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
  • 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: [email protected].
  • 5. Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 16000 Prague 6, Czech Republic. Electronic address: [email protected].
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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