{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T10:17:25Z","timestamp":1770459445707,"version":"3.49.0"},"reference-count":38,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T00:00:00Z","timestamp":1634860800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2022,1,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A series of acyclic nucleoside phosphonates (ANPs) was designed as inhibitors of bacterial adenylate cyclases (ACs), where adenine was replaced with 2\u2010amino\u20104\u2010arylthiazoles. The target compounds were prepared using the halogen dance reaction. Final AC inhibitors were evaluated in cell\u2010based assays (prodrugs) and cell\u2010free assays (phosphono diphosphates). Novel ANPs were potent inhibitors of adenylate cyclase toxin (ACT) from <jats:italic>Bordetella pertussis<\/jats:italic> and edema factor (EF) from <jats:italic>Bacillus anthracis<\/jats:italic>, with substantial selectivity over mammalian enzymes AC1, AC2, and AC5. Six of the new ANPs were more potent or equipotent ACT inhibitors (IC<jats:sub>50<\/jats:sub>=9\u201318\u2005nM), and one of them was more potent EF inhibitor (IC<jats:sub>50<\/jats:sub>=12\u2005nM), compared to adefovir diphosphate (PMEApp) with IC<jats:sub>50<\/jats:sub>=18\u2005nM for ACT and IC<jats:sub>50<\/jats:sub>=36\u2005nM for EF. Thus, these compounds represent the most potent ACT\/EF inhibitors based on ANPs reported to date. The potency of the phosphonodiamidates to inhibit ACT activity in J774A.1 macrophage cells was somewhat weaker, where the most potent derivative had IC<jats:sub>50<\/jats:sub>=490\u2005nM compared to IC<jats:sub>50<\/jats:sub>=150\u2005nM of the analogous adefovir phosphonodiamidate. The results suggest that more efficient type of phosphonate prodrugs would be desirable to increase concentrations of the ANP\u2010based active species in the cells in order to proceed with the development of ANPs as potential antitoxin therapeutics.<\/jats:p>","DOI":"10.1002\/cmdc.202100568","type":"journal-article","created":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T06:56:14Z","timestamp":1634021774000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Halogen\u2010Dance\u2010Based Synthesis of Phosphonomethoxyethyl (PME) Substituted 2\u2010Aminothiazoles as Potent Inhibitors of Bacterial Adenylate Cyclases"],"prefix":"10.1002","volume":"17","author":[{"given":"Michal","family":"\u010cesnek","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m. 542\/2 16000 Prague 6 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"\u0160afr\u00e1nek","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m. 542\/2 16000 Prague 6 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4495-0070","authenticated-orcid":false,"given":"Martin","family":"Dra\u010d\u00ednsk\u00fd","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m. 542\/2 16000 Prague 6 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Tlou\u0161\u0165ov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m. 542\/2 16000 Prague 6 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Mertl\u00edkov\u00e1\u2010Kaiserov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m. 542\/2 16000 Prague 6 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael P.","family":"Hayes","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology College of Pharmacy Purdue University  575 Stadium Mall Drive West Lafayette IN, 47907 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1581-2936","authenticated-orcid":false,"given":"Val J.","family":"Watts","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology College of Pharmacy Purdue University  575 Stadium Mall Drive West Lafayette IN, 47907 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4654-679X","authenticated-orcid":false,"given":"Zlatko","family":"Janeba","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m. 542\/2 16000 Prague 6 Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,10,22]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1111\/brv.12020"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0955-0674(91)90141-K"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.41.1.145"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.36.040196.002333"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408410490468795"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2020.03.003"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2688"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2012.04.002"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201104384"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201104384"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600800"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0306552101"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.49.34742"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201500183"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201800332"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201600439"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201700715"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113581"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502983102"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja074871l"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm8001235"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm101035x"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr5002035"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/128_2014_561"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc-2018-0591"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01685-13"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol026609h"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1039\/B607701N"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo0484326"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.200900092"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2011.05.040"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1135\/cccc19872801"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201800504"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1177\/2040206618775243"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8OB02870B"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.118.111849"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aah5381"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.113.207449"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202100568","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.202100568","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202100568","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T19:07:35Z","timestamp":1760296055000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202100568"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,22]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,1,5]]}},"alternative-id":["10.1002\/cmdc.202100568"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202100568","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,22]]},"assertion":[{"value":"2021-08-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-10-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202100568"}}