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1.
J Inorg Biochem ; 160: 114-24, 2016 07.
Article in English | MEDLINE | ID: mdl-26765999

ABSTRACT

The new silver(I) compound {[AgBr(µ2-S-MMI)(TPP))]2} (1) and the known one [AgCl(TPP)2(MMI)] (2) were obtained by refluxing toluene solutions of silver(I) halide with triphenylphosphine (TPP) and the anti-thyroid drug 2-mercapto-1-methyl-imidazole or methimazole (MMI). The complexes were characterized by m.p., vibrational spectroscopy (mid-FT-IR), (1)H, (31)P-NMR, UV-Vis spectroscopic techniques and X-ray crystallography. The antibacterial effect of 1 and 2 against the bacterial species Pseudomonas aeruginosa (PAO) and Escherichia coli was evaluated. Compound 1 exhibits comparable activity to the corresponding one of the silver nitrate which is an antibacterial drug in use. The in vivo genotoxicity of 1-2 by the mean of Allium cepa test shows no alterations in the mitotic index values due to the absence of chromosomal aberrations. The mechanism of action of the title compounds is evaluated. The DNA binding tests indicate the ability of the complexes 1-2 to modify the activity of the bacteria. The binding constants of 1-2 towards CT-DNA indicate interaction through opening of the hydrogen bonds of DNA. Docking studies on DNA-complexes interactions confirm the binding of both complexes 1-2 in the major groove of the CT-DNA. In conclusion the silver complex 1 is an anti-bacterial and non-genotoxic material, which can be applied to antibacterial drug in the future.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antithyroid Agents/chemical synthesis , Coordination Complexes/chemical synthesis , Methimazole/chemical synthesis , Silver/chemistry , Anti-Bacterial Agents/pharmacology , Antithyroid Agents/pharmacology , Binding Sites , Coordination Complexes/pharmacology , DNA/chemistry , Drug Repositioning , Escherichia coli/drug effects , Escherichia coli/growth & development , Hydrogen Bonding , Methimazole/pharmacology , Microbial Sensitivity Tests , Mitotic Index , Molecular Docking Simulation , Onions/cytology , Onions/drug effects , Onions/genetics , Organophosphorus Compounds/chemistry , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/growth & development , Silver Nitrate/pharmacology , Toluene/chemistry
2.
Bioorg Med Chem ; 22(9): 2809-15, 2014 May 01.
Article in English | MEDLINE | ID: mdl-24703463

ABSTRACT

In this study, we synthesized 4 methimazole (2-mercapto-1-methylimidazole, MMI) derivatives. The kinetics of inhibition on mushroom tyrosinase by methimazole and its derivatives were investigated. The results indicated that tert-butyl 3-methyl-2-sulfanylidene-2,3-dihydro-1H-imidazole-1-carboxylate (compound 3; 3), 2-mercaptoimidazole (MI; compound 1; 1) and MMI (compound 2; 2) significantly inhibited tyrosinase activity in a dose-dependent manner, exhibiting an IC50 value of 1.50mM, 4.11 mM, and 1.43 mM. However, compound 4 (4), compound 5 (5), and compound 6 (6) exerted no inhibitory effect on mushroom tyrosinase activity. Kinetic analysis indicated that 3 was a noncompetitive tyrosinase inhibitor, whereas both 1 and 2 were exhibited as mixed-type tyrosinase inhibitors. Furthermore, 3 exerted a potent inhibitory effect on intracellular melanin formation in the B16/F10 murine melanoma cells and did not cause cytotoxicity, as 1 and 2 did.


Subject(s)
Enzyme Inhibitors/chemistry , Melanins/metabolism , Methimazole/chemistry , Monophenol Monooxygenase/antagonists & inhibitors , Agaricales , Animals , Cell Line, Tumor , Cell Survival/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/toxicity , Kinetics , Methimazole/chemical synthesis , Methimazole/toxicity , Mice , Monophenol Monooxygenase/metabolism
3.
Biometals ; 23(2): 255-64, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20012553

ABSTRACT

Methimazole (MeimzH) is an anti-thyroid drug and the first choice for patients with Grave's disease. Two new copper(II) complexes of this drug: [Cu(MeimzH)(2)(NO(3))(2)]*0.5H(2)O and [Cu(MeimzH)(2)(H(2)O)(2)](NO(3))(2)*H(2)O were synthesized and characterized by elemental analysis, dissolution behavior, thermogravimetric analysis and UV-vis, diffuse reflectance, FTIR and EPR spectroscopies. As it is known that copper(II) cation can act as an inhibitor of alkaline phosphatase (ALP), the inhibitory effect of methimazole and its copper(II) complexes on ALP activity has also been investigated.


