Investigation of the antibacterial and antifungal activity of thiolated naphthoquinones

The WHO has stated that antibiotic resistance is escalating to perilously high levels globally and that traditional therapies of antimicrobial drugs are futile against infections caused by resistant microorganisms. Novel antimicrobial drugs are therefore required. We report in this study on the inhibitory activity of the 1,4-naphthoquinone-2,3-bis-sulfides and 1,4-naphthoquinone sulfides against two bacteria and a fungus to determine their antimicrobial properties. The 1,4-naphthoquinone sulfides have potent activity with a minimum inhibitory concentration (MIC) of 7.8 μg/mL against Staphylococcus aureus (Gram +ve), an MIC of 23.4 μg/mL against the fungus, Candida albicans, which was better than that of Amphotericin B (MIC = 31.3 μg/mL), and against Escherichia coli (Gram −ve) an MIC of 31.3 μg/mL was obtained. The 1,4-naphthoquinone had an MIC of 11.7 μg/mL against S. aureus and the 1,4-naphthohydroquinone also had the same activity against E. coli.

Design,synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase

BackgroundAcetylcholine deficiencies in hippocampus and cortex, aggregation of β-amyloid, and β-secretase over activity have been introduced as main reasons in pathogenesis of Alzheimer’s disease.MethodsColorimetric Ellman’s method was used for determination of IC₅₀ value in AChE and BChE inhibitory activity. The kinetic studies, neuroprotective and β-secretase inhibitory activities, evaluation of inhibitory potency on β-amyloid (Aβ) aggregations induced by AChE, and docking study were performed for prediction of the mechanism of action.Result and discussionA new series of cinnamic acids-tryptamine hybrid was designed, synthesized, and evaluated as dual cholinesterase inhibitors. These compounds demonstrated in-vitro inhibitory activities against acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). Among of these synthesized compounds, (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (5q) demonstrated the most potent AChE inhibitory activity (IC₅₀ = 11.51 μM) and (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(2-chlorophenyl)acrylamide (5b) were the best anti-BChE (IC₅₀ = 1.95 μM) compounds. In addition, the molecular modeling and kinetic studies depicted 5q and 5b were mixed type inhibitor and bound with both the peripheral anionic site (PAS) and catalytic sites (CAS) of AChE and BChE. Moreover, compound 5q showed mild neuroprotective in PC12 cell line and weak β-secretase inhibitory activities. This compound also inhibited aggregation of β-amyloid (Aβ) in self-induced peptide aggregation test at concentration of 10 μM.ConclusionIt is worth noting that both the kinetic study and the molecular modeling of 5q and 5b depicted that these compounds simultaneously interacted with both the catalytic active site and the peripheral anionic site of AChE and BChE. These findings match with those resulted data from the enzyme inhibition assay. Graphical abstractOpen in a separate windowA new series of cinnamic-derived acids-tryptamine hybrid derivatives were designed, synthesized and evaluated as butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibitors and neuroprotective agents. Compound 5b and 5q, as the more potent compounds, interacted with both the peripheral site and the choline binding site having mixed type inhibition. Results suggested that derivatives have a therapeutic potential for the treatment of AD.Electronic supplementary materialThe online version of this article (10.1007/s40199-020-00346-9) contains supplementary material, which is available to authorized users.     

桂枝中酚类提取物潜在作用靶点的探索

目的?研究桂枝中酚类提取物木脂素的潜在作用靶点。方法?在药效团模型数据库中筛选出与木脂素衍生物匹配值（FitValue）大于0.75的药效团模型；运用反向对接技术，从上述药效团模型所对应的靶点蛋白中挑选出与木脂素衍生物结合能最低的蛋白；以该靶蛋白已报道的抑制剂建立3D-QSAR药效团模型预测木脂素衍生物的活性，同时通过荧光偏振实验测试化合物1与Tankyrase 1蛋白的结合力，通过Western blot实验测试加入化合物1后细胞中Tankyrase 1蛋白的含量变化；最后用分子动力学模拟分析木脂素衍生物与该蛋白的作用模式。结果?与木脂素衍生物匹配值大于0.75的药效团模型有17个，其中4个为神经保护类靶点，占比（24%）最大；反向对接结果显示该化合物与Tankyrase 1蛋白（PDB ID:4TOR）的结合能（E=-66?kcal/mol）最低；预测该化合物的活性为0.61?μmol/L，荧光偏振实验测得化合物1与Tankyrase 1蛋白的结合力Ki=（0.15±0.01）μmol/L，属于中等抑制，Western blot表明在SW480细胞中化合物1使Tankyrase 1蛋白的表达下降；且分子动力学结果显示对接构象与该靶点已报道的抑制剂类似。结论?经过对桂枝中酚类提取物木脂素衍生物的反向找靶，以及活性测试确定其对Tankyrase 1蛋白具有潜在的抑制活性。      

