A series of acyclic nucleoside phosphonates (ANPs) was designed as inhibitors of bacterial adenylate cyclases (ACs), where adenine was replaced with 2-amino-4-arylthiazoles. The target compounds were prepared using the halogen dance reaction. Final AC inhibitors were evaluated in cell-based assays (prodrugs) and cell-free assays (phosphono diphosphates). Novel ANPs were potent inhibitors of adenylate cyclase toxin (ACT) from Bordetella pertussis and edema factor (EF) from Bacillus anthracis, with substantial selectivity over mammalian enzymes AC1, AC2, and AC5. Six of the new ANPs were more potent or equipotent ACT inhibitors (IC50 =9-18 nM), and one of them was more potent EF inhibitor (IC50 =12 nM), compared to adefovir diphosphate (PMEApp) with IC50 =18 nM for ACT and IC50 =36 nM 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 IC50 =490 nM compared to IC50 =150 nM of the analogous adefovir phosphonodiamidate. The results suggest that more efficient type of phosphonate prodrugs would be desirable to increase concentrations of the ANP-based active species in the cells in order to proceed with the development of ANPs as potential antitoxin therapeutics.

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 Flemingovo nám 542 2 16000 Prague 6 Czech Republic

See more in PubMed

Gancedo JM, Biol. Rev 2013, 88, 645–668. PubMed

McKnight GS, Curr. Opin. Cell Biol 1991, 3, 213–217. PubMed

Hanoune J, Defer N, Annu. Rev. Pharmacol. Toxicol 2001, 41, 145–174. PubMed

Sunahara RK, Dessauer CW, Gilman AG, Annu. Rev. Pharmacol. Toxicol 1996, 36, 461–480. PubMed

Ahuja N, Kumar P, Bhatnagar R, Crit. Rev. Microbiol 2004, 30, 187–196. PubMed

Khannpnavar B, Mehta V, Qi C, Korkhov V, Curr. Opin. Struct. Biol 2020, 63, 34–41. PubMed

McDonough K, Rodriguez A, Nat. Rev. Microbiol 2012, 10, 27–38. PubMed PMC

Seifert R, Dove S, Trends Microbiol 2012, 20, 343–351. PubMed

Ivarsson ME, Leroux J-C, Castagner B, Angew. Chem. Int. Ed 2012, 51, 4024–4045. PubMed

Guo Q, Shen Y, Lee Y-S, Gibbs CS, Mrksich M, Tang W-J, EMBO J 2005, 24, 3190–3201. PubMed PMC

Shen Y, Zhukovskaya NL, Zimmer MI, Soelaiman S, Bergson P, Wang C-R, Gibbs CS, Tang W-J, Proc. Natl. Acad. Sci. USA 2004, 101, 3242–3247. PubMed PMC

Shoshani I, Laux WHG, Périgaud C, Gosselin G, Johnson RA, J. Biol. Chem 1999, 274, 34742–34744. PubMed

Česnek M, Jansa P, Šmídková M, Mertlíková-Kaiserová H, Dračínský M, Brust TF, Pávek P, Tretnar F, Watts VJ, Janeba Z, ChemMedChem 2015, 10, 1351–1364. PubMed

Česnek M, Skácel J, Jansa P, Dračínský M, Šmídková M, Mertlíková-Kaiserová H, Soto-Velasquez MP, Watts VJ, Janeba Z, ChemMedChem 2018, 13, 1779–1796. PubMed PMC

Břehová P, Šmídková M, Skácel J, Dračínský M, Mertlíková-Kaiserová H, Soto-Velasquez MP, Watts VJ, Janeba Z, ChemMedChem 2016, 11, 2534–2546. PubMed PMC

Frydrych J, Skácel J, Šmídková M, Mertlíková-Kaiserová H, Dračínský M, Gnanasekaran R, Lepšík M, Soto-Velasquez M, Watts VJ, Janeba Z, ChemMedChem 2018, 13, 199–206. PubMed

