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1.
Bioorg Chem ; 104: 104216, 2020 11.
Article in English | MEDLINE | ID: mdl-32911191

ABSTRACT

The article is devoted to the targeted synthesis and study of cyclic thiourea and their various new derivatives as new organic compounds containing polyfunctional group in the molecule. First time the reaction of the corresponding synthesized pyrimidinethione with 1,2-epoxy-3-chlorpropane at the presence of AlCl3 catalyst in 75-80% yield alkyl-1-(3-chloro-2-hydroxypropyl)-4-alkyl-6-phenyl-2-thioxo-1,2,5,6- tetrahydropyrimidine-5-carboxylates. In the next stage, new cyclic thiourea derivatives of aminoalcohols were synthesised from the reaction of chlorinated derivatives of pyrimidinethiones with single amines and their structures were investigated by spectroscopic methods. In this study, a series of novel compounds were tested towards some metabolic enzymes including α-glycosidase (α-Gly) and α-amylase (α-Amy) enzymes. Novel compounds showed Kis in ranging of 10.43 ± 0.94-111.37 ± 13.25 µM on α-glycosidase and IC50 values in ranging of 14.38-106.51 µM on α-amylase. The novel cyclic thiourea derivatives of aminoalcohols had effective inhibition profiles against all tested metabolic enzymes. Binding affinity and inhibition mechanism of the most active compounds were detected with in silico studies and have shown that 2-Hydroxypropyl and butan-1-aminium moieties play a key role for inhibition of the enzymes.


Subject(s)
Aluminum Chloride/chemistry , Amino Alcohols/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolases/antagonists & inhibitors , Thiourea/pharmacology , alpha-Amylases/antagonists & inhibitors , Amino Alcohols/chemistry , Catalysis , Dose-Response Relationship, Drug , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolases/metabolism , Humans , Molecular Docking Simulation , Molecular Structure , Saccharomyces cerevisiae/enzymology , Structure-Activity Relationship , Thiourea/chemical synthesis , Thiourea/chemistry , alpha-Amylases/metabolism
2.
J Biochem Mol Toxicol ; 32(2)2018 Feb.
Article in English | MEDLINE | ID: mdl-29283199

ABSTRACT

The conversion reactions of pyrimidine-thiones with nucleophilic reagent were studied during this scientific research. For this purpose, new compounds were synthesized by the interaction between 1,2-epoxy propane, 1,2-epoxy butane, and 4-chlor-1-butanol and pyrimidine-thiones. These pyrimidine-thiones derivatives (A-K) showed good inhibitory action against acetylcholinesterase (AChE), and human carbonic anhydrase (hCA) isoforms I and II. AChE inhibition was in the range of 93.1 ± 33.7-467.5 ± 126.9 nM. The hCA I and II were effectively inhibited by these compounds, with Ki values in the range of 4.3 ± 1.1-9.1 ± 2.7 nM for hCA I and 4.2 ± 1.1-14.1 ± 4.4 nM for hCA II. On the other hand, acetazolamide clinically used as CA inhibitor showed Ki value of 13.9 ± 5.1 nM against hCA I and 18.1 ± 8.5 nM against hCA II. The antioxidant activity of the pyrimidine-thiones derivatives (A-K) was investigated by using different in vitro antioxidant assays, including Cu2+ and Fe3+ reducing, 1,1-diphenyl-2-picrylhydrazyl (DPPH• ) radical scavenging, and Fe2+ chelating activities.


Subject(s)
Antioxidants/pharmacology , Carbonic Anhydrase Inhibitors/pharmacology , Cholinesterase Inhibitors/pharmacology , Drug Design , Pyrimidines/pharmacology , Thiones/pharmacology , Acetazolamide/chemistry , Acetazolamide/pharmacology , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Antioxidants/chemical synthesis , Antioxidants/chemistry , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrases/chemistry , Carbonic Anhydrases/isolation & purification , Carbonic Anhydrases/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Humans , Iron Chelating Agents/chemical synthesis , Iron Chelating Agents/chemistry , Iron Chelating Agents/pharmacology , Isoenzymes/antagonists & inhibitors , Isoenzymes/isolation & purification , Isoenzymes/metabolism , Kinetics , Molecular Structure , Nootropic Agents/chemical synthesis , Nootropic Agents/chemistry , Nootropic Agents/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Thiones/chemical synthesis , Thiones/chemistry , Transition Temperature
3.
J Biochem Mol Toxicol ; 31(7)2017 Jul.
Article in English | MEDLINE | ID: mdl-28117934

ABSTRACT

In the presence of trifluoracetic acid (TFAA), an efficient method for the synthesis of tetra(hexa)hydropyrimidinethione-carboxylates has been used on the basis of three-component condensation of thiourea with its different aldehydes and ß-diketones. Some novel cyclic thioureas were synthesized, and their hCA I, hCA II, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitors and metal-chelating properties were evaluated. Ki values of novel synthesized compounds for AChE and BChE are in the range of 51.84-135.96 and 143.96-274.55 nM, respectively. Also, HCA I and II were effectively inhibited by these novel compounds, with Ki values in the range of 404.16-745.13 nM for hCA I and of 434.20-689.57 nM for hCA II, respectively. Additionally, acetazolamide (AZA), clinically used as a CA inhibitor, with a Ki value of 883.68 ± 121.27 nM in hCA I and 1008.66 ± 144.70 nM in hCA II. Also, tacrine inhibited AChE and BChE showed Ki values of 314.63 ± 31.66 and 373.57 ± 75.07 nM, respectively.


