Halogen-Dance-Based Synthesis of Phosphonomethoxyethyl (PME) Substituted 2-Aminothiazoles as Potent Inhibitors of Bacterial Adenylate Cyclases
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F22%3A00551643" target="_blank" >RIV/61388963:_____/22:00551643 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.1002/cmdc.202100568" target="_blank" >https://doi.org/10.1002/cmdc.202100568</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/cmdc.202100568" target="_blank" >10.1002/cmdc.202100568</a>
Alternative languages
Result language
angličtina
Original language name
Halogen-Dance-Based Synthesis of Phosphonomethoxyethyl (PME) Substituted 2-Aminothiazoles as Potent Inhibitors of Bacterial Adenylate Cyclases
Original language description
A series of acyclic nucleoside phosphonates (ANPs) was designed as inhibitors of bacterial adenylate cyclases (ACs), where adenine was replaced with 2-amino-4-arylthiazoles. The target compounds were prepared using the halogen dance reaction. Final AC inhibitors were evaluated in cell-based assays (prodrugs) and cell-free assays (phosphono diphosphates). Novel ANPs were potent inhibitors of adenylate cyclase toxin (ACT) from Bordetella pertussis and edema factor (EF) from Bacillus anthracis, with substantial selectivity over mammalian enzymes AC1, AC2, and AC5. Six of the new ANPs were more potent or equipotent ACT inhibitors (IC50=9–18 nM), and one of them was more potent EF inhibitor (IC50=12 nM), compared to adefovir diphosphate (PMEApp) with IC50=18 nM for ACT and IC50=36 nM for EF. Thus, these compounds represent the most potent ACT/EF inhibitors based on ANPs reported to date. The potency of the phosphonodiamidates to inhibit ACT activity in J774A.1 macrophage cells was somewhat weaker, where the most potent derivative had IC50=490 nM compared to IC50=150 nM of the analogous adefovir phosphonodiamidate. The results suggest that more efficient type of phosphonate prodrugs would be desirable to increase concentrations of the ANP-based active species in the cells in order to proceed with the development of ANPs as potential antitoxin therapeutics.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10401 - Organic chemistry
Result continuities
Project
<a href="/en/project/LTAUSA18086" target="_blank" >LTAUSA18086: Design, synthesis and biological evaluation of potential modulators of human adenylate cyclases</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
ChemMedChem
ISSN
1860-7179
e-ISSN
1860-7187
Volume of the periodical
17
Issue of the periodical within the volume
1
Country of publishing house
DE - GERMANY
Number of pages
13
Pages from-to
e202100568
UT code for WoS article
000709901300001
EID of the result in the Scopus database
2-s2.0-85117435638