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Molecules 2018, 23(11), 2913; https://doi.org/10.3390/molecules23112913

Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Thiouracil Derivatives as Potential Antithyroid Agents

1
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo 11795, Egypt
2
Pharmaceutical Sciences Department, School of Pharmacy, Shaqra University, P.O. Box 11961, Dawadmi 11911, Saudi Arabia
3
Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo 11795, Egypt
4
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA
*
Author to whom correspondence should be addressed.
Received: 10 September 2018 / Revised: 29 October 2018 / Accepted: 30 October 2018 / Published: 8 November 2018
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
Full-Text   |   PDF [1874 KB, uploaded 8 November 2018]   |  

Abstract

Hyperthyroidism is the result of uncontrolled overproduction of the thyroid hormones. One of the mostly used antithyroid agents is 6-n-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. View Full-Text
Keywords: hyperthyroidism; thiouracil; pyrimidine; antithyroid; PTU; LPO hyperthyroidism; thiouracil; pyrimidine; antithyroid; PTU; LPO
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Awad, S.M.; Zohny, Y.M.; Ali, S.A.; Mahgoub, S.; Said, A.M. Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Thiouracil Derivatives as Potential Antithyroid Agents. Molecules 2018, 23, 2913.

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