Synthesis of N-alkyl (aril)-tetra pyrimidine thiones and investigation of their human carbonic anhydrase I and II inhibitory effects.
01 Nov 2016-Journal of Enzyme Inhibition and Medicinal Chemistry (Taylor & Francis)-Vol. 31, Iss: 6, pp 1192-1197
TL;DR: Tetrahydropyrimidine thiones, which are cyclic thiocarbamides derivatives, were synthesised from thiourea, β-diketones and substituted benzaldehydes, and tested for inhibition of the cytosolic human isoforms I and II.
Abstract: Tetrahydropyrimidine thiones, which are cyclic thiocarbamides derivatives, were synthesised from thiourea, β-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.
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TL;DR: The novel synthesized compounds (MZ1-MZ11) have a higher enzyme inhibitory potential than ACR, TAC, and AZA, respectively and may have the potential to be used as alternative medicines after further research in the treatment of many diseases such as diabetes, Alzheimer's disease, heart failure, ulcer, and epilepsy.
103 citations
01 Jan 2014
TL;DR: Sulphamides and sulphonamides are important biologically active compounds as mentioned in this paper and have potential use in the treatment of depression,neuropathic and inflammatory pains.
Abstract: Sulphamides [1] and sulphonamides [2] are importantbiologically active compounds. In the last decades a lot ofsulphamide and sulphonamide drugs have appeared inthe markets. Quinagolide (1), a dopaminergic drug, isan antihyperprolactinemia agent [3]. Compound 2 (JNJ-26990990) has potential use in the treatment of depression,neuropathic and inflammatory pains [4]. The sulphonamidedrug sultiame (3) is an anticonvulsant used in the treatmentof epilepsy and West syndrome [5]. Acetazolamide (AZA, 4), adrug alsoknownas carbonicanhydrase (CA) inhibitor,isusedin the treatment of glaucoma [6] and idiopathic intracranialhypertension [7] (Figure 1).CA (E.C.: 4.2.1.1) is a protein that is well suited to serve as amodel in many types of biophysical, bioanalytical andphysical-organic chemical studies as well as for inhibitordrug design studies. This enzyme catalyses the hydration ofcarbon dioxide (CO
91 citations
TL;DR: Compounds containing nitrogen and sulfur atoms can be widely used in various fields such as industry, medicine, biotechnology and chemical technology and the inhibitory effects of these molecules were investigated against acetylcholinesterase, butyrylcholinersterase and carbonic anhydrase I, and II isoenzymes.
Abstract: Compounds containing nitrogen and sulfur atoms can be widely used in various fields such as industry, medicine, biotechnology and chemical technology. Therefore, the reactions of aminomethylation and alkoxymethylation of mercaptobenzothiazole, mercaptobenzoxazole and 2-aminothiazole were developed. Additionally, the alkoxymethyl derivatives of mercaptobenzoxazole and 2-aminothiazole were synthesized by a reaction with hemiformals, which are prepared by the reaction of alcohols and formaldehyde. In this study, the inhibitory effects of these molecules were investigated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) enzymes and carbonic anhydrase I, and II isoenzymes (hCA I and II). Both hCA isoenzymes were significantly inhibited by the recently synthesized molecules, with Ki values in the range of 58–157 nM for hCA I, and 81–215 nM for hCA II. Additionally, the Ki parameters of these molecules for BChE and AChE were calculated in the ranges 23–88 and 18–78 nM, respectively.
75 citations
Cites background from "Synthesis of N-alkyl (aril)-tetra p..."
...hCA I is involved in retinal edema and cerebral and the inhibition of hCA I can be a significant factor for eliminating of these conditions.(83) 2....
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TL;DR: Newly synthesized hetaryl sulfonamides exhibited impressive inhibition profiles with Ki values in the range of 1.42–6.58’nM against hCA I, 1.72–7.41 nMAgainst AChE and BChE, respectively, and acetazolamide showed Ki values of 43.69 ± 6.82 − 2.08 against AChe and BE.
Abstract: 1-(4-Methylsulfonyl)-2-thione-4-aryl-5-Z-6-methyl and oxyalkyl-imidazoles were synthesized from different tetrahydropyrimidinethiones and aryl sulfonyl chloride. These compunds were tested for metal chelating effects and to determine the phrase in which inhibition occured between two physiologically pertinent compunds and carbonic anhydrase (CA) isozymes I and II (hCA I and II), butyrylcholinesterase (BChE) and acetylcholinesterase (AChE). AChE was detected in high concentrations in the brain and red blood cells. BChE is another enzymes that is abundant available in the liver and released into the blood in a soluble form. Newly synthesized hetaryl sulfonamides exhibited impressive inhibition profiles with Ki values in the range of 1.42–6.58 nM against hCA I, 1.72–7.41 nM against hCA II, 0.20–1.14 nM against AChE and 1.55–5.92 nM against BChE. Moreover, acetazolamide showed Ki values of 43.69 ± 6.44 nM against hCA I and 31.67 ± 8.39 nM against hCA II. Additionally, tacrine showed Ki values of 25.75...
65 citations
TL;DR: The inhibitory effects of the synthesized novel sulfamides derived from β-benzylphenethylamines were compared to those of acetazolamide and dorzolamide as clinical hCA I and II isoenzymes inhibitors and tacrine as a clinical AChE and BChE enzymes inhibitors.
62 citations
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TL;DR: Using an improved method of gel electrophoresis, many hitherto unknown proteins have been found in bacteriophage T4 and some of these have been identified with specific gene products.
Abstract: Using an improved method of gel electrophoresis, many hitherto unknown proteins have been found in bacteriophage T4 and some of these have been identified with specific gene products. Four major components of the head are cleaved during the process of assembly, apparently after the precursor proteins have assembled into some large intermediate structure.
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TL;DR: This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr with little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose.
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Journal Article•
TL;DR: Using an improved method of gel electrophoresis, many hitherto unknown proteins have been found in bacteriophage T4 and some of these have been identified with specific gene products as mentioned in this paper.
Abstract: Using an improved method of gel electrophoresis, many hitherto unknown proteins have been found in bacteriophage T4 and some of these have been identified with specific gene products. Four major components of the head are cleaved during the process of assembly, apparently after the precursor proteins have assembled into some large intermediate structure.
203,017 citations
TL;DR: On the basis of the assumed theory the rate of the observed reaction is directly proportional to the concentration of the enzyme-substrate compound, where (E:l = (ES).
Abstract: On the basis of the assumed theory the rate of the observed reaction is directly proportional to the concentration of the enzyme-substrate compound, (ES), a t all values of the concentration of the substrate, (S). It is proportional to (S) only a t low values of (S). The numerical value of the dissociation constant is given by the substrate concentration a t half-maximum velocity, where (E:l = (ES). The equilibrium in equation 1 may be heterogeneous or homogeneous. Hitchcock'\" has pointed
11,349 citations
TL;DR: The biological rationale for the novel uses of inhibitors or activators of CA activity in multiple diseases is discussed, and progress in the development of specific modulators of the relevant CA isoforms is highlighted, some of which are now being evaluated in clinical trials.
Abstract: Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including gluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth and virulence of various pathogens. In addition to the established role of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently emerged that CAIs could have potential as novel anti-obesity, anticancer and anti-infective drugs. Furthermore, recent studies suggest that CA activation may provide a novel therapy for Alzheimer's disease. This article discusses the biological rationale for the novel uses of inhibitors or activators of CA activity in multiple diseases, and highlights progress in the development of specific modulators of the relevant CA isoforms, some of which are now being evaluated in clinical trials.
2,649 citations