2. Academic Validation
  3. 2,6-Disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines as a new class of potent antitubercular agents inhibiting DprE1

2,6-Disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines as a new class of potent antitubercular agents inhibiting DprE1

  • Eur J Med Chem. 2023 Oct 5;258:115611. doi: 10.1016/j.ejmech.2023.115611.
Vladimir Finger 1,  Tomas Kucera 2,  Radka Kafkova 3,  Lubica Muckova 4,  Rafael Dolezal 5,  Jan Kubes 6,  Martin Novak 1,  Lukas Prchal 5,  Levente Lakatos 7,  Martin Andrs 5,  Michaela Hympanova 4,  Jan Marek 4,  Martin Kufa 1,  Vojtech Spiwok 8,  Ondrej Soukup 5,  Eva Mezeiova 5,  Jiri Janousek 5,  Lenka Nevosadova 6,  Marketa Benkova 5,  Russell R A Kitson 6,  Martin Kratky 6,  Szilvia Bősze 7,  Katarina Mikusova 3,  Ruben Hartkoorn 9,  Jaroslav Roh 10,  Jan Korabecny 11
Affiliations

Affiliations

  • 1 Faculty of Pharmacy in Hradec Králové, Charles University, Akademika, Heyrovskeho 1203, 50005, Hradec Králové, Czech Republic; Biomedical Research Center, University Hospital Hradec Králové, Sokolska 581, 500 05, Hradec Králové, Czech Republic.
  • 2 Faculty of Military Health Sciences, University of Defence, Trebesska, 1575, 500 01, Hradec Králové, Czech Republic.
  • 3 Faculty of Natural Sciences, Department of Biochemistry, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 842 15, Bratislava, Slovakia.
  • 4 Biomedical Research Center, University Hospital Hradec Králové, Sokolska 581, 500 05, Hradec Králové, Czech Republic; Faculty of Military Health Sciences, University of Defence, Trebesska, 1575, 500 01, Hradec Králové, Czech Republic.
  • 5 Biomedical Research Center, University Hospital Hradec Králové, Sokolska 581, 500 05, Hradec Králové, Czech Republic.
  • 6 Faculty of Pharmacy in Hradec Králové, Charles University, Akademika, Heyrovskeho 1203, 50005, Hradec Králové, Czech Republic.
  • 7 ELKH-ELTE Research Group of Peptide Chemistry, Eötvös Loránd University, Pázmány Péter Sétány 1/A, H-1117, Budapest, Hungary; National Public Health Center, Albert Flórián út 2-6, Budapest, 1097, Hungary.
  • 8 Department of Biochemistry and Microbiology, University of Chemistry and Technology, Technicka 5, 166 28, Prague, Czech Republic.
  • 9 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000, Lille, France.
  • 10 Faculty of Pharmacy in Hradec Králové, Charles University, Akademika, Heyrovskeho 1203, 50005, Hradec Králové, Czech Republic. Electronic address: jaroslav.roh@faf.cuni.cz.
  • 11 Biomedical Research Center, University Hospital Hradec Králové, Sokolska 581, 500 05, Hradec Králové, Czech Republic. Electronic address: jan.korabecny@fnhk.cz.
PMID: 37421887 DOI: 10.1016/j.ejmech.2023.115611
Abstract

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-β-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.

Keywords

DprE1; Mycobacterium tuberculosis; Purine; Structure-activity relationships; Tuberculosis.

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