Subject(s)
Acetylcholinesterase/chemistry , Butyrylcholinesterase/chemistry , Carbonic Anhydrase Inhibitors , Carbonic Anhydrases/chemistry , Cholinesterase Inhibitors , Thiourea , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Thiourea/chemical synthesis , Thiourea/chemistry
4.
J Enzyme Inhib Med Chem ; 31(sup3): 1-9, 2016.
Article in English | MEDLINE | ID: mdl-27329935

ABSTRACT

A series of tetrahydropyrimidinethiones were synthesized from thiourea, ß-diketones and aromatic aldehydes, such as p-tolualdehyde, p-anisaldehyde, o-tolualdehyde, salicylaldehyde and benzaldehyde. These cyclic thioureas showed good inhibitory action against acetylcholine esterase (AChE), butyrylcholine esterase (BChE), and human (h) carbonic anhydrase (CA) isoforms I and II. AChE and BChE inhibitions were in the range of 6.11-16.13 and 6.76-15.68 nM, respectively. hCA I and II were effectively inhibited by these compounds, with Ki values in the range of 47.40-76.06 nM for hCA I, and of 30.63-76.06 nM for hCA II, respectively. The antioxidant activity of the cyclic thioureas was investigated by using different in vitro antioxidant assays, including 1,1-diphenyl-2-picrylhydrazyl (DPPH·) radical scavenging, Cu2+ and Fe3+ reducing, and Fe2+ chelating activities.


Subject(s)
Acetylcholinesterase/metabolism , Antioxidants/pharmacology , Butyrylcholinesterase/metabolism , Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase I/antagonists & inhibitors , Carbonic Anhydrase Inhibitors/pharmacology , Cholinesterase Inhibitors/pharmacology , Pyrimidines/pharmacology , Antioxidants/chemical synthesis , Antioxidants/chemistry , Carbonic Anhydrase I/metabolism , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship
5.
J Enzyme Inhib Med Chem ; 31(6): 1531-9, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27050248

ABSTRACT

2-(Methacryloyloxy)ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate, is a cyclic urea derivative synthesized from urea, 2-(methacryloyloxy) ethyl acetoacetate and substituted benzaldehyde, and tested in terms of the inhibition of two physiologically relevant carbonic anhydrase (CA) isozymes I and II. Acetylcholinesterase (AChE) is found in high concentrations in the red blood cells and brain. Butyrylcholinesterase (BChE) is another enzyme abundantly present in the liver and released into blood in a soluble form. Also, they were tested for the inhibition of AChE and BChE enzymes and demonstrated effective inhibition profiles with Ki values in the range of 429.24-530.80 nM against hCA I, 391.86-530.80 nM against hCA II, 68.48-97.19 nM against AChE and 104.70-214.15 nM against BChE. On the other hand, acetazolamide clinically used as CA inhibitor, showed Ki value of 281.33 nM against hCA I, and 202.70 nM against hCA II. Also, Tacrine inhibited AChE and BChE showed Ki values of 396.03 and 209.21 nM, respectively.


Subject(s)
Acetylcholinesterase/drug effects , Butyrylcholinesterase/drug effects , Carbonic Anhydrase Inhibitors/pharmacology , Carboxylic Acids/chemical synthesis , Chelating Agents/pharmacology , Cholinesterase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Carboxylic Acids/pharmacology , Models, Molecular , Pyrimidines/chemistry
6.
J Enzyme Inhib Med Chem ; 31(6): 1192-7, 2016 Dec.
Article in English | MEDLINE | ID: mdl-26586381

ABSTRACT

Tetrahydropyrimidine thiones, which are cyclic thiocarbamides derivatives, were synthesised from thiourea, ß-diketones and substituted benzaldehydes. A tautomeric form of these derivatives incorporates the thiol functionality, which is known to interact with metal ions from metalloenzymes active sites, such as the carbonic anhydrases (CAs, EC 4.2.1.1) among others. This is a superfamily of widespread enzymes, which catalyses a crucial biochemical reaction, the reversible hydration of carbon dioxide to bicarbonate and protons (H(+)). The newly synthesised N-alkyl (aril)-tetrahydropyrimidine thiones were tested for inhibition of the cytosolic human isoforms I and II (hCA I and II). Both isoforms were effectively inhibited by the newly synthesised thiones. Ki values were in the range of 218.5 ± 23.9-261.0 ± 41.5 pM for hCA I, and of 181.8 ± 41.9-273.6 ± 41.4 pM for hCA II, respectively. This under-investigated class of derivatives may bring interesting insights in the field of non-sulphonamide CA inhibitors.


Subject(s)
Carbonic Anhydrase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Thiones/chemistry , Humans , Pyrimidines/chemistry
7.
Acta Crystallogr Sect E Struct Rep Online ; 68(Pt 2): o276, 2012 Feb 01.
Article in English | MEDLINE | ID: mdl-22346918

ABSTRACT

In the title compound, C(13)H(14)N(2)OS, four C atoms of the phenyl ring are disordered over two sets of sites in a 0.60 (3):0.40 (3) ratio. The heterocyclic ring is essentially planar (r.m.s. deviation = 0.017 Å) and forms dihedral angles of 82.0 (2) and 79.3 (3)°, respectively, with the major and minor occupancy components of the phenyl ring. The crystal packing features N-H⋯O hydrogen bonds, which link the mol-ecules into C(6) chains running parallel to the b axis.

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