银杏酸C17:1衍生物增效达托霉素抗粪肠球菌的发现与机制的初步研究

目的 发现有抗菌活性或是增效活性的银杏酸C17:1衍生物。方法 以银杏酸C17:1为底物，利用一些基团取代苯环上的羧基从而获得银杏酸C17:1衍生物，棋盘法设计试验，测定银杏酸C17:1及其衍生物联合抗生素的增效作用，通过测定Zeta电位、ROS、NPN吸收来探究增效机制。结果 银杏酸C17:1衍生物Ⅱ与达托霉素联合抗粪肠球菌的部分抑菌浓度指数(FICIs)为0.125~0.25，具有明显的协同效应，不仅能产生较高的活性氧，而且能在一定程度改变细胞膜的通透性。结论 银杏酸衍生物Ⅱ对达托霉素体外抗耐药株具有较好的增效作用，可能和ROS的激增以及膜通透性的改变有关。     

Synthesis and antiproliferative activity of new mycophenolic acid conjugates with adenosine derivatives

New conjugates of mycophenolic acid (MPA) and adenosine derivatives were synthesized and assessed as potential immunosuppressants on Jurkat cell line and peripheral blood mononuclear cells (PBMC) from healthy donors. As compared to MPA, all compounds were found to be more active against Jurkat cell line. The antiproliferative activities were compared with MPA and adenosine, in both 2′,3′-O-isopropylidene protected and free hydroxyl groups possessing forms. The obtained results were also discussed in terms of selectivity index, defined as SI = IC₅₀/EC₅₀.     

Sinapic acid derivatives in microwave-pretreated rapeseeds and minor components in oils

Microwave pretreatment has been considered to improve the quality of rapeseed oil for canolol generation. Canolol is assumed to be formed by the decarboxylation of sinapic acid (SA). In this work, sinapic acid derivatives in 39 microwave-pretreated rapeseeds and their roles in the enhanced oxidative stability of rapeseed oils were investigated. The average contents of sinapic acid derivatives in rapeseeds, including (from high to low) sinapine, sinapoyl glucoside (SG), disinapoyl gentiobioside (DSG), quercetin-sinapoyl-di-hexosepentose (QSDG), sinapoyl malate (SM), disinapoyl glucoside (DDSG) and SA, were determined. After microwave pretreatment, the canolol content in rapeseed increased from nil to 6.16–76.1 mg/100 g, while sinapic acid derivatives contents decreased. The degradation rates of SG, DDSG, DSG, SM, SA and sinapine were 59.1%, 40.2%, 33.7%, 27.4%, 14.4% and 11.3%, respectively. There was no correlation relationship between sinapine and canolol. However, SG, DSG, SM and DDSG were regarded to be the precursor substances of canolol. Additionally, the tocopherols, sterols and canolol contents, along with the induction period (IP) of microwaved rapeseed oil increased by 3.79%, 10.0%, 76.8 times and 38.7%, respectively. There was a significant positive correlation between IP and canolol content. These findings clarify the precursor substances of canolol and provide a theoretical support for the development and utilization of canolol.     

Molecular approaches to allergen‐specific immunotherapy: Are we so far from clinical implementation?

