P218   Click here for help

GtoPdb Ligand ID: 9740

Synonyms: MMV000147
PDB Ligand Antimalarial Ligand
Compound class: Synthetic organic
Comment: The antifolate compound P218 is a potent and selective inhibitor of P. falciparum bifunctional dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) and was designed to overcome the emergence of parasite resistance to this class of antimalarial compound [7].

The Malaria tab on this ligand page provides additional curator comments of relevance to the Guide to MALARIA PHARMACOLOGY.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 3
Rotatable bonds 10
Topological polar surface area 133.58
Molecular weight 360.18
XLogP 1.72
No. Lipinski's rules broken 0
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Canonical SMILES CCc1nc(N)nc(c1OCCCOc1ccccc1CCC(=O)O)N
Isomeric SMILES CCc1nc(N)nc(c1OCCCOc1ccccc1CCC(=O)O)N
InChI InChI=1S/C18H24N4O4/c1-2-13-16(17(19)22-18(20)21-13)26-11-5-10-25-14-7-4-3-6-12(14)8-9-15(23)24/h3-4,6-7H,2,5,8-11H2,1H3,(H,23,24)(H4,19,20,21,22)
1. Chughlay MF, El Gaaloul M, Donini C, Campo B, Berghmans PJ, Lucardie A, Marx MW, Cherkaoui-Rbati MH, Langdon G, Angulo-Barturen I et al.. (2021)
Chemoprotective Antimalarial Activity of P218 against Plasmodium falciparum: A Randomized, Placebo-Controlled Volunteer Infection Study.
Am J Trop Med Hyg, 104 (4): 1348-1358. [PMID:33556040]
2. Chughlay MF, Rossignol E, Donini C, El Gaaloul M, Lorch U, Coates S, Langdon G, Hammond T, Möhrle J, Chalon S. (2020)
First-in-human clinical trial to assess the safety, tolerability and pharmacokinetics of P218, a novel candidate for malaria chemoprotection.
Br J Clin Pharmacol, 86 (6): 1113-1124. [PMID:31925817]
3. Posayapisit N, Pengon J, Prommana P, Shoram M, Yuthavong Y, Uthaipibull C, Kamchonwongpaisan S, Jupatanakul N. (2021)
Transgenic pyrimethamine-resistant plasmodium falciparum reveals transmission-blocking potency of P218, a novel antifolate candidate drug.
Int J Parasitol, 51 (8): 635-642. [PMID:33713651]
4. Roth A, Maher SP, Conway AJ, Ubalee R, Chaumeau V, Andolina C, Kaba SA, Vantaux A, Bakowski MA, Thomson-Luque R et al.. (2018)
A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum.
Nat Commun, 9 (1): 1837. [PMID:29743474]
5. Täubel J, Lorch U, Ferber G, Spencer CS, Freier A, Coates S, El Gaaloul M, Donini C, Chughlay MF, Chalon S. (2022)
Concentration-QT modelling of the novel DHFR inhibitor P218 in healthy male volunteers.
Br J Clin Pharmacol, 88 (1): 128-137. [PMID:34075612]
6. Tarnchhompoo B, Yuthavong Y, Vilaivan T, Chitnumsub P et al.. (2009)
Antimalarial compounds with flexible side-chains.
Patent number: WO2009048957A1. Assignee: MEDICINES FOR MALARIA VENTURE. Priority date: 08/10/2007. Publication date: 16/04/2009.
7. Yuthavong Y, Tarnchompoo B, Vilaivan T, Chitnumsub P, Kamchonwongpaisan S, Charman SA, McLennan DN, White KL, Vivas L, Bongard E et al.. (2012)
Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target.
Proc Natl Acad Sci USA, 109 (42): 16823-8. [PMID:23035243]