2-Aminoquinazolin-4(3H)-one based plasmepsin inhibitors with improved hydrophilicity and selectivity
| Autor: | Iveta Kanepe-Lapsa, Kristaps Jaudzems, Dace Rasina, Aigars Jirgensons, Oleksandr V. Borysov, Teodors Pantelejevs, Raitis Bobrovs, Georgijs Stakanovs, Kaspars Tars |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
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 |
| Zdroj: | Bioorganicmedicinal chemistry. 26(9) |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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