Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India; Department of Chemistry, TNB College, TM Bhagalpur University, Bhagalpur, 812007, India.
Centre for Chemical Biology, Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500607, India.
Eur J Med Chem. 2019 Feb 1;163:67-82. doi: 10.1016/j.ejmech.2018.11.053. Epub 2018 Nov 22.
A series of diketo esters and their pertinent bioisosteres were designed and synthesized as potent antibacterial agents by targeting methionine amino peptidases (MetAPs). In the biochemical assay against purified MetAPs from Streptococcus pneumoniae (SpMetAP1a), Mycobacterium tuberculosis (MtMetAP1c), Enterococcus faecalis (EfMetAP1a) and human (HsMetAP1b), compounds 3a, 4a and 5a showed more than 85% inhibition of all the tested MetAPs at 100 μM concentration. Compounds 4a and 5a also exhibited antibacterial potential with MIC values 62.5 μg/mL (S. pneumoniae), 31.25 μg/mL (E. faecalis), 62.5 μg/mL (Escherichia coli) and 62.5 μg/mL (S. pneumoniae), 62.5 μg/mL (E. coli), respectively. Moreover, 5a also significantly inhibited the growth of multidrug resistant E. coli strains at 512 μg/mL conc., while showing no cytotoxic effect towards healthy CHO cells and thus being selected. Growth kinetics study showed significant inhibition of bacterial growth when treated with different conc. of 5a. TEM analysis also displayed vital damage to bacterial cells by 5a at MIC conc. Moreover, significant inhibition of biofilm formation was observed in bacterial cells treated with MIC conc. of 5a as visualized by SEM micrographs. Interestingly, 5a did not cause an alteration in the hemocyte density in Galleria mellonella larvae which is considered in vivo model for antimicrobial studies and was non-toxic up to a conc. of 2.5 mg/mL.
一系列二酮酯及其相关的生物等排体被设计并合成，作为针对甲硫氨酸氨肽酶（MetAPs）的有效抗菌剂。在针对肺炎链球菌（SpMetAP1a）、结核分枝杆菌（MtMetAP1c）、粪肠球菌（EfMetAP1a）和人（HsMetAP1b）的纯化 MetAP 的生化测定中，化合物 3a、4a 和 5a 在 100µM 浓度下对所有测试的 MetAP 表现出超过 85%的抑制作用。化合物 4a 和 5a 还表现出抗菌潜力，MIC 值分别为 62.5μg/mL（肺炎链球菌）、31.25μg/mL（粪肠球菌）、62.5μg/mL（大肠杆菌）和 62.5μg/mL（肺炎链球菌）、62.5μg/mL（大肠杆菌）。此外，5a 还在 512µg/mL 浓度下显著抑制了多重耐药大肠杆菌菌株的生长，同时对健康 CHO 细胞没有细胞毒性作用，因此被选中。生长动力学研究表明，用不同浓度的 5a 处理时，细菌生长受到显著抑制。TEM 分析还显示，5a 在 MIC 浓度下对细菌细胞造成了严重的损伤。此外，SEM 显微照片显示，用 MIC 浓度的 5a 处理细菌细胞时，生物膜形成明显受到抑制。有趣的是，5a 不会引起大蜡螟幼虫血淋巴密度的改变，大蜡螟幼虫被认为是抗菌研究的体内模型，在 2.5mg/mL 浓度下是非毒性的。
