疟疾是由雌性按蚊叮咬引起的最已知的媒介传播疾病之一。根据WHO,据估计,2021年全球约有2.47亿疟疾病例和61.9万人死亡,其中95%的病例和96%的死亡发生在非洲地区。可悲的是,大约80%的疟疾死亡是五岁以下的儿童。尽管有不同的杀虫剂用于控制这种疾病,耐药蚊子的出现威胁公众健康。这个,反过来,强调了对在不同幼虫生命阶段有效的新型杀幼虫剂的需求。本研究旨在鉴定新型杀幼虫剂。为此,通过Biginelli反应作为关键步骤,使用三步化学合成方法合成了一系列2,4,6-三取代的-1,4-二氢嘧啶-5-羧酸乙酯8a-i。所有标题化合物均针对阿拉伯按蚊进行筛选,以确定其杀幼虫活性。其中,两个导数,2-((4-溴苯基)氨基)-4-(4-氟苯基)-6-甲基-1,4-二氢嘧啶-5-甲酸乙酯8b和2-((4-溴-2-氰基苯基)氨基)-4-(4-氟苯基)-6-甲基-1,4-二氢嘧啶-5-甲酸乙酯8f,显示出最高的杀幼虫活动,死亡率分别为94%和91%,分别,并成为潜在的杀幼虫剂。此外,计算研究,包括分子对接和分子动力学模拟,进行了研究,以研究其作用机制。计算结果表明,乙酰胆碱酯酶似乎是其杀幼虫特性的合理分子靶标。由RamaswamyH.Sarma沟通。
Malaria is one of the most known vector-borne diseases caused by female Anopheles mosquito bites. According to WHO, about 247 million cases of malaria and 619,000 deaths were estimated worldwide in 2021, of which 95% of the cases and 96% of deaths occurred in the African region. Sadly, about 80% of all malaria deaths were of children under five years old. Despite the availability of different insecticides used to control this disease, the emergence of drug-resistant mosquitoes threatens public health. This, in turn, highlighted the need for new larvicidal agents that are effective at different larval life stages. This study aimed to identify novel larvicidal agents. To this end, a series of ethyl 2,4,6-trisubstituted-1,4-dihydropyrimidine-5-carboxylates 8a-i was synthesized using a three-step chemical synthetic approach via a Biginelli reaction employed as a key step. All title compounds were screened against Anopheles arabiensis to determine their larvicidal activities. Among them, two derivatives, ethyl 2-((4-bromophenyl)amino)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 8b and ethyl 2-((4-bromo-2-cyanophenyl)amino)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 8f, showed the highest larvicidal activity, with mortality of 94% and 91%, respectively, and emerged as potential larvicidal agents. In addition, computational studies, including molecular docking and molecular dynamics simulations, were carried out to investigate their mechanism of action. The computational results showed that acetylcholinesterase appears to be a plausible molecular target for their larvicidal property.Communicated by Ramaswamy H. Sarma.