5′-Methylene-triazole-substituted-aminoribosyl uridines as MraY inhibitors: synthesis, biological evaluation and molecular modeling

Abstract

The straightforward synthesis of 5'-methylene-[1,4]-triazole-substituted aminoribosyl uridines is described. Two families of compounds were synthesized from a unique epoxide which was regioselectively opened by acetylide ions (for compounds II) or azide ions (for compounds III). Sequential diastereoselective glycosylation with a ribosyl fluoride derivative, Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with various complementary azide and alkyne partners afforded the targeted compounds after final deprotection. The biological activity of the 16 resulting compounds together with that of 14 previously reported compounds I, lacking the 5' methylene group, was evaluated on the MraY transferase activity. Out of the 30 tested compounds, 18 compounds revealed MraY inhibition with IC 50 ranging from 15 to 150 µM. A molecular modeling study was performed to rationalize the observed structure-activity relationships (SAR), which allowed us to correlate the activity of the most potent compounds with an interaction involving Leu191 of MraY AA . The antibacterial activity was also evaluated and seven compounds exhibited a good activity against Gram-positive bacterial pathogens with MIC ranging from 8 to 32 µg mL −1

Improving the N-terminal diversity of sansanmycin through mutasynthesis

“…Recently, crystal structure of Aquifex aeolicus MraY has been published [ 34 ], and the residues (Asp 117 , Asp 118 , Asp 265 , and His 324 ) important for the activity of MraY in the active site have been elucidated [ 34 ]. The structural information of MraY from A. aeolicus sets foundations for homologous modeling of MraY from M. tuberculosis [ 34 , 35 ], which will facilitate the study on structure activity relationship (SAR) of novel chemically diverse UPA derivatives obtained by further rationale genetic engineering manipulation.…”

The Membrane Steps of Bacterial Cell Wall Synthesis as Antibiotic Targets

“…The 14 molecules investigated in this study exhibited IC 50 values typically between 50 and 100 µM. Follow-up investigation using docking models showed that the activity of the most potent inhibitors correlates with their interaction with Leu191 in TM3 of AaMraY [ 73 ]. It was suggested that the introduction of a long lipid chain on the triazole substituent drastically improved the inhibitory activity.…”

Inhibition of phospho-MurNAc-pentapeptide translocase (MraY) by nucleoside natural product antibiotics, bacteriophage ϕX174 lysis protein E, and cationic antibacterial peptides

“…Fer et al have also synthesised a series of triazole-containing analogues of the caprazamycins, which show IC50 values of 100-1000 µM against B. subtilis MraY, and show antibacterial activity against Staphylococcus aureus [31]. total synthesis of pacidamycin D [32], and have used the synthetic route to investigate structure-activity relationships in he N-terminal dipeptide chain [33], shown previously to be important for biological activity in the mureidomycin series [34].…”