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
Click here for help

2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

✖
Click here for structure editor
Physico-chemical Properties
Click here for help

Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

✖
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
Click here for help

SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

✖
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]