Several α-ketoamides from natural as well as synthetic sources have been shown to possess multitude of biological activities due to their versatile nature and presence of multiple reactive centres giving them both electrophilic and nucleophilic characters. This makes them a key scaffold in biology chemistry and chemical biology. In this paper, we have reported the synthesis of N-benzyl-4-(4-chlorophenyl)-2-oxobutanamide (1) from β,γ-unsaturated α-hydroxythioester. Single crystal X-ray diffraction study was performed to determine the three-dimensional (3D) structure of the compound 1. Further, the 3D structure was optimised through DFT calculations using B3LYP/6-311G(d,p) basis set, followed by FTIR and NMR spectra calculation. The wavelength of maximum absorbance (λ) and the band gap energy of compound 1 were derived for methanol using the TD-DFT/6-311G(d,p) approach and compared to experimental results. The different intermolecular and intramolecular interactions such as H-O, H-Cl, H-C, H-N, and other possible interactions in the crystal structure were explored using Hirsfeld surfaces analysis and fingerprint plots. Additionally, Coulomb energy, dispersion energy, total energy, and total energy annotated were calculated by energy framework calculations demonstrating that electrostatic and repulsion forces are relevant to the topology of the overall interaction energies in the crystal. Finally, from the DFT optimized structure, the molecular electrostatic potential (MEP) map and Mulliken charges were generated and the natural bond (NBO) analysis was performed in order to investigate the interaction between various orbital and lone pairs occurring within the compounds. Based on the geometric and spectroscopic parameters, the experimental and theoretical results were indistinguishable. Additionally, in vitro amyloid beta 1-42 (Aβ₄₂) aggregation assay revealed that the compound 1 modulated the aggregation profile of Aβ₄₂ and the MTT cellular cytotoxicity assay showed that the compound is not toxic to cells. Further, molecular docking study resulted in the determination of interaction of compound 1 with the Aβ₄₂ fibrils. In summary, the present work can be helpful for the design, and synthesis of novel α-ketoamides as potential modulators of amyloid beta aggregation.

来自天然和合成来源的几种α -酮酰胺已被证明具有多种生物活性，这是由于它们的多用途性质和多个反应中心的存在赋予它们亲电和亲核特性。这使它们成为生物化学和化学生物学的关键支架。在本文中，我们报道了从β,γ-不饱和α-羟基硫酯合成N-苄基-4-(4-氯苯基)-2-氧代丁酰胺 (1) 。进行单晶 X 射线衍射研究以确定化合物 1 的三维 (3D) 结构。此外，通过使用 B3LYP/6-311G(d,p) 基组的 DFT 计算优化 3D 结构，然后进行 FTIR 和 NMR 光谱计算。化合物1的最大吸收波长( λ )和带隙能量使用 TD-DFT/6-311G(d,p) 方法导出甲醇，并与实验结果进行比较。使用 Hirsfeld 表面分析和指纹图探索了晶体结构中不同的分子间和分子内相互作用，例如 H2O、H-Cl、HC、HN 和其他可能的相互作用。此外，库仑能、色散能、总能量和注释的总能量是通过能量框架计算计算的，表明静电和排斥力与晶体中整体相互作用能的拓扑结构相关。最后，从DFT优化结构，生成了分子静电势 (MEP) 图和 Mulliken 电荷，并进行了自然键 (NBO) 分析，以研究化合物中出现的各种轨道和孤电子对之间的相互作用。基于几何和光谱参数，实验和理论结果无法区分。此外，体外淀粉样蛋白 1-42 (Aβ ₄₂ ) 聚集测定表明化合物 1 调节了 A β ₄₂的聚集特征， MTT 细胞毒性测定表明该化合物对细胞没有毒性。此外，分子对接研究导致确定化合物1与 A β ₄₂原纤维的相互作用。总之，目前的工作有助于设计和合成新型α-酮酰胺作为淀粉样蛋白 β 聚集的潜在调节剂。