W.K.; Ager, A.L.; Lewis, N.J. PS-15: A potent, orally active antimalarial from a new class of folic acid antagonists. Am. J. Trop. Med. Hyg., 1993, 49(1), 121-126.
[http://dx.doi.org/10.4269/ajtmh.1993.49.121] [PMID: 8352384]
[119]
Rieckmann, K.H.; Yeo, A.E.T.; Edstein, M.D. Activity of PS-15 and its metabolite, WR99210, against Plasmodium falciparum in an in vivo-in vitro model. Trans. R. Soc. Trop. Med. Hyg., 1996, 90(5), 568-571.
[http://dx.doi.org/10.1016/S0035-9203(96)90326-0] [PMID: 8944276]
[120]
Jensen, N.P.; Ager, A.L.; Bliss, R.A.; Canfield, C.J.; Kotecka, B.M.; Rieckmann, K.H.; Terpinski, J.; Jacobus, D.P. Phenoxypropoxybiguanides, prodrugs of DHFR-inhibiting diaminotriazine antimalarials. J. Med. Chem., 2001, 44(23), 3925-3931.
[http://dx.doi.org/10.1021/jm010089z] [PMID: 11689078]
[121]
Shearer, T.W.; Kozar, M.P.; O’Neil, M.T.; Smith, P.L.; Schiehser, G.A.; Jacobus, D.P.; Diaz, D.S.; Yang, Y.S.; Milhous, W.K.; Skillman, D.R. In vitro metabolism of phenoxypropoxybiguanide analogues in human liver microsomes to potent antimalarial dihydrotriazines. J. Med. Chem., 2005, 48(8), 2805-2813.
[http://dx.doi.org/10.1021/jm049683+] [PMID: 15828818]
[122]
Baird, J.K.; Hoffman, S.L. Primaquine therapy for malaria. Clin. Infect. Dis., 2004, 39(9), 1336-1345.
[http://dx.doi.org/10.1086/424663] [PMID: 15494911]
[123]
Bolchoz, L.J.; Budinsky, R.A.; McMillan, D.C.; Jollow, D.J. Primaquine-induced hemolytic anemia: Formation and hemotoxicity of the arylhydroxylamine metabolite 6-methoxy-8-hydroxylaminoquinoline. J. Pharmacol. Exp. Ther., 2001, 297(2), 509-515.
[http://dx.doi.org/10.1124/jpet.103.062984] [PMID: 11303037]
[124]
Price, R.N.; Nosten, F. Single-dose radical cure of Plasmodium vivax: A step closer. Lancet, 2014, 383(9922), 1020-1021.
[http://dx.doi.org/10.1016/S0140-6736(13)62672-0] [PMID: 24360370]
[125]
Llanos-Cuentas, A.; Lacerda, M.V.; Rueangweerayut, R.; Krudsood, S.; Gupta, S.K.; Kochar, S.K.; Arthur, P.; Chuenchom, N.; Möhrle, J.J.; Duparc, S.; Ugwuegbulam, C.; Kleim, J.P.; Carter, N.; Green, J.A.; Kellam, L. Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): A multicentre, double-blind, randomised, phase 2b dose-selection study. Lancet, 2014, 383(9922), 1049-1058.
[http://dx.doi.org/10.1016/S0140-6736(13)62568-4] [PMID: 24360369]
[126]
Nanayakkara, N.P.D.; Ager, A.L., Jr; Bartlett, M.S.; Yardley, V.; Croft, S.L.; Khan, I.A.; McChesney, J.D.; Walker, L.A. Antiparasitic activities and toxicities of individual enantiomers of the 8-aminoquinoline 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate. Antimicrob. Agents Chemother., 2008, 52(6), 2130-2137.
[http://dx.doi.org/10.1128/AAC.00645-07] [PMID: 18378716]
[127]
Hamerly, T.; Tweedell, R.E.; Hritzo, B.; Nyasembe, V.O.; Tekwani, B.L.; Nanayakkara, N.P.D.; Walker, L.A.; Dinglasan, R.R. NPC1161B, an 8-aminoquinoline analog, is metabolized in the mosquito and inhibits Plasmodium falciparum oocyst maturation. Front. Pharmacol., 2019, 10, 1265.
