Synthesis, molecular docking and antibacterial activity of an oxadiazole-based lipoteichoic acid inhibitor and its metabolites

Improved Antibacterial Activity of 1,3,4-Oxadiazole-Based Compounds That Restrict Staphylococcus aureus Growth Independent of LtaS Function

“…Using this approach, 1771 did not show inhibitory activity; however, the azo dye Congo red blocked LtaS function. 11 On the contrary, our 21 and others 14 in silico investigations highlighted that 1771 might behave as a competitive inhibitor of LtaS, in line with biophysical data indicating binding between 1771 and derivatives with the extracellular domain of LtaS (eLtaS). 12,14 In this study, we sought to design and synthesize a small series of derivatives of 1771 with the aim to not only improve the antistaphylococcal activity of 1771 but also correlate the compound's activity with its in silico interaction with LtaS.…”

“…Chemistry. Compounds 9−14 were synthesized using the same convergent synthesis method previously reported for 1771, 21 as shown in Scheme 1. Briefly, transesterification of ethyl 4-chloro-3-oxobutanoate 2 with naphthalen-2-ol (3a) or 6-methoxynaphthalen-2-ol (3b) after Pechmann condensation yielded the corresponding desired angular chlorocoumarines 4a,b, which under basic conditions underwent a rearrangement to give compounds 5a,b.…”

“…The docking poses of the newly synthesized derivatives 9–14 was compared to that of the parent compound 1771 previously reported . As shown in Figure b, the phenyl-1,3,4-oxadiazole portion of 1771 (cyan sticks) can fit into a deep part of the LtaS active site, while the same moiety is located in the rim of the pocket in the case of compounds 9–14 .…”

“…Richter et al observed that 1771 inhibited eLtaS binding to and cleavage of PG in vitro using size exclusion chromatography, nitro-benzoxadiazole glycerol-phosphate as a substrate for eLtaS, and mass spectrometry . We and others have performed molecular docking of 1771 in the eLtaS catalytic site. Overall, both in silico investigations highlighted that 1771 might function as a competitive inhibitor of LtaS and emphasized the key role of the oxadiazole ring in the ligand–protein recognition process, in agreement with the experimental studies according to which this moiety is crucial for activity .…”

“…The docking poses of the newly synthesized derivatives 9− 14 was compared to that of the parent compound 1771 previously reported. 21 As shown in Figure 6b, the phenyl-1,3,4oxadiazole portion of 1771 (cyan sticks) can fit into a deep part of the LtaS active site, while the same moiety is located in the rim of the pocket in the case of compounds 9−14. Significantly, the oxadiazole ring, which appeared to play a pivotal role in the binding to LtaS in the docking model reported by both us 21 and Chee Wezen et al, 14 is not involved in the interaction between the enzyme and compounds 9−14.…”