Subject(s)
Alkaline Phosphatase/antagonists & inhibitors , Antithyroid Agents/chemical synthesis , Antithyroid Agents/metabolism , Antithyroid Agents/therapeutic use , Copper/chemistry , Graves Disease/drug therapy , Methimazole/chemical synthesis , Methimazole/metabolism , Methimazole/therapeutic use , Animals , Antithyroid Agents/chemistry , Electron Spin Resonance Spectroscopy , Humans , Methimazole/chemistry , Spectrophotometry, Ultraviolet , Spectroscopy, Fourier Transform Infrared
4.
Biochem Pharmacol ; 48(7): 1447-53, 1994 Oct 07.
Article in English | MEDLINE | ID: mdl-7524506

ABSTRACT

Methimazole (MMI), unlike propylthiouracil (PTU) is a poor inhibitor of type I iodothyronine deiodinase (ID-1). Inhibition of the enzyme by PTU was attributed initially to formation of a mixed disulfide between PTU and a cysteine residue at the active site. Presumably, MMI was unable to form a stable mixed disulfide and thus did not inhibit the enzyme. However, it has been demonstrated recently that ID-1 is a selenium-containing enzyme, with selenocysteine, rather than cysteine, at the active site. This observation raised the possibility that the selenium analog of MMI, methyl selenoimidazole (MSeI), might be a better inhibitor of ID-1 than MMI itself, as formation of the Se-Se bond with the enzyme would be expected to occur more readily than formation of the S-SE bond. To test this possibility, we developed a procedure for the synthesis of MSeI and compared MSeI with MMI and PTU for inhibition of ID-1 and for antithyroid activity. For inhibition of ID-1, MMI and MSeI were tested at concentrations of 10-300 microM. No significant inhibition was observed with MMI. MSeI showed slight but significant inhibition only in the 100-300 microM range. PTU, on the other hand, showed marked inhibition at 1 microM. Thus, replacement of the sulfur in MMI with selenium only marginally increases its inhibitory effect on ID-1. As an inhibitor of ID-1, MSeI is much less than 1% as potent as PTU. MMI and MSeI were also compared for antithyroid activity, both in vivo and in vitro. As an inhibitor of the catalytic activity of thyroid peroxidase, MMI was 4-5 times more potent than MSeI in a guaiacol assay, but only twice as potent in an iodination assay. In in vivo experiments with rats, MMI was at least 50 times more potent than MSeI in inhibiting thyroidal organic iodine formation. The relatively low potency of MSeI in vivo suggests that it is much less well concentrated by the thyroid than in MMI.


Subject(s)
Antithyroid Agents/pharmacology , Iodide Peroxidase/antagonists & inhibitors , Methimazole/pharmacology , Selenium/pharmacology , Animals , Dose-Response Relationship, Drug , Hydrogen Peroxide , Iodide Peroxidase/pharmacology , Methimazole/analogs & derivatives , Methimazole/chemical synthesis , Microsomes, Liver/enzymology , Oxidation-Reduction , Propylthiouracil/antagonists & inhibitors , Rats , Time Factors
5.
J Pharm Sci ; 70(12): 1322-4, 1981 Dec.
Article in English | MEDLINE | ID: mdl-7320844

ABSTRACT

A series of five 6-alkyl- and 6-aryl-mesoionic 1-methylimidazo[2,1-b][1,3]thiazine-5,7-diones was synthesized and found to produce 1-methyl-3H-imidazole-2-thione (methimazole) upon alkaline hydrolysis or treatment with amine or thiol reagents. The alkaline hydrolysis followed a second-order rate expression, being dependent on both substrate and hydroxide-ion concentrations. The rate constants for the five derivatives fell within 6-15 x 10(-2) liter/mole min at 40 degrees. These compounds were stable in aqueous acidic solutions and in human serum or rat liver homogenate under conditions producing rapid hydrolysis of the methimazole prodrug 1-carbethoxy-2-methylimidazole-2-thione (carbimazole).


Subject(s)
Methimazole/analogs & derivatives , Animals , Kinetics , Liver/metabolism , Male , Methimazole/chemical synthesis , Methimazole/metabolism , Rats , Rats, Inbred Strains
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