Shukla Deepanjali, Azad Iqbal, Khan Mohd Arsh, Husain Ziaul, Kamal Azhar, Sheikh Sabahat Yasmeen, Alotibi Ibrahim, Ahmad Varish, Hassan Firoj
Department of Chemistry, Integral University, Lucknow 226026, India.
Department of Bioengineering, Integral University, Lucknow 226026, India.
Antibiotics (Basel). 2025 Jun 9;14(6):595. doi: 10.3390/antibiotics14060595.
BACKGROUND/OBJECTIVES: The current need for new antibacterial compounds that target non-classical pathways is highlighted by the emergence of multidrug-resistant . In the development of antibiotics, DNA adenine methyltransferase (Dam), a key regulator of bacterial gene expression and pathogenicity, is still underutilized. Epoxy-functionalized analogues of isatin derivatives have not been adequately investigated for their antibacterial activity, particularly as Dam inhibitors. In the pursuit of antimicrobial agents, this study synthesized an epoxy-functionalized isatin derivative () using a one-pot reaction. The compound was characterized using FT-IR, ¹H-NMR, C-NMR, HR-MS, and UV-Vis spectroscopy.
evaluation performed by using ADMETlab3 and SwissADME. While molecular docking studies were achieved by AutoDock and Vina to find 's interaction with potential antibacterial target (Dam protein in ). In addition, the antibacterial potential of was evaluated using minimum inhibitory concentration (MIC) assays against , , , and .
Among these, exhibited potential inhibitory activity against , with a MIC value of 93.75 μg/mL. evaluations confirmed 's favorable drug-like properties, including potential oral bioavailability, blood-brain barrier (BBB) permeability, and low plasma protein binding (PPB). The compound satisfied Lipinski's and other drug-likeness rules as well as getting a quantitative estimate of drug-likeness (QED) score of 0.52. Here, a homology model of Dam protein in was generated using the SWISS-MODEL server and validated using computational tools. Targeted docking analysis revealed that exhibited significant potential binding affinity against Dam protein, with binding energies of -6.4 kcal/mol and -4.85 kcal/mol, as determined by Vina and AutoDock, respectively. The associated inhibition constant was calculated as 280.35 µM. Further interaction analysis identified the formation of hydrogen bonds with TRP7 and PHE32, along with Van der Waals' interactions involving GLY9, ASP51, and ASP179.
These findings highlight as a promising scaffold for antimicrobial drug development, particularly in targeting Dam protein in . Furthermore, the ADMET profiling and physicochemical properties of support its potential as a drug-like candidate.
背景/目的：多重耐药菌的出现凸显了当前对靶向非经典途径的新型抗菌化合物的需求。在抗生素的研发中，作为细菌基因表达和致病性关键调节因子的DNA腺嘌呤甲基转移酶（Dam）仍未得到充分利用。异吲哚酮衍生物的环氧官能化类似物的抗菌活性，尤其是作为Dam抑制剂的活性，尚未得到充分研究。为了寻找抗菌剂，本研究通过一锅法反应合成了一种环氧官能化异吲哚酮衍生物（）。该化合物通过傅里叶变换红外光谱（FT-IR）、¹H-核磁共振（¹H-NMR）、碳-核磁共振（C-NMR）、高分辨质谱（HR-MS）和紫外-可见光谱进行了表征。
使用ADMETlab3和SwissADME进行评估。同时，通过AutoDock和Vina进行分子对接研究，以发现与潜在抗菌靶点（中的Dam蛋白）的相互作用。此外，使用针对、、和的最低抑菌浓度（MIC）测定法评估了的抗菌潜力。
其中，对表现出潜在的抑制活性，MIC值为93.75μg/mL。评估证实了具有良好的类药性质，包括潜在的口服生物利用度、血脑屏障（BBB）通透性和低血浆蛋白结合率（PPB）。该化合物符合Lipinski规则及其他类药规则，类药定量估算（QED）得分为0.52。在此，使用SWISS-MODEL服务器生成了中的Dam蛋白同源模型，并使用计算工具进行了验证。靶向对接分析表明，对Dam蛋白表现出显著的潜在结合亲和力，Vina和AutoDock分别测定的结合能为-6.4 kcal/mol和-4.85 kcal/mol。计算得出的相关抑制常数为280.35µM。进一步的相互作用分析确定了与TRP7和PHE32形成氢键，以及与GLY9、ASP51和ASP179的范德华相互作用。
这些发现突出了作为抗菌药物开发的有前景的骨架，特别是针对中的Dam蛋白。此外，的ADMET分析和理化性质支持其作为类药候选物的潜力。
