Hassaballah Aya I, El-Ziaty A K, Gado Marwa M, Sayed Hayam A E, Kamal Mahmoud, Ali Rania S
Department of Chemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
Department of Microbiology, Faculty of Science, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
Sci Rep. 2025 Jun 3;15(1):19370. doi: 10.1038/s41598-025-03272-5.
The synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 was produced and exploited in the creation of a wide variety of highly reactive heterocyclic compounds, by its interaction with diverse nitrogen nucleophiles. Using spectral and elemental analysis, the structures of each synthesized heterocycles were fully investigated. Ten of the thirteen novel heterocycles showed encouraging efficacy against antibiotic-resistant bacteria (MRSA). Among these, compounds 6, 7, 10, 13b, and 14 demonstrated the highest antibacterial activity, showing inhibition zones near 4 cm. However, molecular docking studies revealed varied binding affinities for Penicillin-Binding Protein 2a (PBP2a), a crucial target in MRSA resistance. Some compounds, such as 7, 10, and 14, displayed higher binding affinities and interaction stability within the PBP2a active site compared to the co-crystallized quinazolinone ligand. In contrast, compounds 6 and 13b exhibited lower docking scores but still showed substantial antimicrobial activity, with 6 showing the lowest MIC (9.7 μg/100 μL) and MBC (78.125 μg/100 μL) values. The docking analysis revealed key interactions, including hydrogen bonding and π-stacking, particularly with residues like Lys 273, Lys 316, and Arg 298, which were identified as interacting with the co-crystallized ligand within the crystal structure of PBP2a. These residues are essential for the enzymatic activity of PBP2a. These findings suggest that the synthesized compounds could serve as promising anti-MRSA agents, highlighting the importance of integrating molecular docking with biological assays to identify effective therapeutic candidates.
合成子3-(蒽-9-基)-2-氰基丙烯酰氯4通过与多种氮亲核试剂相互作用而制备，并用于合成各种高反应性杂环化合物。利用光谱和元素分析对每个合成杂环的结构进行了全面研究。13种新型杂环化合物中有10种对耐抗生素细菌（耐甲氧西林金黄色葡萄球菌，MRSA）显示出令人鼓舞的疗效。其中，化合物6、7、10、13b和14表现出最高的抗菌活性，抑菌圈接近4厘米。然而，分子对接研究表明，这些化合物对MRSA耐药的关键靶点青霉素结合蛋白2a（PBP2a）的结合亲和力各不相同。与共结晶的喹唑啉酮配体相比，一些化合物，如7、10和14，在PBP2a活性位点内表现出更高的结合亲和力和相互作用稳定性。相比之下，化合物6和13b的对接分数较低，但仍表现出显著的抗菌活性，其中6的最低抑菌浓度（MIC，9.7 μg/100 μL）和最低杀菌浓度（MBC，78.125 μg/100 μL）值最低。对接分析揭示了关键相互作用，包括氢键和π-堆积，特别是与Lys 273、Lys 316和Arg 298等残基的相互作用，这些残基在PBP2a晶体结构中被确定为与共结晶配体相互作用。这些残基对PBP2a的酶活性至关重要。这些发现表明，合成的化合物有望成为抗MRSA药物，突出了将分子对接与生物学测定相结合以确定有效治疗候选物的重要性。
