Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo 11795, Egypt.
Pharmaceutical Sciences Department, School of Pharmacy, Shaqra University, P.O. Box 11961, Dawadmi 11911, Saudi Arabia.
Molecules. 2018 Nov 8;23(11):2913. doi: 10.3390/molecules23112913.
Hyperthyroidism is the result of uncontrolled overproduction of the thyroid hormones. One of the mostly used antithyroid agents is 6-propyl-2-thiouracil (PTU). The previously solved X-ray crystal structure of the PTU bound to mammalian lactoperoxidase (LPO) reveals that the LPO-PTU binding site is basically a hydrophobic channel. There are two hydrophobic side chains directed towards the oxygen atom in the C-4 position of the thiouracil ring. In the current study, the structural activity relationship (SAR) was performed on the thiouracil nucleus of PTU to target these hydrophobic side chains and gain more favorable interactions and, in return, more antithyroid activity. Most of the designed compounds show superiority over PTU in reducing the mean serum T4 levels of hyperthyroid rats by 3% to 60%. In addition, the effect of these compounds on the levels of serum T3 was found to be comparable to the effect of PTU treatment. The designed compounds in this study showed a promising activity profile in reducing levels of thyroid hormones and follow up experiments will be needed to confirm the use of the designed compounds as new potential antithyroid agents.
甲状腺功能亢进症是甲状腺激素过度产生失控的结果。最常用的抗甲状腺药物之一是 6-丙基-2-硫代尿嘧啶（PTU）。之前解决的 PTU 与哺乳动物乳过氧化物酶（LPO）结合的 X 射线晶体结构表明，LPO-PTU 结合位点基本上是一个疏水性通道。有两个指向硫代尿嘧啶环 C-4 位置氧原子的疏水性侧链。在当前的研究中，对 PTU 的硫代尿嘧啶核进行了结构活性关系（SAR）研究，以针对这些疏水性侧链，获得更有利的相互作用，并相应地提高抗甲状腺活性。大多数设计的化合物在降低甲状腺功能亢进大鼠血清 T4 水平方面均优于 PTU，降低幅度为 3%至 60%。此外，发现这些化合物对血清 T3 水平的影响与 PTU 治疗的效果相当。本研究设计的化合物在降低甲状腺激素水平方面表现出有希望的活性特征，需要进行后续实验来确认设计化合物作为新的潜在抗甲状腺药物的用途。
