ω‐Aminomethyl Longifolene Amide Derivatives: Synthesis, Crystal Structure, Hirshfeld Surface, DFT, Antimicrobial, and Molecular Docking Studies

Twelve novel ω‐aminomethyl longifolene amide derivatives (6 a–6 l) were synthesized and characterized. The intermolecular contacts and the relationship of structure‐property for the synthesized compounds were performed with the use of two‐dimensional fingerprint plots and Hirshfeld surface method. Moreover, the chemical reactivity and geometrical characteristics of target compounds were investigated using density functional theory (DFT) method. Molecular docking studies were performed to investigate the interactions between compounds 6 a–6 l and sortase A (SrtA) from S. aureus, the carboxy terminal domain of colicin E5 (E5‐CRD) and Serine/Threonine phosphatase Z1 (PPZ1) from C. albicans, respectively, and together with their biological activities. The docking results of the synthesized compounds 6 a–6 l showed different binding efficiencies and inhibitory effects on S. aureus, E. coli and C. albicans. Furthermore, preliminary antimicrobial activity assay showed that compounds 6 f, 6 i and 6 k exhibited comparable or superior antibacterial activity against S. aureus, B. subtilis and K. pneumoniae compared to rifampicin with minimum inhibitory concentration (MIC) values from 0.488 to 0.977 μg/mL. In addition, the absorption, distribution, metabolism and excretion (ADME) and drug‐likeness properties of the synthesized derivatives were evaluated as well. A series of ω‐aminomethyl longifolene amide derivatives have been synthesized through multistep routes starting from longifolene as naturally occurring. These derivatives have been characterized using FT‐IR, NMR, HRMS and GC‐MS, while compound 6 f has also been confirmed by X‐ray crystallography and Hirshfeld Surface analysis. Their theoretical computed properties (DFT, molecular docking and ADME predictions) and antimicrobial activities were further explored. Several compounds have shown potential as antibacterial agents.