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2-Aminoquinazolin-4(3H)-one based plasmepsin inhibitors with improved hydrophilicity and selectivity
- Source :
- Bioorganicmedicinal chemistry. 26(9)
- Publication Year :
- 2018
-
Abstract
- 2-Aminoquinazolin-4(3H)-ones were previously discovered as perspective leads for antimalarial drug development targeting the plasmepsins. Here we report the lead optimization studies with the aim to reduce inhibitor lipophilicity and increase selectivity versus the human aspartic protease Cathepsin D. Exploiting the solvent exposed area of the enzyme provides an option to install polar groups (R1) the 5-position of 2-aminoquinazolin-4(3H)-one to inhibitors such as carboxylic acid without scarifying enzymatic potency. Moreover, introduction of R1 substituents increased selectivity factors of compounds in this series up to 100-fold for Plm II, IV vs CatD inhibition. The introduction of flap pocket substituent (R2) at 7-postion of 2-aminoquinazolin-4(3H)-one allows to remove Ph group from THF ring without notably impairing Plm inhibitory potency. Based on these findings, inhibitors were developed, which show Plm II and IV inhibitory potency in low nanomolar range and remarkable selectivity against Cathepsin D along with decreased lipophilicity and increased solubility.
- Subjects :
- 0301 basic medicine
Carboxylic acid
Clinical Biochemistry
Plasmodium falciparum
Substituent
Plasmepsin
Protozoan Proteins
Pharmaceutical Science
Cathepsin D
Molecular Dynamics Simulation
01 natural sciences
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
Drug Discovery
Potency
Aspartic Acid Endopeptidases
Protease Inhibitors
Molecular Biology
Quinazolinones
Cathepsin
chemistry.chemical_classification
Binding Sites
Molecular Structure
010405 organic chemistry
Organic Chemistry
Combinatorial chemistry
0104 chemical sciences
Molecular Docking Simulation
030104 developmental biology
chemistry
Solubility
Lipophilicity
Molecular Medicine
Selectivity
Hydrophobic and Hydrophilic Interactions
Subjects
Details
- ISSN :
- 14643391
- Volume :
- 26
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry
- Accession number :
- edsair.doi.dedup.....2b597d7efb08386fc8baa6ae03ec8ac7