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

Autor: Sahar A. Ali, Samir M. Awad, Shahenda Mahgoub, Yasser M. Zohny, Ahmed M. Said
Rok vydání: 2018
Předmět:
Models
Molecular
0301 basic medicine
pyrimidine
endocrine system
endocrine system diseases
Pyrimidine
Molecular model
medicine.medical_treatment
LPO
Pharmaceutical Science
030209 endocrinology & metabolism
Pharmacology
PTU
Hyperthyroidism
Article
Thiouracil
Analytical Chemistry
lcsh:QD241-441
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
lcsh:Organic chemistry
Antithyroid Agents
Drug Discovery
medicine
Animals
Lactoperoxidase
Physical and Theoretical Chemistry
Binding site
Uracil
Biological evaluation
antithyroid
Binding Sites
Chemistry
Antithyroid agent
Organic Chemistry
Rats
Disease Models
Animal
030104 developmental biology
Design synthesis
Chemistry (miscellaneous)
Triiodothyronine
Molecular Medicine
Hydrophobic and Hydrophilic Interactions
hormones
hormone substitutes
and hormone antagonists
Zdroj: Molecules
Molecules, Vol 23, Iss 11, p 2913 (2018)
Volume 23
Issue 11
ISSN: 1420-3049
DOI: 10.3390/molecules23112913
Popis: 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.
Databáze: OpenAIRE
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