Hamoud Mohamed M S, Ghanim Amany M, Hassan Abdalla E A, Abdel-Fattah Hanan A, Abbas Hisham A, Seleem Noura M, Kothayer Hend, Osman Nermine A
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, 44519, Egypt.
BMC Chem. 2025 Jul 11;19(1):209. doi: 10.1186/s13065-025-01560-9.
employs -acylated L-homoserine lactones (AHLs) as autoinducers (AIs) for quorum sensing, which in the end is responsible for biofilm and virulence factor production along with the development of antibiotic resistance in bacteria. Here, we designed and synthesized a library of -alkyl-1,3,4-oxadiazoles bearing nicotinamide moiety targeting AHLs receptors (LasR and RhlR) and evaluated their efficacy as new inhibitors of quorum sensing. The minimum inhibitory concentrations of the synthesized compounds against PAO1 were determined, and they ranged from 2.5 to 5 mg/ml. All the compounds were subjected to further investigation against protease and pyocyanin. The oxadiazole derivative was the most potent compound that reduced both protease activity and pyocyanin production by 38.46% and 70.27% respectively. Moreover, compound showed a significant reduction of the biofilm formation by 81.72%. A docking study was performed to explore the potential binding interactions with quorum-sensing receptors (LasR and RhlR), which are responsible for the expression of virulence genes. Molecular docking results indicated that compound showed a comparable binding affinity to the co-crystalized ligands of two QS targets (lasR and RhlR) with higher affinity towards LasR than RhIR active sites. Our findings highlight the promising potential of 1,3,4-oxadiazole-nicotinamide hybrid as an anti-virulence agent to combat .
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利用N-酰化L-高丝氨酸内酯（AHLs）作为群体感应的自诱导物（AIs），最终群体感应负责生物膜和毒力因子的产生以及细菌中抗生素耐药性的发展。在此，我们设计并合成了一系列带有烟酰胺部分的N-烷基-1,3,4-恶二唑文库，靶向AHLs受体（LasR和RhlR），并评估了它们作为群体感应新抑制剂的功效。测定了合成化合物对PAO1的最低抑菌浓度，范围为2.5至5mg/ml。所有化合物都进一步针对蛋白酶和绿脓菌素进行了研究。恶二唑衍生物是最有效的化合物，分别将蛋白酶活性和绿脓菌素产量降低了38.46%和70.27%。此外，化合物显示生物膜形成显著减少了81.72%。进行了对接研究以探索与负责毒力基因表达的群体感应受体（LasR和RhlR）的潜在结合相互作用。分子对接结果表明，化合物与两个群体感应靶点（lasR和RhlR）的共结晶配体具有相当的结合亲和力，对LasR活性位点的亲和力高于RhIR。我们的研究结果突出了1,3,4-恶二唑-烟酰胺杂化物作为抗毒力剂对抗[具体对象未明确]的潜在前景。
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