Srinivasarao Singireddi, Nandikolla Adinarayana, Nizalapur Shashidhar, Yu Tsz Tin, Pulya Sravani, Ghosh Balaram, Murugesan Sankaranarayanan, Kumar Naresh, Chandra Sekhar Kondapalli Venkata Gowri
Department of Chemistry, Birla Institute of Technology and Science Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal Hyderabad - 500078 Telangana India
School of Chemistry, UNSW Sydney NSW 2052 Australia.
RSC Adv. 2019 Sep 17;9(50):29273-29292. doi: 10.1039/c9ra05059k. eCollection 2019 Sep 13.
Bacteria regulate their phenotype, growth and population a signalling pathway known as quorum sensing. In this process, bacteria produce signalling molecules (autoinducers) to recognize their population density. Inhibiting this quorum sensing signalling pathway is one of the potential methods to treat bacterial infection. 2-Aminobenimdazoles are reported to be the strongest inhibitors of quorum sensing against wild-type . 1,2,3-Triazole based acyl homoserine lactones are found to be good inhibitors of the quorum sensing LasR receptor. Hence, in our current study, forty 1,2,3-triazole based 2-aminobenzimdazoles were synthesized and characterized using IR, NMR, MS and elemental analysis. A single crystal was developed for -(1-benzo[]imidazol-2-yl)-2-(4-nonyl-1-1,2,3-triazol-1-yl)acetamide (6d). All final compounds were screened for quorum sensing inhibitory activity against . The quorum sensing inhibitory activity was determined in the LasR expressing MH602 reporter strain by measuring green fluorescent protein production. Among the title compounds, -(1-benzo[]imidazol-2-yl)-2-(4-(4-chlorophenyl)-1-1,2,3-triazol-1-yl)acetamide (6i) exhibited good quorum sensing inhibitory activity of 64.99% at 250 μM. -(1-Benzo[]imidazol-2-yl)-2-(4-(4-nitrophenyl)-1-1,2,3-triazol-1-yl)acetamide (6p) exhibited the most promising quorum sensing inhibitory activity with 68.23, 67.10 and 63.67% inhibition at 250, 125 and 62.5 μM, respectively. -(1-Benzo[]imidazol-2-yl)-2-(4-(4-(trifluoromethyl)phenyl)-1-1,2,3-triazol-1-yl)acetamide (6o) and -(5,6-dimethyl-1-benzo[]imidazol-2-yl)-2-(4-(4-(trifluoromethyl)phenyl)-1-1,2,3-triazol-1-yl)acetamide (7l) also exhibited 64.25% and 65.80% quorum sensing inhibition at 250 μM. Compound 6p, the most active quorum sensing inhibitor, also displayed low cytotoxicity at the tested concentrations (25, 50 and 100 μM) against normal human embryonic kidney cell lines. Finally, a docking study using Schrodinger Glide elucidated the possible putative binding mode of the significantly active compound 6p at the active site of the target LasR receptor (PDB ID: 2UV0).
细菌通过一种称为群体感应的信号通路来调节其表型、生长和种群数量。在这个过程中，细菌产生信号分子（自诱导物）以识别其种群密度。抑制这种群体感应信号通路是治疗细菌感染的潜在方法之一。据报道，2-氨基苯并咪唑是针对野生型群体感应最强的抑制剂。发现基于1,2,3-三唑的酰基高丝氨酸内酯是群体感应LasR受体的良好抑制剂。因此，在我们目前的研究中，合成了四十种基于1,2,3-三唑的2-氨基苯并咪唑，并通过红外光谱、核磁共振、质谱和元素分析对其进行了表征。为-(1-苯并咪唑-2-基)-2-(4-壬基-1,2,3-三唑-1-基)乙酰胺(6d)培养出了单晶。对所有最终化合物进行了针对群体感应抑制活性的筛选。通过测量绿色荧光蛋白的产生，在表达LasR的MH602报告菌株中测定群体感应抑制活性。在标题化合物中，-(1-苯并咪唑-2-基)-2-(4-(4-氯苯基)-1,2,3-三唑-1-基)乙酰胺(6i)在250μM时表现出64.99%的良好群体感应抑制活性。-(1-苯并咪唑-2-基)-2-(4-(4-硝基苯基)-1,2,3-三唑-1-基)乙酰胺(6p)表现出最有前景的群体感应抑制活性，在250、125和62.5μM时的抑制率分别为68.23%、67.10%和63.67%。-(1-苯并咪唑-2-基)-2-(4-(4-(三氟甲基)苯基)-1,2,3-三唑-1-基)乙酰胺(6o)和-(5,6-二甲基-1-苯并咪唑-2-基)-2-(4-(4-(三氟甲基)苯基)-1,2,3-三唑-1-基)乙酰胺(7l)在250μM时也表现出64.25%和65.80%的群体感应抑制率。活性最高的群体感应抑制剂化合物6p在测试浓度(25、50和100μM)下对正常人胚肾细胞系也显示出低细胞毒性。最后，使用Schrodinger Glide进行的对接研究阐明了活性显著的化合物6p在靶标LasR受体活性位点（PDB ID：2UV0）的可能推定结合模式。