[http://dx.doi.org/10.3389/fphar.2019.01265] [PMID: 31708786]
[128]
Lu, K.Y.; Derbyshire, E.R. Tafenoquine: A Step toward Malaria Elimination. Biochemistry, 2020, 59(8), 911-920.
[http://dx.doi.org/10.1021/acs.biochem.9b01105] [PMID: 32073254]
[129]
Fernández, E.; Castellote, M.I.; Chaparro, M.J.; Díaz, B.; Fernández, J.; Gordo, M.; de las Heras, L.; León, M.L.; Rueda, L.; Calderón, F. A decade of malaria phenotypic screenings: key lessons on the discovery and development of new antimalarial drugs. In: Annual Reports in Medicinal Chemistry;; Elsevier, 2019; 53, pp. 1-23.
[http://dx.doi.org/10.1016/bs.armc.2019.07.001]
[130]
Medicines for Malaria Venture. Preclinical IWY357 GSK484 GSK GSK701., 2022. Available from: https://www.mmv.org/portfolio-type/preclinical
[131]
Castellote Alvaro, M. Discovery of GSK701, a novel orally effective preclinical drug candidate for the treatment of malaria. American Journal of Tropical Medicine and Hygiene, 2018, 99, 95-96.
[132]
Murithi, J.M.; Pascal, C.; Bath, J.; Boulenc, X.; Gnädig, N.F.; Pasaje, C.F.A.; Rubiano, K.; Yeo, T.; Mok, S.; Klieber, S.; Desert, P.; Jiménez-Díaz, M.B.; Marfurt, J.; Rouillier, M.; Cherkaoui-Rbati, M.H.; Gobeau, N.; Wittlin, S.; Uhlemann, A.C.; Price, R.N.; Wirjanata, G.; Noviyanti, R.; Tumwebaze, P.; Cooper, R.A.; Rosenthal, P.J.; Sanz, L.M.; Gamo, F.J.; Joseph, J.; Singh, S.; Bashyam, S.; Augereau, J.M.; Giraud, E.; Bozec, T.; Vermat, T.; Tuffal, G.; Guillon, J.M.; Menegotto, J.; Sallé, L.; Louit, G.; Cabanis, M.J.; Nicolas, M.F.; Doubovetzky, M.; Merino, R.; Bessila, N.; Angulo-Barturen, I.; Baud, D.; Bebrevska, L.; Escudié, F.; Niles, J.C.; Blasco, B.; Campbell, S.; Courtemanche, G.; Fraisse, L.; Pellet, A.; Fidock, D.A.; Leroy, D. The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance. Sci. Transl. Med., 2021, 13(603), eabg6013.
[http://dx.doi.org/10.1126/scitranslmed.abg6013] [PMID: 34290058]
[133]
Trauner, D.; Peitsinis, Z. Beating resistant Plasmodium parasites with the antimalarial MMV688533. Synfacts, 2021, 17(10), 1154.
[http://dx.doi.org/10.1055/s-0040-1720206]
[134]
Zhang, Y.K.; Plattner, J.J.; Easom, E.E.; Jacobs, R.T.; Guo, D.; Sanders, V.; Freund, Y.R.; Campo, B.; Rosenthal, P.J.; Bu, W.; Gamo, F.J.; Sanz, L.M.; Ge, M.; Li, L.; Ding, J.; Yang, Y. Benzoxaborole antimalarial agents. Part 4. discovery of potent 6-(2-(Alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles. J. Med. Chem., 2015, 58(13), 5344-5354.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00678] [PMID: 26067904]
[135]
Zhang, Y.K.; Plattner, J.J.; Easom, E.E.; Jacobs, R.T.; Guo, D.; Freund, Y.R.; Berry, P.; Ciaravino, V.; Erve, J.C.L.; Rosenthal, P.J.; Campo, B.; Gamo, F.J.; Sanz, L.M.; Cao, J. Benzoxaborole antimalarial agents. Part 5. Lead optimization of novel amide pyrazinyloxy benzoxaboroles and identification of a preclinical candidate. J. Med. Chem., 2017, 60(13), 5889-5908.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00621] [PMID: 28635296]
[136]
Sindhe, K.M.V.; Wu, W.; Legac, J.; Zhang, Y.K.; Easom, E.E.; Cooper, R.A.; Plattner, J.J.; Freund, Y.R.; DeRisi, J.L.; Rosenthal, P.J. Plasmodium falciparum resistance to a lead benzoxaborole due to blocked compound activation and altered ubiquitination or sumoylation. MBio, 2020, 11(1), e02640-19.
