Synthesis, biological evaluation and molecular modeling of urea-containing MraY inhibitors

Abstract

The straightforward synthesis of aminoribosyl uridines substituted by a 5’-methylene-urea is described. Their convergent synthesis involves the urea formation from various activated amides and an azidoribosyl uridine substituted at the...

A Sub-Micromolar MraYAA Inhibitor with an Aminoribosyl Uridine Structure and a (S,S)-Tartaric Diamide: Synthesis, Biological Evaluation and Molecular Modeling

“…Hits bind to hotspots (HSs) of MraY that were identified by Chung et al [ 31 ] by following two modes (one in 5CKR and one in 6OYH), as previously observed for the urea 13 [ 32 ].…”

“…The inhibitory activity of the synthesized compounds 2 , ( S , S )- 3a , ( R , R )- 3b , 4 and 5 was evaluated on MraY transferase purified from Aquifex aeolicu s (MraY AA ), which was prepared as previously described by Chung et al [ 39 ]. Their activity was compared to the inhibitory activity of the unprotected amino precursor 12 , urea-containing inhibitor 13 and C - and N -triazole-containing inhibitors 14 and 15 ( Figure 4 ) that we previously synthesized [ 29 , 32 ] ( Table 1 ). Commercially available tunicamycin from Streptomyces sp.…”

“…Indeed, we previously reported that the urea 13 with a C10 alkyl chain does not display antibacterial activity, since it is probably not able to cross the cytoplasmic membrane to reach its target. Our previous data on differently substituted urea [ 32 ] suggested that a linear chain of at least 12 carbon atoms, or a branched substituent, is required to show antibacterial activity. Therefore, further optimization of the lipophilic side chain is still required to increase the antibacterial activity by modulating the lipophilicity of the molecule.…”

“…However, the docking of these triazole-containing inhibitors in either the 5CKR [ 30 ] or 6OYH [ 31 ] structural models revealed no significant interactions of the triazole with aminoacids of the MraY active site. We then focused on the synthesis of urea-containing compounds [ 32 ] with various substituents ( Figure 2 B), and the most active inhibitor (IC 50 equal to 1.9 µM) was the one bearing a decyl chain. Molecular dynamics experiments showed that the urea linker could interact with H324 and H325 ( Figure 2 B), but that this interaction was not stable [ 32 ].…”

“…We then focused on the synthesis of urea-containing compounds [ 32 ] with various substituents ( Figure 2 B), and the most active inhibitor (IC 50 equal to 1.9 µM) was the one bearing a decyl chain. Molecular dynamics experiments showed that the urea linker could interact with H324 and H325 ( Figure 2 B), but that this interaction was not stable [ 32 ]. This result prompted us to study the effect of other linkers ( Figure 2 C) that are able to interact by hydrogen bonds with key residues of the MraY active site [ 31 ], notably H324 and H325, in order to improve their potency compared to that of the urea-containing compounds.…”