2-Aminoquinazolin-4(3H)-one based plasmepsin inhibitors with improved hydrophilicity and selectivity.

Autor: Rasina D; Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia., Stakanovs G; Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia., Borysov OV; Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia., Pantelejevs T; Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia., Bobrovs R; Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia., Kanepe-Lapsa I; Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia., Tars K; Biomedical Research and Study Centre, Ratsupites 1, Riga LV-1067, Latvia., Jaudzems K; Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia., Jirgensons A; Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia. Electronic address: aigars@osi.lv.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 May 15; Vol. 26 (9), pp. 2488-2500. Date of Electronic Publication: 2018 Apr 05.
DOI: 10.1016/j.bmc.2018.04.012
Abstrakt: 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 (R 1 ) the 5-position of 2-aminoquinazolin-4(3H)-one to inhibitors such as carboxylic acid without scarifying enzymatic potency. Moreover, introduction of R 1 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 (R 2 ) 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.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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