cipargamin   Click here for help

GtoPdb Ligand ID: 9721

Synonyms: KAE609 | NITD609
Antimalarial Ligand
Compound class: Synthetic organic
Comment: Cipargamin is an antimalarial drug candidate, under clinical development. It is the optimised lead for the spiroindolones, a novel class of compounds identified from a phenotypic screen as having antimalarial activity [2,7] and awarded MMV Project of the Year (2009).
The active enantiomer is shown here, with the 1R,3S configuration essential for antimalarial activity [2].

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 3
Hydrogen bond donors 3
Rotatable bonds 0
Topological polar surface area 56.92
Molecular weight 389.05
XLogP 4.62
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES CC1Cc2c3cc(F)c(cc3[nH]c2C2(N1)C(=O)Nc1c2cc(Cl)cc1)Cl
Isomeric SMILES C[C@H]1Cc2c3cc(F)c(cc3[nH]c2[C@@]2(N1)C(=O)Nc1c2cc(Cl)cc1)Cl
InChI InChI=1S/C19H14Cl2FN3O/c1-8-4-11-10-6-14(22)13(21)7-16(10)23-17(11)19(25-8)12-5-9(20)2-3-15(12)24-18(19)26/h2-3,5-8,23,25H,4H2,1H3,(H,24,26)/t8-,19+/m0/s1
InChI Key CKLPLPZSUQEDRT-WPCRTTGESA-N
References
1. Goldgof GM, Durrant JD, Ottilie S, Vigil E, Allen KE, Gunawan F, Kostylev M, Henderson KA, Yang J, Schenken J et al.. (2016)
Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor.
Sci Rep, 6: 27806. [PMID:27291296]
2. Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J et al.. (2010)
Spiroindolones, a potent compound class for the treatment of malaria.
Science, 329 (5996): 1175-80. [PMID:20813948]
3. Spillman NJ, Allen RJ, McNamara CW, Yeung BK, Winzeler EA, Diagana TT, Kirk K. (2013)
Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials.
Cell Host Microbe, 13 (2): 227-37. [PMID:23414762]
4. Stein DS, Jain JP, Kangas M, Lefèvre G, Machineni S, Griffin P, Lickliter J. (2015)
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, 59 (6): 3493-500. [PMID:25845867]
5. van Pelt-Koops JC, Pett HE, Graumans W, van der Vegte-Bolmer M, van Gemert GJ, Rottmann M, Yeung BK, Diagana TT, Sauerwein RW. (2012)
The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector.
Antimicrob Agents Chemother, 56 (7): 3544-8. [PMID:22508309]
6. White NJ, Pukrittayakamee S, Phyo AP, Rueangweerayut R, Nosten F, Jittamala P, Jeeyapant A, Jain JP, Lefèvre G, Li R et al.. (2014)
Spiroindolone KAE609 for falciparum and vivax malaria.
N Engl J Med, 371 (5): 403-10. [PMID:25075833]
7. Yeung BK, Zou B, Rottmann M, Lakshminarayana SB, Ang SH, Leong SY, Tan J, Wong J, Keller-Maerki S, Fischli C et al.. (2010)
Spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria.
J Med Chem, 53 (14): 5155-64. [PMID:20568778]