2. Academic Validation
  3. Discovery of a potent and selective human AC2 inhibitor based on 7-deazapurine analogues of adefovir

Discovery of a potent and selective human AC2 inhibitor based on 7-deazapurine analogues of adefovir

  • Bioorg Med Chem. 2023 Nov 15:95:117508. doi: 10.1016/j.bmc.2023.117508.
Pavel Kraina 1,  Michal Česnek 2,  Eva Tloušťová 2,  Helena Mertlíková-Kaiserová 2,  Camryn J Fulton 3,  Emily K Davidson 3,  Brenton P Smith 3,  Val J Watts 4,  Zlatko Janeba 5
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 16000 Prague 6, Czech Republic; Department of Organic Chemistry, University of Chemistry and Technology Prague, 16628 Prague 6, Czech Republic.
  • 2 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 16000 Prague 6, Czech Republic.
  • 3 Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
  • 4 Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA. Electronic address: wattsv@purdue.edu.
  • 5 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 16000 Prague 6, Czech Republic. Electronic address: janeba@uochb.cas.cz.
PMID: 37931521 DOI: 10.1016/j.bmc.2023.117508
Abstract

Adefovir based acyclic nucleoside phosphonates were previously shown to modulate Bacterial and, to a certain extent, human adenylate cyclases (mACs). In this work, a series of 24 novel 7-substituted 7-deazaadefovir analogues were synthesized in the form of prodrugs. Twelve analogues were single-digit micromolar inhibitors of Bordetella pertussis Adenylate Cyclase toxin with no cytotoxicity to J774A.1 macrophages. In HEK293 cell-based assays, compound 14 was identified as a potent (IC50 = 4.45 μM), non-toxic, and selective mAC2 inhibitor (vs. mAC1 and mAC5). Such a compound represents a valuable addition to a limited number of small-molecule probes to study the biological functions of individual endogenous mAC isoforms.

Keywords

7-Deazapurine; Acyclic nucleoside phosphonates; Adefovir; Adenylate cyclase; Prodrugs.

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