Department of Chemistry and Environmental Sciences, Institute of Biosciences, Humanities and Exact Sciences, Sao Paulo State University (Unesp), Sao Jose do Rio Preto 15054-000, SP, Brazil.
Department of Biology, Institute of Biosciences, Humanities and Exact Sciences, Sao Paulo State University (Unesp), Sao Jose do Rio Preto15054-000, SP, Brazil.
Med Chem. 2020;16(7):881-891. doi: 10.2174/1573406415666190724145158.
Chalcones substituted by methoxyl groups have presented a broad spectrum of bioactivities, including antifungal, antibacterial and antiproliferative effects. However, a clear and unambiguous investigation about the relevance of this substituent on the chalcone framework has not been described.
The purpose of this work is to assess the antibacterial, antifungal and antiproliferative activities of the two series of seventeen synthesized regioisomeric methoxychalcones. Series I and II were constituted by chalcones substituted by methoxyl groups on rings A (5-12) and B (13-21), respectively. In addition, the library of methoxychalcones was submitted to in silico drug-likeness and pharmacokinetics properties predictions.
Methoxychalcones were synthesized and their structures were confirmed by NMR spectral data analyses. Evaluations of antimicrobial activity were performed against five species of Candida, two Gram-negative and five Gram-positive species. For antiproliferative activity, methoxychalcones were evaluated against four human tumorigenic cell lines, as well as human non-tumorigenic keratinocytes. Drug-likeness and pharmacokinetics properties were predicted using Molinspiration and PreADMET toolkits.
In general, chalcones of series I are the most potent antifungal, antibacterial and antiproliferative agents. 3', 4', 5'-Trimethoxychalcone (12) demonstrated potent antifungal activity against Candida krusei (MIC = 3.9 μg/mL), eight times more potent than fluconazole (reference antifungal drug). 3'-Methoxychalcone (6) displayed anti-Pseudomonas activity (MIC = 7.8 μg/mL). 2',5'-Dimethoxychalcone (9) displayed potent antiproliferative effect against C-33A (cervix), A-431 (skin) and MCF-7 (breast), with IC50 values ranging from 7.7 to 9.2 μM. Its potency was superior to curcumin (reference antiproliferative compound), which exhibited IC50 values ranging from 10.4 to 19.0 μM.
Our studies corroborated the relevance of methoxychalcones as antifungal, antibacterial and antiproliferative agents. In addition, we elucidated influence of the position and number of methoxyl groups toward bioactivity. In silico predictions indicated good drug-likeness and pharmacokinetics properties to the library of methoxychalcones.
甲氧基取代的查耳酮具有广泛的生物活性，包括抗真菌、抗菌和抗增殖作用。然而，关于该取代基在查尔酮骨架上的相关性，尚未有明确和明确的研究。
本工作旨在评估两个系列十七个合成的区域异构甲氧基查尔酮的抗菌、抗真菌和抗增殖活性。系列 I 和 II 由甲氧基分别取代 A 环（5-12）和 B 环（13-21）的查尔酮组成。此外，甲氧基查尔酮库还进行了药物相似性和药代动力学性质的预测。
合成了甲氧基查尔酮，并通过 NMR 谱数据分析确证了它们的结构。对五种念珠菌、两种革兰氏阴性菌和五种革兰氏阳性菌进行了抗菌活性评价。对于抗增殖活性，甲氧基查尔酮对四种人肿瘤细胞系以及人非肿瘤角质形成细胞进行了评价。使用 Molinspiration 和 PreADMET 工具包预测了药物相似性和药代动力学性质。
一般来说，系列 I 的查尔酮是最有效的抗真菌、抗菌和抗增殖剂。3'，4'，5'-三甲氧基查尔酮（12）对克鲁斯念珠菌（MIC = 3.9 μg/mL）表现出很强的抗真菌活性，比氟康唑（参考抗真菌药物）强 8 倍。3'-甲氧基查尔酮（6）对铜绿假单胞菌具有抗活性（MIC = 7.8 μg/mL）。2'，5'-二甲氧基查尔酮（9）对 C-33A（宫颈）、A-431（皮肤）和 MCF-7（乳腺）具有很强的抗增殖作用，IC50 值范围为 7.7 至 9.2 μM。其活性优于姜黄素（参考抗增殖化合物），其 IC50 值范围为 10.4 至 19.0 μM。
我们的研究证实了甲氧基查尔酮作为抗真菌、抗菌和抗增殖剂的相关性。此外，我们阐明了甲氧基取代基的位置和数量对生物活性的影响。计算机预测表明，甲氧基查尔酮库具有良好的药物相似性和药代动力学性质。