Břehová P, Chaloupecká E, Česnek M, Skácel J, Dračínský M, Tloušťová E, Mertlíková-Kaiserová H, Soto-Velasquez MP, Watts VJ, Janeba Z, European J Med. Chem 2021, 222, 113581. PubMed PMC

Erion MD, van Poelje PD, Dang Q, Kasibhatla SR, Potter SC, Reddy MR, Reddy KR, Jiang T, Lipscomb WN, PNAS 2005, 102, 7970–7975. PubMed PMC

Dang Q, Kasibhatla SR, Reddy KR, Jiang T, Reddy MR, Potter SC, Fujitaki JM, van Poelje PD, Huang J, Lipscomb WN, Erion MD, J. Am. Chem. Soc 2007, 129, 15491–15502. PubMed

Dang Q, Kasibhatla SR, Jiang T, Fan K, Liu Y, Taplin F, Schulz W, Cashion DK, Reddy KR, van Poelje PD, Fujitaki JM, Potter SC, Erion MD, J. Med. Chem 2008, 51, 4331–4339. PubMed

Dang Q, Liu Y, Cashion DK, Kasibhatla SR, Jiang T, Taplin F, Jacintho JD, Li H, Sun Z, Fan Y, Da Re J, Tian F, Li W, Gibson T, Lemus R, van Poelje PD, Potter SC, Erion MD, J. Med. Chem 2011, 54, 153–165. PubMed

Pradere U, Garnier-Amblard EC, Coats SJ, Amblard F, Schinazi RF, Chem. Rev 2014, 114, 9154–9218. PubMed PMC

Wiemer AJ, Wiemer DF, Top. Curr. Chem 2015, 360, 115–160. PubMed PMC

Heidel KM, Dowd CS, Future Med. Chem 2019, 11, 1625–1643. PubMed PMC

Šmídková M, Dvořáková A, Tloušťová E, Česnek M, Janeba Z, Mertlíková-Kaiserová H, Antimicrob. Agents Chemother 2014, 58, 664–671. PubMed PMC

Guianvarc’h D, Fourrey J-L, Maurisse R, Sun J-S, Benhida R, Org. Lett 2002, 4, 4209–4212. PubMed

Schnürch M, Spina M, Khan AF, Mihovilovic MD, Stanetty P, Chem. Soc. Rev 2007, 36, 1046–1057. PubMed

Stanetty P, Schnürch M, Mereiter K, Mihovilovic MD, J. Org. Chem 2005, 70, 567–574. PubMed

Schnürch M, Khan AF, Mihovilovic MD, Stanetty P, Eur. J. Org. Chem 2009, 19, 3228–3236.

Jansa P, Baszczyňski O, Dračínský M, Votruba I, Zídek Z, Bahador G, Stepan G, Cihlar T, Mackman R, Holý A, Janeba Z, Eur. J. Med. Chem 2011, 46, 3748–3754. PubMed

Holý A, Rosenberg I, Collect. Czech. Chem. Commun 1987, 52, 2801–2809.

Slusarczyk M, Ferrari V, Serpi M, Gönczy B, Balzarini J, McGuigan C, ChemMedChem 2018, 13, 2305–2316. PubMed

Slusarczyk M, Serpi M, Pertusati F, Antivir. Chem. Chemother 2018, 26, 1–31. PubMed PMC

Procházková E, Navrátil R, Janeba Z, Roithová J, Baszczyňski O, Org. Biomol. Chem 2019, 17, 315–320. PubMed

Soto-Velasquez M, Hayes MP, Alpsoy A, Dykhuizen EC, Watts VJ, Mol Pharmacol 2018, 94, 963–972. PubMed PMC

Brust TF, Alongkronrusmee D, Soto-Velasquez M, Baldwin TA, Ye Z, Dai M, Dessauer CW, van Rijn RM, Watts VJ, Sci. Signaling 2017, 10, eaah5381. PubMed PMC

Conley JM, Brand CS, Bogard AS, Pratt EP, Xu R, Hockerman GH, Ostrom R, Dessauer CW, Watts VJ, J. Pharmacol. Exp. Ther 2013, 347, 276–287. PubMed PMC

Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects