Synthesis, anti-biofilm and molecular docking of amino-substituted chalcones targeting <i>Staphylococcus aureus</i> sortase A
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Antibiotic resistance is an urgent global health challenge that requires the development of new antibacterial agents. In this study, 14 aminochalcones bearing electron-withdrawing groups were synthesized and evaluated for antibacterial activity. Chalcone <b>C5</b>, with an <i>ortho</i>-chlorine on ring B, demonstrated the most potent effect, notably against methicillin-susceptible and methicillin-resistant <i>Staphylococcus aureus</i> (MICs of 1.9 and 3.9 µg/mL, respectively), comparable to vancomycin. <b>C5</b> showed synergistic interaction with vancomycin, reducing its MIC tenfold. Time-kill assays confirmed C5’s bactericidal action within 8 h, with no bacterial regrowth up to 12 h. <b>C5</b> also significantly inhibited bacterial adhesion to keratinocytes (HaCaT) and reduced biofilm formation and survival at both MIC and 10× MIC, showing effects comparable to vancomycin. <i>In silico,</i> ADMET predictions indicated favorable pharmacokinetic and safety profiles, including high intestinal absorption and lack of hERG inhibition or cytotoxicity. Molecular docking against <i>S. aureus</i> sortase A (SrtA) suggests strong interactions with key residues (Arg197, Glu105, Asn114), supporting the anti-adhesion activity. Furthermore, <i>in vivo</i> toxicity assessment using <i>Galleria mellonella</i> larvae showed minimal toxicity at 100× MIC. These findings support chalcone <b>C5</b> as a promising lead compound for the development of new antibacterial agents, particularly for combating <i>S. aureus</i> infections and biofilm-associated pathologies.
抗生素耐药性是一项亟待解决的全球性公共卫生难题，亟需开发新型抗菌制剂。本研究合成并评价了14种带有吸电子基团的氨基查尔酮（aminochalcones）的抗菌活性。查尔酮<b>C5</b>在B环带有邻位氯原子，展现出最强的抗菌活性，尤其对甲氧西林敏感型及耐甲氧西林金黄色葡萄球菌的最低抑菌浓度（Minimum Inhibitory Concentration, MIC）分别为1.9和3.9 µg/mL，活性与万古霉素相当。C5可与万古霉素产生协同作用，使万古霉素的MIC降至原浓度的1/10。时间杀菌实验证实，C5可在8小时内发挥杀菌作用，且12小时内无细菌复增现象。C5还可显著抑制细菌对角质形成细胞（HaCaT）的黏附，并在MIC及10倍MIC浓度下均能减少生物被膜的形成与活菌存活，其效果与万古霉素相当。计算机模拟实验（in silico）的ADMET（Absorption, Distribution, Metabolism, Excretion, Toxicity）预测结果显示，C5具有良好的药代动力学与安全性特征，包括高肠道吸收率，且无hERG（human Ether-à-go-go Related Gene）抑制作用或细胞毒性。针对金黄色葡萄球菌分选酶A（sortase A, SrtA）的分子对接实验表明，C5可与关键氨基酸残基（Arg197、Glu105、Asn114）产生强相互作用，为其抗黏附活性提供了理论支撑。此外，以大蜡螟（Galleria mellonella）幼虫为模型开展的体内实验（in vivo）毒性评价结果显示，C5在100倍MIC浓度下仅表现出极低的毒性。上述研究结果表明，查尔酮<b>C5</b>有望成为开发新型抗菌制剂的先导化合物，尤其可用于对抗金黄色葡萄球菌感染及生物被膜相关疾病。
