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There is an urgent need to develop potent and selective inhibitors of bacterial ACs with prospects for the development of potential antibacterial therapeutics and to study their molecular interactions with the target enzymes. Novel fluorescent 5\u2010chloroanthraniloyl\u2010substituted acyclic nucleoside phosphonates (Cl\u2010ANT\u2010ANPs) were designed and synthesized in the form of their diphosphates (Cl\u2010ANT\u2010ANPpp) as competitive ACT and EF inhibitors with sub\u2010micromolar potency (IC<jats:sub>50<\/jats:sub> values: 11\u2013622\u2005n<jats:sc>m<\/jats:sc>). Fluorescence experiments indicated that Cl\u2010ANT\u2010ANPpp analogues bind to the ACT active site, and docking studies suggested that the Cl\u2010ANT group interacts with Phe306 and Leu60. Interestingly, the increase in direct fluorescence with Cl\u2010ANT\u2010ANPpp having an ester linker was strictly calmodulin (CaM)\u2010dependent, whereas Cl\u2010ANT\u2010ANPpp analogues with an amide linker, upon binding to ACT, increased the fluorescence even in the absence of CaM. Such a dependence of binding on structural modification could be exploited in the future design of potent inhibitors of bacterial ACs. Furthermore, one Cl\u2010ANT\u2010ANP in the form of a bisamidate prodrug was able to inhibit <jats:italic>B.\u2005pertussis<\/jats:italic> ACT activity in macrophage cells with IC<jats:sub>50<\/jats:sub>=12\u2005\u03bc<jats:sc>m<\/jats:sc>.<\/jats:p>","DOI":"10.1002\/cmdc.201600439","type":"journal-article","created":{"date-parts":[[2016,10,24]],"date-time":"2016-10-24T05:54:38Z","timestamp":1477288478000},"page":"2534-2546","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Design and Synthesis of Fluorescent Acyclic Nucleoside Phosphonates as Potent Inhibitors of Bacterial Adenylate Cyclases"],"prefix":"10.1002","volume":"11","author":[{"given":"Petra","family":"B\u0159ehov\u00e1","sequence":"first","affiliation":[{"name":"The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m.\u20052 166\u200510 Prague 6 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark\u00e9ta","family":"\u0160m\u00eddkov\u00e1","sequence":"additional","affiliation":[{"name":"The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m.\u20052 166\u200510 Prague 6 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Sk\u00e1cel","sequence":"additional","affiliation":[{"name":"The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m.\u20052 166\u200510 Prague 6 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Dra\u010d\u00ednsk\u00fd","sequence":"additional","affiliation":[{"name":"The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m.\u20052 166\u200510 Prague 6 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Mertl\u00edkov\u00e1\u2010Kaiserov\u00e1","sequence":"additional","affiliation":[{"name":"The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m.\u20052 166\u200510 Prague 6 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica P. 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