Preservatives have to be added in food, pharmaceuticals and cosmetics products to maintain their shelf life. However, the existing chemical based preservatives have been associated with severe side effects that compel the researchers to find better safe preservatives based on natural products. G-6-P synthase is an important enzyme for bacterial and fungal cell wall synthesis and offers as a potential target to find better G-6-P synthase inhibitors based antimicrobial compounds. Naringenin, a flavanone, has been reported for a wide range of pharmacological activities including antimicrobial activity, which makes it a potential candidate to be explored as novel G-6-P synthase inhibitor. The synthesis of naringenin derivatives with potent G-6-P synthase inhibitor having remarkable antioxidant, antimicrobial and preservative efficacy was performed. Among the synthesized compounds, the compound 1 possessed good antioxidant activity (IC50 value, 6.864 ± 0.020 µM) as compared to standard ascorbic acid (IC50 value, 8.110 ± 0.069 µM). The antimicrobial activity of synthesized compounds revealed compound 1 as the most potent compound (pMIC 1.79, 1.79, 1.49, 1.49, 1.49 and 1.49 μM/mL for P. mirabilis, P. aeruginosa, S. aureus, E. coli, C. albicans and A. niger respectively) as compared to standard drugs taken. The compound 2 showed comparable activity against P. mirabilis (pMIC 1.14 μM/mL), C. albicans (pMIC 1.14 μM/mL) while the compound 3 also showed comparable activity against C. albicans (pMIC 1.16 μM/mL) as well A. niger (pMIC 1.46 μM/mL), likewise the compound 4 showed comparable activity against P. mirabilis (pMIC 1.18 μM/mL) as compared to the standard drugs streptomycin (pMIC 1.06, 1.36, 1.06 and 1.96 μM/mL for P. mirabilis, P. aeruginosa, S. aureus and E. coli respectively), ciprofloxacin (pMIC 1.12, 1.42, 1.12 and 1.42 μM/mL for P. mirabilis, P. aeruginosa, S. aureus and E. coli respectively), ampicillin (pMIC 1.14, 0.84, 0.84 and 1.74 μM/mL for P. mirabilis, P. aeruginosa, S. aureus and E. coli respectively) and fluconazole (pMIC 1.08 and 1.38 μM/mL for C. albicans and A. niger respectively). The molecular docking with the target G-6-P synthase pdb id 1moq resulted with an better dock score for compound 1 (− 7.42) as compared to standard antimicrobial drugs, ciprofloxacin (− 5.185), ampicillin (− 5.065) and fluconazole (− 5.129) that supported the wet lab results. The preservative efficacy test for compound 1 in White Lotion USP showed the log CFU/mL value within the prescribed limit and results were comparable to standard sodium benzoate, ethyl paraben and propyl paraben as per USP standard protocol. The synthesized naringenin derivatives exhibited significant G-6-P synthase inhibitory potential with good selectivity towards the selected target G-6-P synthase. Compound 1, bearing nitro group showed good antioxidant, antimicrobial and preservative efficacy compared with the standard drugs taken. The mechanistic insight about the compounds within the active site was completed by molecular docking that supported the results for novel synthesized G-6-P synthase inhibitors.

中文翻译：

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柚皮素衍生物作为 6-磷酸氨基葡萄糖合酶抑制剂：合成、抗氧化剂、抗菌、防腐功效、分子对接和计算机 ADMET 分析。


食品、药品和化妆品中必须添加防腐剂以维持其保质期。然而，现有的化学防腐剂具有严重的副作用，迫使研究人员寻找基于天然产品的更安全的防腐剂。 G-6-P 合酶是细菌和真菌细胞壁合成的重要酶，可作为寻找更好的基于 G-6-P 合酶抑制剂的抗菌化合物的潜在靶标。据报道，柚皮素是一种黄烷酮，具有广泛的药理活性，包括抗菌活性，这使其成为新型 G-6-P 合酶抑制剂的潜在候选者。柚皮素衍生物与强效G-6-P合酶抑制剂的合成具有显着的抗氧化、抗菌和防腐功效。在合成的化合物中，与标准抗坏血酸（IC50值，8.110±0.069μM）相比，化合物1具有良好的抗氧化活性（IC50值，6.864±0.020μM）。合成化合物的抗菌活性表明化合物 1 是最有效的化合物（对奇异果、铜绿假单胞菌、金黄色葡萄球菌、大肠杆菌、白色念珠菌的 pMIC 为 1.79、1.79、1.49、1.49、1.49 和 1.49 μM/mL）和 A. niger）与服用的标准药物相比。化合物 2 对奇异假单胞菌 (pMIC 1.14 μM/mL)、白色念珠菌 (pMIC 1.14 μM/mL) 显示出相当的活性，而化合物 3 也对白色念珠菌 (pMIC 1.16 μM/mL) 以及 A 表现出相当的活性。与标准药物链霉素（pMIC 1.06、1.36、1.06 和 1.96 μM/mL）相比，化合物 4 对奇异变形杆菌（pMIC 1.18 μM/mL）也表现出相当的活性。奇异果、铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌。 分别为大肠杆菌）、环丙沙星（对于奇异果、铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌，pMIC 分别为 1.12、1.42、1.12 和 1.42 μM/mL）、氨苄青霉素（对于奇异果、铜绿假单胞菌和大肠杆菌，pMIC 分别为 1.14、0.84、0.84 和 1.74 μM/mL）分别为奇异假单胞菌、铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌）和氟康唑（白色念珠菌和黑曲霉的 pMIC 分别为 1.08 和 1.38 μM/mL）。与标准抗菌药物环丙沙星 (− 5.185)、氨苄青霉素 (− 5.065) 和氟康唑 (− 5.065) 相比，与目标 G-6-P 合酶 pdb id 1moq 的分子对接使化合物 1 (− 7.42) 获得更好的对接分数。 5.129）支持湿实验室结果。 USP 白色乳液中化合物 1 的防腐功效测试显示 log CFU/mL 值在规定限度内，并且结果与按照 USP 标准方案的标准苯甲酸钠、对羟基苯甲酸乙酯和对羟基苯甲酸丙酯相当。合成的柚皮素衍生物表现出显着的 G-6-P 合酶抑制潜力，对所选目标 G-6-P 合酶具有良好的选择性。与标准药物相比，带有硝基的化合物1表现出良好的抗氧化、抗菌和防腐功效。通过分子对接完成了对活性位点内化合物的机制了解，这支持了新型合成的 G-6-P 合酶抑制剂的结果。