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

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Publikācijas valoda English (en)
Nosaukums oriģinālvalodā 2-Aminoquinazolin-4(3H)-One Based Plasmepsin Inhibitors with Improved Hydrophilicity and Selectivity
Pētniecības nozare 1. Dabaszinātnes
Pētniecības apakšnozare 1.4. Ķīmija
Autori D. Rasiņa
G. Stakanovs
O.V. Borysov
T. Pantelejevs
R. Bobrovs
I. Kanepe-Lapsa
K. Tars
Kristaps Jaudzems
Aigars Jirgensons
Atslēgas vārdi 2-Aminoquinazolin-4(3H)-ones, Cathepsin D, Inhibitors, Malaria, Plasmepsins, Plasmodium falciparum
Anotācija 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
Hipersaite: https://www.sciencedirect.com/science/article/pii/S0968089618304012?via%3Dihub 
Atsauce 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, 2488.-2500.lpp. ISSN 0968-0896. Pieejams: doi:10.1016/j.bmc.2018.04.012
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