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.

Borch Department of Medicinal Chemistry and Molecular Pharmacology College of Pharmacy Purdue University 575 Stadium Mall Drive West Lafayette IN 47907 USA

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences 16000 Prague 6 Czech Republic

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

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