[http://dx.doi.org/10.1128/mBio.02640-19] [PMID: 31992618]
[137]
Bellini, V.; Swale, C.; Brenier-Pinchart, M.P.; Pezier, T.; Georgeault, S.; Laurent, F.; Hakimi, M.A.; Bougdour, A. Target identification of an antimalarial oxaborole identifies AN13762 as an alternative chemotype for targeting CPSF3 in apicomplexan parasites. iScience, 2020, 23(12), 101871.
[http://dx.doi.org/10.1016/j.isci.2020.101871] [PMID: 33336164]
[138]
Li, N.; Jiang, S.; Fu, R.; Lv, J.; Yao, J.; Mai, J.; Hua, X.; Chen, H.; Liu, J.; Lu, M. Cleavage and polyadenylation-specific factor 3 induces cell cycle arrest via PI3K/Akt/GSK-3β signaling pathways and predicts a negative prognosis in hepatocellular carcinoma. Biomarkers Med., 2021, 15(5), 347-358.
[http://dx.doi.org/10.2217/bmm-2021-0039] [PMID: 33666519]
[139]
Ross, N.T.; Lohmann, F.; Carbonneau, S.; Fazal, A.; Weihofen, W.A.; Gleim, S.; Salcius, M.; Sigoillot, F.; Henault, M.; Carl, S.H.; Rodríguez-Molina, J.B.; Miller, H.R.; Brittain, S.M.; Murphy, J.; Zambrowski, M.; Boynton, G.; Wang, Y.; Chen, A.; Molind, G.J.; Wilbertz, J.H.; Artus-Revel, C.G.; Jia, M.; Akinjiyan, F.A.; Turner, J.; Knehr, J.; Carbone, W.; Schuierer, S.; Reece-Hoyes, J.S.; Xie, K.; Saran, C.; Williams, E.T.; Roma, G.; Spencer, M.; Jenkins, J.; George, E.L.; Thomas, J.R.; Michaud, G.; Schirle, M.; Tallarico, J.; Passmore, L.A.; Chao, J.A.; Beckwith, R.E.J. CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing’s sarcoma. Nat. Chem. Biol., 2020, 16(1), 50-59.
[http://dx.doi.org/10.1038/s41589-019-0424-1] [PMID: 31819276]
[140]
Rashidi, S.; Tuteja, R.; Mansouri, R.; Ali-Hassanzadeh, M.; Shafiei, R.; Ghani, E.; Karimazar, M.; Nguewa, P.; Manzano-Román, R. The main post-translational modifications and related regulatory pathways in the malaria parasite Plasmodium falciparum: An update. J. Proteomics, 2021, 245, 104279.
[http://dx.doi.org/10.1016/j.jprot.2021.104279] [PMID: 34089893]
[141]
Cheuka, P.M. Drug discovery and target identification against schistosomiasis: a reality check on progress and future prospects. CTMC, 2021, 21.
[http://dx.doi.org/10.2174/1568026621666210924101805] [PMID: 34565320]
[142]
Mairet-Khedim, M.; Leang, R.; Marmai, C.; Khim, N.; Kim, S.; Ke, S.; Kauy, C.; Kloeung, N.; Eam, R.; Chy, S.; Izac, B.; Mey Bouth, D.; Dorina Bustos, M.; Ringwald, P.; Ariey, F.; Witkowski, B. Clinical and in vitro resistance of Plasmodium falciparum to artesunate-amodiaquine in cambodia. Clin. Infect. Dis., 2021, 73(3), 406-413.
[http://dx.doi.org/10.1093/cid/ciaa628] [PMID: 32459308]

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