Omar A Mohsen M E, Aboulwafa Omaima M, Issa Doaa A E, El-Shoukrofy Mai S M, Amr May E, El-Ashmawy Ibrahim M
Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Alexandria University , 21521 , Alexandria , Egypt.
Department of Pharmaceutical Sciences, Faculty of Pharmacy , Beirut Arab University , 115020 , Beirut , Lebanon . Email:
Medchemcomm. 2017 May 12;8(7):1440-1451. doi: 10.1039/c7md00140a. eCollection 2017 Jul 1.
In the framework of pursuing the design and synthesis of a new series of substituted 6-methoxybenzothiazole-2-carbamates as potential anthelmintics, and as a continuation of the expended efforts in part I, we have set out to develop novel compounds with enhanced anthelmintic activity by blocking the 6-position of benzothiazole with side chains of different polarities. Guided by the findings in part I, and reporting the paramphistomicidal activity of oxadiazoline derivatives and , we aimed to synthesize target benzothiazoles designed to comprise some planar heterocyclic ring systems, namely, 1,3,4-oxadiazoles and 1,2,4-triazoles, bearing a variety of hydrophobic and hydrophilic components. The synthesis of the desired compounds was primarily achieved by cyclization of 6-acetohydrazide, . The paramphistomicidal activity of all synthesized carbamates was evaluated. Four synthesized carbamates exhibited notable activity. Compound , methyl 6-[(5-(4-bromophenacylsulfanyl)-[1,3,4]-oxadiazol-2-yl)methoxy]benzothiazole-2-carbamate, displayed an equipotent effect to the reference drug oxyclozanide at a concentration of 80 μg mL; compounds , and showed high orders of anthelmintic effect. A structural computational study on the polar nature and hydrophilic-lipophilic properties of the synthesized carbamates was undertaken to discuss their structure-activity relationship (SAR). Besides, pharmacophore mapping was performed using eight active compounds as a training set. The generated pharmacophore model revealed five common features and was validated using fenbendazole, triclabendazole and triclabendazole sulfoxide.
在致力于设计和合成一系列新型取代的6-甲氧基苯并噻唑-2-氨基甲酸酯作为潜在驱虫剂的框架内，并且作为第一部分所做大量工作的延续，我们已着手通过用不同极性的侧链封闭苯并噻唑的6-位来开发具有增强驱虫活性的新型化合物。以第一部分的研究结果为指导，并报告恶唑啉衍生物 和 的双口吸虫杀虫活性，我们旨在合成目标苯并噻唑，其设计包含一些平面杂环系统，即1,3,4-恶二唑和1,2,4-三唑，带有各种疏水和亲水成分。所需化合物的合成主要通过6-乙酰肼的环化反应实现。对所有合成的氨基甲酸酯的双口吸虫杀虫活性进行了评估。四种合成的氨基甲酸酯表现出显著活性。化合物6-[(5-(4-溴苯甲酰硫基)-[1,3,4]-恶二唑-2-基)甲氧基]苯并噻唑-2-氨基甲酸甲酯在浓度为80 μg/mL时对参比药物奥昔氯唑酰胺显示出等效效果；化合物 、 和 表现出高等级的驱虫效果。对合成的氨基甲酸酯的极性性质和亲水-亲脂性质进行了结构计算研究，以讨论它们的构效关系（SAR）。此外，使用八种活性化合物作为训练集进行了药效团映射。生成的药效团模型揭示了五个共同特征，并使用芬苯达唑、三氯苯达唑和三氯苯达唑亚砜进行了验证。
