2,6-Disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines as a new class of potent antitubercular agents inhibiting DprE1
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F23%3A10465555" target="_blank" >RIV/00216208:11160/23:10465555 - isvavai.cz</a>
Alternative codes found
RIV/60162694:G44__/24:00560287 RIV/60461373:22330/23:43927857 RIV/00179906:_____/23:10465555
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=xB1lCkuz71" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=xB1lCkuz71</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejmech.2023.115611" target="_blank" >10.1016/j.ejmech.2023.115611</a>
Alternative languages
Result language
angličtina
Original language name
2,6-Disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines as a new class of potent antitubercular agents inhibiting DprE1
Original language description
Phenotypic screening of an in-house library of small molecule purine derivatives against Mycobacterium tuberculosis (Mtb) led to the identification of 2-morpholino-7-(naphthalen-2-ylmethyl)-1,7-dihydro-6H-purin-6-one 10 as a potent antimycobacterial agent with MIC99 of 4 µM. Thorough structure-activity relationship studies revealed the importance of 7-(naphthalen-2-ylmethyl) substitution for antimycobacterial activity, yet opened the possibility of structural modifications at positions 2 and 6 of the purine core. As the result, optimized analogues with 6-amino or ethylamino substitution 56 and 64, respectively, were developed. These compounds showed strong in vitro antimycobacterial activity with MIC of 1 µM against Mtb H37Rv and against several clinically isolated drug-resistant strains, had limited toxicity to mammalian cell lines, medium clearance with respect to phase I metabolic deactivation (27 and 16.8 µL/min/mg), sufficient aqueous solubility (>90 µM) and high plasma stability. Interestingly, investigated purines, including compounds 56 and 64, lacked activity against a panel of Gram-negative and Gram-positive bacterial strains, indicating a specific mycobacterial molecular target. To investigate the mechanism of action, Mtb mutants resistant to hit compound 10 were isolated and their genomes were sequenced. Mutations were found in dprE1 (Rv3790), which encodes decaprenylphosphoryl-beta-D-ribose oxidase DprE1, enzyme essential for the biosynthesis of arabinose, a vital component of the mycobacterial cell wall. Inhibition of DprE1 by 2,6-disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines was proved using radiolabelling experiments in Mtb H37Rv in vitro. Finally, structure-binding relationships between selected purines and DprE1 using molecular modeling studies in tandem with molecular dynamic simulations revealed the key structural features for effective drug-target interaction.
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
30104 - Pharmacology and pharmacy
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
European Journal of Medicinal Chemistry
ISSN
0223-5234
e-ISSN
1768-3254
Volume of the periodical
258
Issue of the periodical within the volume
October
Country of publishing house
FR - FRANCE
Number of pages
26
Pages from-to
115611
UT code for WoS article
001041021000001
EID of the result in the Scopus database
2-s2.0-85165144703