Synthesis of α‐Branched Acyclic Nucleoside Phosphonates as Potential Inhibitors of Bacterial Adenylate Cyclases

Abstract

Inhibition of Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF), key virulence factors with adenylate cyclase activity, represents a potential method for treating or preventing toxemia related to whooping cough and anthrax, respectively. Novel α‐branched acyclic nucleoside phosphonates (ANPs) having a hemiaminal ether moiety were synthesized as potential inhibitors of bacterial adenylate cyclases. ANPs prepared as bisamidates were not cytotoxic, but did not exhibit any profound activity (IC50>10 μm) toward ACT in J774A.1 macrophages. The apparent lack of activity of the bisamidates is speculated to be due to the inefficient formation of the biologically active species (ANPpp) in the cells. Conversely, two 5‐haloanthraniloyl‐substituted ANPs in the form of diphosphates were shown to be potent ACT and EF inhibitors with IC50 values ranging from 55 to 362 nm.

Nucleobase Modified Adefovir (PMEA) Analogues as Potent and Selective Inhibitors of Adenylate Cyclases from Bordetella pertussis and Bacillus anthracis

“…Molecular modelling of the most potent inhibitor for all studied bacterial adenylate cyclases, 7-deaza-PMEApp ( 40a ), was performed using the recently reinterpreted 57 crystal structure of adenylate cyclase domain (ACD) from B. pertussis ACT with calmodulin (CaM) and PMEApp (PDB ID:1ZOT). 41 The docking revealed almost identical binding mode for both PMEApp ( II ) and compound 40a (Fig.…”

“…Recently reinterpreted 57 crystal structure of adenylate cyclase domain (ACD) from Bordetella pertussis adenylate cyclase toxin (ACT) with calmodulin (CaM) and bound PMEApp (PDB ID:1ZOT, resolution 2.2 Å) 41 was used for molecular modelling study. The pre-processed protein was prepared with MOE Structure Preparation and Protonate 3D tools with the default setup.…”

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

“…[12] Subsequently, an extensive structure-activity relationship study was performed with structurally modified adefovir (PMEA) analogues as inhibitors of bacterial adenylate cyclase toxins: the SAR study covered adefovir derivatives modified either at the nucleobase [13,14] or at the aliphatic moiety. [15,16] Some of the compounds also exhibited an ability to selectively modulate mammalian ACs (especially AC1), with an anticipated potential for development of non-opioid alternatives for the treatment of inflammatory and neuropathic pain. [14] It has been recently reported, [17] that the adenine moiety in adefovir could be replaced by another heterocycle that is able to mimic the adenine nucleobase, namely 2-aminothiazole, leading to compounds II (Figure 2).…”