Conventional allergen‐specific immunotherapy (AIT), based on administrations of allergen extracts, represents up to now the unique protocol for the desensitization of allergic patients. Whereas the effectiveness of AIT was evidenced for the treatment of allergic rhinitis and allergic asthma, such strategy remains experimental for food allergies up to now. However, important issues are commonly associated with AIT as the quality of natural allergen extracts, the long duration and adverse side‐effects which negatively affect successful desensitization together with the patient compliance. The rapid progression of molecular allergology made possible the quest of safer, shorter and more effective immunotherapeutic approaches. The aim of this review was to provide an update on these different innovative recombinant derivatives including their efficacy but also their limitations. Despite promising preclinical and early clinical studies, the absence of convincing data in large phase III trials precludes so far the translation of these immunotherapeutic candidates into the clinic.     

芳姜黄酮衍生物对A375人黑素瘤细胞增殖及凋亡作用的机制研究

目的：研究一种芳姜黄酮衍生物（ATD）对人皮肤黑色素瘤A375细胞增殖及凋亡的影响。方法不同浓度（5、10、20、40、80μmol/L）ATD、长春新碱及芳姜黄酮体外作用A375及人皮肤成纤维细胞（HSF）48 h。CCK?8法检测细胞增殖抑制率；吖啶橙/溴化乙锭（AO/EB）染色，倒置显微镜观察细胞凋亡形态；DNA片段化检测细胞凋亡；比色法检测半胱氨酸天冬氨酸蛋白酶3（caspase?3）活性；流式细胞仪检测细胞凋亡及周期。结果ATD、长春新碱及芳姜黄酮对A375细胞有抑制增殖作用，且呈剂量依赖性（ATD：R2=0.99，F=340.96；长春新碱：R2=0.99，F=349.19；芳姜黄酮：R2=0.89，F=25.41，均P<0.05），三者IC50分别为（15.96±0.02）、（77.00±0.04）及（356.95±0.01）μmol/L。当药物浓度为5μmol/L及10μmol/L时，ATD对HSF增殖抑制率分别为（8±0.06）%和（25±0.02）%，长春新碱为（33±0.04）%和（29±0.08）%，芳姜黄酮为（49±0.09）%和（34±0.07）%；ATD对A375细胞抑制率分别为（26±0.06）%和（39±0.02）%，长春新碱为（8±0.04）%和（17±0.08）%，芳姜黄酮为（6±0.09）%和（10±0.07）%，与二甲基亚砜相比，差异均有统计学意义（P＜0.05），且ATD对A375细胞增殖抑制活性强于长春新碱及芳姜黄酮（P＜0.05），但对HSF细胞毒性却明显低于长春新碱及芳姜黄酮（P＜0.05）。ATD、长春新碱及芳姜黄酮均可诱导A375细胞凋亡，caspase?3活性随3种药物浓度增加而增强，且药效为ATD>长春新碱>芳姜黄酮。流式细胞仪检测证实，3种药物都能诱导细胞发生不同程度凋亡，同芳姜黄酮及长春新碱相比，ATD能显著诱导细胞凋亡，且以晚期凋亡为主。随药物浓度增加，ATD组G1期A375细胞逐渐增多，G2期及S期细胞数明显减少。结论 ATD对A375细胞有抑制增殖及促凋亡作用，该作用明显强于芳姜黄酮及长春新碱，其机制可能是激活caspase?3，使细胞周期阻滞在G1期，进而抑制肿瘤细胞分化与增殖。     

Critical features of periodontal flaps with regard to blood clot stability: A review

BackgroundWound healing is a multifactorial procedure involving different cell types and biological mediators. The principles of wound healing are also applicable to periodontal tissues. The formation and stability of blood clots play a vital role in successful healing of wounds in periodontal tissues. The aim of the present review was to highlight the vital factors of periodontal flaps associated with blood clot stability.HighlightThe data on periodontal regeneration and wound healing have evolved greatly in light of several factors, including space for blood clots and blood clot stabilization. In periodontal osseous defects, the stability of blood clots seems critical to wound healing. If mechanical forces can be managed by wound stabilization, the gingival flap-tooth root interface may show connective tissue repair. However, compromised adhesion is susceptible to mechanical forces and can cause wound breakage and epithelialization.ConclusionThe presence of a thick blood clot may hinder the plasmatic circulation between the recipient bed and graft during the initial stage of healing, which is critical in cases of mucogingival surgery. Root conditioning can also determine the healing consequence by enhancing blood clot adhesion.