合成、分子对接及 lawsone 及其衍生物对登革热传播媒介埃及伊蚊的杀蚊活性
Synthesis, Molecular Docking and Mosquitocidal Efficacy of Lawsone and its Derivatives Against the Dengue Vector L. (Diptera: Culicidae).
机构信息
State Key Laboratory of Subtropical Silviculture, Department of Traditional Chinese Medicine, Zhejiang A&F University, Hangzhou 311300, China and Zhejiang Provincial Key Laboratory of Resources Protection and Innovation of Traditional Chinese Medicine, Zhejiang A&F University, Hangzhou 311300, China.
Department of Chemistry, Nirmala College for Women, Coimbatore 641018, Tamil Nadu, India.
出版信息
Med Chem. 2022;18(2):170-180. doi: 10.2174/1573406417666210727121654.
BACKGROUND
Aedes aegypti is the primary vector of dengue, a significant public health problem in many countries. Controlling of Ae. aegypti is the biggest challenge in the mosquito control programe, and there is a need for finding bioactive molecules to control Ae. aegypti in order to prevent dengue virus transmission.
OBJECTIVE
To assess the mosquitocidal property of lawsone and its 3-methyl-4H-chromen-3-yl-1- phenylbenzo[6,7]chromeno[2,3,c]pyrazole-dione derivatives (6a-6h) against various life stages of Ae. aegypti. Besides, to study the mode of action of the active compound by molecular docking and histopathological analysis.
METHODS
All derivatives were synthesized from the reaction between 2-hydroxy-1,4-naphthoquinone, chromene-3-carbaldehyde, and 1-phenyl-3-methyl-pyrazol-5-one by using one pot sequential multicomponent reaction. The mosquito life stages were subjected to diverse concentrations ranging from 1.25, 2.5, 5.0, and 10 ppm for lawsone and its derivatives. The structure of all synthesized compounds was characterized by spectroscopic analysis. Docking analysis was performed using autodock tools. Midgut sections of Ae. aegypti larvae were analyzed for histopathological effects.
RESULTS
Among the nine compounds screened, derivative 6e showed the highest mortality on Ae. aegypti life stages. The analyzed LC and LC90 results of derivative 6e were 3.01, 5.87 ppm, and 3.41, 6.28 ppm on larvae and pupae of Ae. aegypti, respectively. In the ovicidal assay, the derivative 6e recorded 47.2% egg mortality after 96-hour post-exposure to 10 ppm concentration. In molecular docking analysis, the derivative 6e confirmed strong binding interaction (-9.09 kcal/mol and -10.17 kcal/mol) with VAL 60 and HIS 62 of acetylcholinesterase 1 (AChE1) model and LYS 255, LYS 263 of kynurenine aminotransferase of Ae. aegypti, respectively. The histopathological results showed that the derivative 6e affected the columnar epithelial cells (CC) and peritrophic membrane (pM).
CONCLUSION
The derivative 6e is highly effective in the life stages of Ae. aegypti mosquito and it could be used in the integrated mosquito management programe.
背景
埃及伊蚊是登革热的主要传播媒介，在许多国家都是一个严重的公共卫生问题。控制埃及伊蚊是蚊虫控制项目中最大的挑战，因此需要寻找具有生物活性的分子来控制埃及伊蚊，以防止登革热病毒的传播。
目的
评估花色酮及其 3-甲基-4H-色烯-3-基-1-苯基苯并[6,7]色烯并[2,3,c]吡唑二酮衍生物（6a-6h）对埃及伊蚊各生活阶段的杀蚊效果。此外，通过分子对接和组织病理学分析研究活性化合物的作用方式。
方法
所有衍生物均通过一锅顺序多组分反应由 2-羟基-1,4-萘醌、色烯-3-甲醛和 1-苯基-3-甲基-吡唑-5-酮反应得到。将不同浓度的蚊幼虫和蛹置于 1.25、2.5、5.0 和 10ppm 的花色酮及其衍生物中。所有合成化合物的结构均通过光谱分析进行了表征。使用 autodock tools 进行对接分析。分析埃及伊蚊幼虫的中肠切片以观察组织病理学影响。
结果
在所筛选的 9 种化合物中，衍生物 6e 对埃及伊蚊的各个生活阶段表现出最高的致死率。衍生物 6e 对埃及伊蚊幼虫和蛹的分析 LC 和 LC90 结果分别为 3.01、5.87ppm 和 3.41、6.28ppm。在杀卵实验中，暴露于 10ppm 浓度 96 小时后，衍生物 6e 记录到 47.2%的卵死亡率。在分子对接分析中，衍生物 6e 与埃及伊蚊乙酰胆碱酯酶 1（AChE1）模型的 VAL 60 和 HIS 62 以及 kynurenine aminotransferase 的 LYS 255 和 LYS 263 均证实具有强结合相互作用（-9.09 kcal/mol 和-10.17 kcal/mol）。组织病理学结果表明，衍生物 6e 影响柱状上皮细胞（CC）和围食膜（pM）。
结论
衍生物 6e 对埃及伊蚊的各个生活阶段都非常有效，可用于综合蚊虫管理计划。
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