Halogen‐Dance‐Based Synthesis of Phosphonomethoxyethyl (PME) Substituted 2‐Aminothiazoles as Potent Inhibitors of Bacterial Adenylate Cyclases

Abstract

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 (IC 50 = 9-18 nM), and one of them was more potent EF inhibitor (IC 50 = 12 nM), compared to adefovir diphosphate (PMEApp) with IC 50 = 18 nM for ACT and IC 50 = 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 IC 50 = 490 nM compared to IC 50 = 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.

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

“…Extraordinary effect to ACT inhibitory potency has replacement of the adenine moiety with another heterocyclic base able to mimic adenine, namely 2-aminothiazole. These compounds are 5-aryl-4-PME-2-aminothiazoles, 4-aryl-5-PME-2-aminothiazoles and their bis(amidate)prodrugs and phosphono diphosphate analogues ( Břehová et al, 2021 ; Česnek at al., 2022 ). The most potent inhibitor was diphosphate of 4-(4-(benzylcarbamoyl)phenyl-5-PME-2-aminothiazole ( Figure 7 ).…”