Adebayo Glory P, Oduselu Gbolahan O, Aderohunmu Damilola V, Klika Karel D, Olasehinde Grace I, Ajani Olayinka O, Adebiyi Ezekiel
Covenant University Bioinformatics Research (CUBRe), Covenant University, Ota, Nigeria.
Biological Sciences Department, Covenant University, Ota, Nigeria.
Arab J Chem. 2024 Feb;17(2). doi: 10.1016/j.arabjc.2023.105573. Epub 2023 Dec 18.
Malaria remains a significant global health concern causing numerous fatalities and the emergence of antimalarial drug resistance highlights the urgent need for novel therapeutic options with innovative mechanisms of action and targets. This study aimed to design potential inhibitors of 6-pyruvoyltetrahydropterin synthase (PTPS), synthesize them, and experimentally validate their efficacy as antimalarial agents. A structure-based approach was employed to design a series of novel derivatives, including amidinyl, amidoximyl and hydroxamic acid analogs (, , , and ), with a focus on their ability to bind to the Zn present in the active site of PTPS. The syntheses of these compounds were accomplished through various multi-step synthetic pathways and their structural identities were confirmed using H and C NMR spectra, mass spectra, and elemental analysis. The compounds were screened for their antiplasmodial activity against the NF54 strain of and cytotoxicity testing was performed using L-6 cells. The acute toxicity of the compounds was evaluated in mice. Docking studies of the compounds with the 3D structure of PTPS revealed their strong binding affinities, with compound exhibiting notable metal-acceptor interaction with the Zn in the protein binding pocket thereby positioning it as a lead compound for PTPS inhibition. The antiplasmodial studies revealed moderate efficacies against the NF54 strain, particularly compounds and which displayed IC < 0.2 μM. No significant cytotoxicity was noted on the L-6 rat cell line. Moreover, studies suggested that compound exhibited both safety and efficacy in treating rodent malaria. The identified lead compound in this study represents a possible candidate for antimalarial drug development and can be further explored in the search for alternative antifolate drugs to combat the malaria menace.
疟疾仍然是一个重大的全球健康问题，导致众多死亡，而抗疟药物耐药性的出现凸显了迫切需要具有创新作用机制和靶点的新型治疗选择。本研究旨在设计6-丙酮酰四氢蝶呤合酶（PTPS）的潜在抑制剂，合成它们，并通过实验验证其作为抗疟剂的功效。采用基于结构的方法设计了一系列新型衍生物，包括脒基、偕胺肟基和异羟肟酸类似物（、、、和），重点关注它们与PTPS活性位点中存在的锌结合的能力。这些化合物的合成通过各种多步合成途径完成，并使用氢谱和碳谱、质谱和元素分析确认了它们的结构特征。筛选了这些化合物对恶性疟原虫NF54株的抗疟活性，并使用L-6细胞进行细胞毒性测试。在小鼠中评估了这些化合物的急性毒性。化合物与PTPS三维结构的对接研究揭示了它们很强的结合亲和力，化合物与蛋白质结合口袋中的锌表现出显著的金属受体相互作用，从而使其成为PTPS抑制的先导化合物。抗疟研究显示对恶性疟原虫NF54株有中等疗效，特别是化合物和显示出IC<0.2μM。在L-6大鼠细胞系上未观察到明显的细胞毒性。此外，研究表明化合物在治疗啮齿动物疟疾方面表现出安全性和有效性。本研究中确定的先导化合物代表了抗疟药物开发的一个可能候选物，可在寻找替代抗叶酸药物以对抗疟疾威胁的研究中进一步探索。
