Rants'o Thankhoe A, Koekemoer Lizette L, van Zyl Robyn L
Pharmacology Division, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; WITS Research Institute for Malaria, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
WITS Research Institute for Malaria, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa.
Parasitol Int. 2023 Apr;93:102713. doi: 10.1016/j.parint.2022.102713. Epub 2022 Nov 28.
Anopheles gambiae, An. coluzzii, An. arabiensis, and An. funestus are major vectors in high malaria endemic African regions. Various terpenoid classes form the main chemical constituent repository of essential oils, many of which have been shown to possess insecticidal effects against Anopheles species. The current study aimed to assess the bioactivity of terpenoids including four sesquiterpene alcohols, farnesol, (-)-α-bisabolol, cis-nerolidol, and trans-nerolidol; a phenylpropanoid, methyleugenol, and a monoterpene, (R)-(+)-limonene, using the larvicidal screening assay against the four Anopheles species. The mechanism of action was investigated through in vitro acetylcholinesterase inhibition assay and in silico molecular modelling. All six terpenoids showed potent larvicidal activity against the four Anopheles species. Insights into the mechanism of action revealed that the six terpenoids are strong AChE inhibitors against An. funestus and An. arabiensis, while there was a moderate inhibitory activity against An. gambiae AChE, but very weak activity against An. coluzzii. Interestingly, in the in silico study, farnesol established a favourable hydrogen bonding interaction with a conserved amino acid residue, Cys, at the entrance to the active site gorge. While (-)-α-bisabolol and methyleugenol displayed a strong interaction with the catalytic Ser and adjacent amino acid residues; but sparing the mutable Gly residue that confers resistance to the current anticholinesterase insecticides. As a result, this study identified farnesol, (-)-α-bisabolol, and methyleugenol as selective bioinsecticidal agents with potent Anopheles AChE inhibition. These terpenoids present as natural compounds for further development as anticholinesterase bioinsecticides.
冈比亚按蚊、科氏按蚊、阿拉伯按蚊和嗜人按蚊是非洲疟疾高流行地区的主要病媒。各类萜类化合物构成了精油的主要化学成分库，其中许多已被证明对按蚊具有杀虫作用。本研究旨在通过对这四种按蚊进行幼虫筛选试验，评估包括四种倍半萜醇（法尼醇、(-)-α-红没药醇、顺式橙花叔醇和反式橙花叔醇）、一种苯丙素（甲基丁香酚）和一种单萜（(R)-(+)-柠檬烯）在内的萜类化合物的生物活性。通过体外乙酰胆碱酯酶抑制试验和计算机模拟分子建模研究其作用机制。所有六种萜类化合物对这四种按蚊均表现出强大的杀幼虫活性。对作用机制的深入研究表明，这六种萜类化合物是针对嗜人按蚊和阿拉伯按蚊的强效乙酰胆碱酯酶抑制剂，而对冈比亚按蚊乙酰胆碱酯酶具有中等抑制活性，对科氏按蚊的活性则非常弱。有趣的是，在计算机模拟研究中，法尼醇在活性位点峡谷入口处与一个保守氨基酸残基半胱氨酸形成了良好的氢键相互作用。而(-)-α-红没药醇和甲基丁香酚与催化丝氨酸及相邻氨基酸残基表现出强烈相互作用；但未与赋予对当前抗胆碱酯酶杀虫剂抗性的可变甘氨酸残基相互作用。因此，本研究确定法尼醇、(-)-α-红没药醇和甲基丁香酚为具有强效按蚊乙酰胆碱酯酶抑制作用的选择性生物杀虫剂。这些萜类化合物作为天然化合物，可进一步开发为抗胆碱酯酶生物杀虫剂。
