ACT-451840   Click here for help

GtoPdb Ligand ID: 10022

Synonyms: ACT451840 | Actelion-451840
Antimalarial Ligand
Compound class: Synthetic organic
Comment: ACT-451840 is an investigational antimalarial drug, selected from a new class of compounds identified from a phenotypic screen [2,4]. Chemically it is a piperazine-containing compound.

The Malaria tab on this ligand page provides additional curator comments of relevance to the Guide to MALARIA PHARMACOLOGY.
2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 9
Hydrogen bond donors 0
Rotatable bonds 15
Topological polar surface area 91.2
Molecular weight 750.43
XLogP 7.49
No. Lipinski's rules broken 2
SMILES / InChI / InChIKey
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Canonical SMILES N#Cc1ccc(cc1)CN1CCN(CC1)C(=O)[C@@H](N(C(=O)/C=C/c1ccc(cc1)C(C)(C)C)Cc1ccc(cc1)N1CCN(CC1)C(=O)C)Cc1ccccc1
Isomeric SMILES N#Cc1ccc(cc1)CN1CCN(CC1)C(=O)[C@@H](N(C(=O)/C=C/c1ccc(cc1)C(C)(C)C)Cc1ccc(cc1)N1CCN(CC1)C(=O)C)Cc1ccccc1
InChI InChI=1S/C47H54N6O3/c1-36(54)50-28-30-51(31-29-50)43-21-16-41(17-22-43)35-53(45(55)23-18-37-14-19-42(20-15-37)47(2,3)4)44(32-38-8-6-5-7-9-38)46(56)52-26-24-49(25-27-52)34-40-12-10-39(33-48)11-13-40/h5-23,44H,24-32,34-35H2,1-4H3/b23-18+/t44-/m0/s1
InChI Key BQZUYCCCNXOADJ-TVNMEPFQSA-N
References
1. Aissaoui H., Boss C., Corminboeuf O., Heidmann B., Siegrist R. (2011)
Piperazines as antimalarial agents.
Patent number: WO2011083413A1. Assignee: Actelion Pharmaceuticals Ltd.. Priority date: 05/01/2010. Publication date: 14/07/2011.
2. Boss C, Aissaoui H, Amaral N, Bauer A, Bazire S, Binkert C, Brun R, Bürki C, Ciana CL, Corminboeuf O et al.. (2016)
Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action.
ChemMedChem, 11 (18): 1995-2014. [PMID:27471138]
3. Bruderer S, Hurst N, de Kanter R, Miraval T, Pfeifer T, Donazzolo Y, Dingemanse J. (2015)
First-in-humans study of the safety, tolerability, and pharmacokinetics of ACT-451840, a new chemical entity with antimalarial activity.
Antimicrob. Agents Chemother., 59 (2): 935-42. [PMID:25421475]
4. Brunner R, Aissaoui H, Boss C, Bozdech Z, Brun R, Corminboeuf O, Delahaye S, Fischli C, Heidmann B, Kaiser M et al.. (2012)
Identification of a new chemical class of antimalarials.
J. Infect. Dis., 206 (5): 735-43. [PMID:22732921]
5. Brunner R, Ng CL, Aissaoui H, Akabas MH, Boss C, Brun R, Callaghan PS, Corminboeuf O, Fidock DA, Frame IJ et al.. (2013)
UV-triggered affinity capture identifies interactions between the Plasmodium falciparum multidrug resistance protein 1 (PfMDR1) and antimalarial agents in live parasitized cells.
J. Biol. Chem., 288 (31): 22576-83. [PMID:23754276]
6. Krause A, Dingemanse J, Mathis A, Marquart L, Möhrle JJ, McCarthy JS. (2016)
Pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of Actelion-451840 in an induced blood stage malaria study in healthy subjects.
Br J Clin Pharmacol, 82 (2): 412-21. [PMID:27062080]
7. Le Bihan A, de Kanter R, Angulo-Barturen I, Binkert C, Boss C, Brun R, Brunner R, Buchmann S, Burrows J, Dechering KJ et al.. (2016)
Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.
PLoS Med., 13 (10): e1002138. [PMID:27701420]
8. Ng CL, Siciliano G, Lee MC, de Almeida MJ, Corey VC, Bopp SE, Bertuccini L, Wittlin S, Kasdin RG, Le Bihan A et al.. (2016)
CRISPR-Cas9-modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs.
Mol. Microbiol., 101 (3): 381-93. [PMID:27073104]