Hamid Aneeqa, Qureshi Naveeda Akhtar, Rehman Ayema, Azam Jawad, Nadeem Humaira, Ulhaq Inzamam, Farzand Shahbaz, Saleem Anber, Irshad Nadeem
Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan.
Department of Zoology, Quaid-i-Azam University, Islamabad, Pakistan.
Bioorg Chem. 2025 Aug;163:108634. doi: 10.1016/j.bioorg.2025.108634. Epub 2025 May 28.
Malaria is a vector-borne and blood-borne disease substantially contributing to morbidity and mortality worldwide for many years, especially in developing countries, causing a serious threat to public health. The growing resistance of the Plasmodium parasite to existing antimalarials highlights the urgent need for novel drugs. The present study aimed to investigate the antiplasmodial effect of three doses of 2-((1H-benzo[d]imidazole-2-yl)thio)-1-(3,5-diphenyl-1H-pyrazol-1-yl)ethenone (3a) on Plasmodium berghei induced malaria in mice using chloroquine as a reference drug. Mice were observed for morphological and behavioral changes, as well as hematological and biochemical analysis. Liver and spleen were subjected to histopathology, antioxidant assays, immunohistochemical analysis, and polymerase chain reaction. Furthermore, molecular docking was performed to assess antimalarial protein targets. The study provides compelling evidence that 3a demonstrated dose-dependent reduction in parasitemia, restoration of hematological and biochemical parameters with 800 μg/kg of 3a, antioxidant potential via decreasing oxidative stress markers and enhancing antioxidant markers. Furthermore, it also supports the anti-inflammatory property of compound via reducing levels of proinflammatory cytokines in immunohistochemistry and polymerase chain reaction. Docking study indicates that binding affinity of 3a with P. falciparum proteins is even better than that of chloroquine especially with P. falciparum plasmepsins. Hence 3a offers a promising alternative candidate in search for new antimalarial agents.
疟疾是一种通过媒介传播和血液传播的疾病，多年来在全球范围内对发病率和死亡率有重大影响，尤其是在发展中国家，对公共卫生构成严重威胁。疟原虫对现有抗疟药物的耐药性不断增强，凸显了对新型药物的迫切需求。本研究旨在以氯喹为对照药物，研究三种剂量的2-((1H-苯并[d]咪唑-2-基)硫代)-1-(3,5-二苯基-1H-吡唑-1-基)乙烯酮(3a)对伯氏疟原虫诱导的小鼠疟疾的抗疟作用。观察小鼠的形态和行为变化，以及血液学和生化分析。对肝脏和脾脏进行组织病理学、抗氧化测定、免疫组织化学分析和聚合酶链反应。此外，进行分子对接以评估抗疟蛋白靶点。该研究提供了令人信服的证据，表明3a表现出剂量依赖性的疟原虫血症降低，800μg/kg的3a可恢复血液学和生化参数，通过降低氧化应激标志物和增强抗氧化标志物具有抗氧化潜力。此外，它还通过在免疫组织化学和聚合酶链反应中降低促炎细胞因子水平来支持该化合物的抗炎特性。对接研究表明，3a与恶性疟原虫蛋白的结合亲和力甚至优于氯喹，尤其是与恶性疟原虫天冬氨酸蛋白酶。因此，3a为寻找新的抗疟药物提供了一个有前景的替代候选物。
