Acyclic nucleoside phosphonates with 2-aminothiazole base as inhibitors of bacterial and mammalian adenylate cyclases

0543267 - ÚOCHB 2022 RIV FR eng J - Článek v odborném periodiku
Břehová, Petra - Chaloupecká, Ema - Česnek, Michal - Skácel, Jan - Dračínský, Martin - Tloušťová, Eva - Mertlíková-Kaiserová, Helena - Soto-Velasquez, M. P. - Watts, V. J. - Janeba, Zlatko
Acyclic nucleoside phosphonates with 2-aminothiazole base as inhibitors of bacterial and mammalian adenylate cyclases.
European Journal of Medicinal Chemistry. Roč. 222, Oct 15 (2021), č. článku 113581. ISSN 0223-5234. E-ISSN 1768-3254
Grant CEP: GA MŠMT LTAUSA18086
Institucionální podpora: RVO:61388963
Klíčová slova: acyclic nucleoside phosphonates * adefovir * adenylate cyclase * Bacillus anthracis * Bordetella pertussis * inhibitors * prodrugs
Obor OECD: Organic chemistry
Impakt faktor: 7.088, rok: 2021
Způsob publikování: Omezený přístup
https://doi.org/10.1016/j.ejmech.2021.113581

A series of novel acyclic nucleoside phosphonates (ANPs) was synthesized as potential adenylate cyclase inhibitors, where the adenine nucleobase of adefovir (PMEA) was replaced with a 5-substituted 2-aminothiazole moiety. The design was based on the structure of MB05032, a potent and selective inhibitor of fructose 1,6-bisphosphatase and a good mimic of adenosine monophosphate (AMP). From the series of eighteen novel ANPs, which were prepared as phosphoroamidate prodrugs, fourteen compounds were potent (single digit micromolar or submicromolar) inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT), mostly without observed cytotoxicity in J774A.1 macrophage cells. Selected phosphono diphosphates (nucleoside triphosphate analogues) were potent inhibitors of ACT (IC50 as low as 37 nM) and B. anthracis edema factor (IC50 as low as 235 nM) in enzymatic assays. Furthermore, several ANPs were found to be selective mammalian AC1 inhibitors in HEK293 cell-based assays (although with some associated cytotoxicity) and one compound exhibited selective inhibition of mammalian AC2 (only 12% of remaining adenylate cyclase activity) but no observed cytotoxicity. The mammalian AC1 inhibitors may represent potential leads in development of agents for treatment of human inflammatory and neuropathic pain.
Trvalý link: http://hdl.handle.net/11104/0320504