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Publikācija: 2-Aminoquinazolin-4(3H)-One Based Plasmepsin Inhibitors with Improved Hydrophilicity and Selectivity

Publication Type Scientific article indexed in SCOPUS or WOS database
Funding for basic activity EU Structural Funds
Defending: ,
Publication language English (en)
Title in original language 2-Aminoquinazolin-4(3H)-One Based Plasmepsin Inhibitors with Improved Hydrophilicity and Selectivity
Field of research 1. Natural sciences
Sub-field of research 1.4 Chemical sciences
Authors D. Rasiņa
G. Stakanovs
O.V. Borysov
T. Pantelejevs
R. Bobrovs
I. Kanepe-Lapsa
K. Tars
Kristaps Jaudzems
Aigars Jirgensons
Keywords 2-Aminoquinazolin-4(3H)-ones, Cathepsin D, Inhibitors, Malaria, Plasmepsins, Plasmodium falciparum
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 R1substituents 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.
DOI: 10.1016/j.bmc.2018.04.012
Hyperlink: https://www.sciencedirect.com/science/article/pii/S0968089618304012?via%3Dihub 
Reference Rasiņa, D., Stakanovs, G., Borysov, O., Pantelejevs, T., Bobrovs, R., Kanepe-Lapsa, I., Tars, K., Jaudzems, K., Jirgensons, A. 2-Aminoquinazolin-4(3H)-One Based Plasmepsin Inhibitors with Improved Hydrophilicity and Selectivity. Bioorganic and Medicinal Chemistry, 2018, Vol.26, Iss.9, pp.2488-2500. ISSN 0968-0896. Available from: doi:10.1016/j.bmc.2018.04.012
Additional information Citation count:
ID 28472