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

Bioorg Med Chem. 2023 Oct 26;95:117508. doi: 10.1016/j.bmc.2023.117508. Online ahead of print.ABSTRACTAdefovir 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.PMID:37931521 | DOI:10.1016/j.bmc.2023.117508

Source: Bioorganic and Medicinal Chemistry - November 6, 2023 Category: Chemistry Authors: Pavel Kraina Michal Česnek Eva Tlou šťová Helena Mertl íková-Kaiserová Camryn J Fulton Emily K Davidson Brenton P Smith Val J Watts Zlatko Janeba Source Type: research