Improved Procedures for the Preparation of Cycloalkyl-, Arylalkyl-, and Arylthioureas

Rasmussen, C. R.; Villani, Frank J.; Weaner, Larry E.; Reynolds, B. E.; Hood, A. R.; Hecker, Leonard R.; Nortey, Samuel; Hanslin, A.; Costanzo, Michael J.; Powell, Eugene T.; Molinari, Aurora

doi:10.1055/s-1988-27605

Cited by 98 publications

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“…On cooling, the reaction mixture was slowly poured into acidified (pH 4-5) chilled water and stirred well with a glass rod. The solid products (1-3) obtained were purified by slow evaporation technique (see Scheme 1) (Rasmussen CR 1988;Rauf MK 2006 4 ] and the reaction mixture was stirred for 6 hours. The yellowish precipitates were filtered off and allowed to stand at room temperature for 2 days.…”

Section: Synthesis Of the N N'-disubstituted Thioureas (1-3)mentioning

confidence: 99%

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Synthesis, Characterization and Urease Inhibition Studies of Transition Metal Complexes of Thioureas Bearing Ibuprofen Moiety

Mumtaz

Arshad

Saeed

et al. 2018

J. Chil. Chem. Soc.

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Starting from ibuprofen, a non-steroidal anti-inflammatory drug, N,N'-disubstituted thiourea derivatives were synthesized by refluxing the acid chloride of ibuprofen with potassium thiocyanate followed by substituted anilines to get N-2- (4-(2-methylpropyl) phenyl)propionoyl-N´-(2´-bromophenyl) thiourea (1), N-2-(4-(2-methylpropyl)phenyl)propionoyl-N´-(2´-chlorophenyl) thiourea (2) and N-2-(4-(2-methylpropyl)phenyl)propionoyl-N´-(3´,4´-dichlorophenyl) thiourea (3).Metal complexes (4-15) of (1-3) were synthesized by refluxing it with one equivalence salts of Co (ΙΙ), Ni(ΙΙ), Pb(ΙΙ) and Cu(Ι). Structures of all the synthesized thiourea ligands and their metal complexes were determined by FTIR and 1 HNMR spectroscopy. Shift in stretching frequency in FTIR and resonance frequency in 1 HNMR spectroscopic data suggested that the ligands and metal are coordinated to afford respective metal complexes M[L] n . The synthesized compounds were tested against urease enzyme and the results were compared with standard thiourea, as positive control. Most of the investigated compounds showed potential inhibitory activity against Jack bean urease. Compound 5 was found to be the most potent urease inhibitor with IC 50 of 14.6 µM, whereas compounds 8, 11 and 12 possessed potent urease inhibition. The tested compounds can be taken as lead molecules for gastrointestinal ulcer therapy.Key words: Amides, Thioureas, Metal complexes, Ibuprofen, Urease. INTRODUCTIONUrease (urea aminohydrolase E.C. 3.5.1.5) is nickel containing metalloenzyme which belongs to the super family of amidohydrolases and phosphotriestreases, responsible for the hydrolytic decomposition of urea (Holm 1997). It was the first enzyme which crystallized from the plant source Canavalia ensiformis and was also the first protein containing nickel in the active site (Saeed et al. 2014;Saeed et al. 2013). Because of these characteristics urease is considered as a paradigm in the development of inorganic biochemistry. Urease catalyses the hydrolysis of urea in different plants, algae, fungi, and microorganisms to produce ammonia and carbamate (Mobley HL 1989). Enzyme catalysed hydrolysis-process occurred at a rate of approximately 10 14 times the rate of the unanalyzed reaction and considered as the final step of nitrogen metabolism in all living organisms. Different types of urease enzymes can be isolated from bacteria, fungi, algae and plants but enzymatic activity is same due to the occarance of the same order of amino acid (Bacanamwo M 2002;Benini S 1999). Urease activity due to infectious microorganism is the major reason for many deceases in humans such as development of infection stones, pyelonephritis, stomach and peptic ulcer, urinary catheter encrustation, and hepatic com (Gripenberg-Lerche C 2000; Mobley et al. 1995;Mobley HL 1989). To overcome these diverse types of problems, urease inhibitors have received special attention over the past few years. These inhibitors generally divided into two classes, substrate structural analogs like hydroxamic acid (Ko...

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Section: Synthesis Of the N N'-disubstituted Thioureas (1-3)mentioning

confidence: 99%

mentioning

confidence: 99%

Synthesis, Characterization and Urease Inhibition Studies of Transition Metal Complexes of Thioureas Bearing Ibuprofen Moiety

Mumtaz

Arshad

Saeed

et al. 2018

J. Chil. Chem. Soc.

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“…This was further reacted with cynaoguanidine (8) in a solution of KOH dissolved in pentan-1-ol to yield the required 1,3,5-triazine derivative 14 in 100% conversion [66] (19) with S-ethylisothiouronium bromide and its further reaction with NaClO 4 in 75% yield [100]. The receptor 20b was prepared by the reaction of 19 with S-methyl-N-phenylisothiouronium iodide [101] in EtOH in 54% yield (Scheme 4) [102].…”

Section: Synthesis Of Flavinsmentioning

confidence: 99%

Exploring the Mechnisms of Molecular Recognition by Flavins

Savan

Geetanjali

Babu

2005

C&B

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The design and development of chemical models for enzymes depends on the fundamental principles observed in biological systems. Molecular recognition of flavins by various receptors has attracted attention due to their applications as chemical models for flavoenzymes. The area of molecular recognition is being investigated through research at the interface of chemistry and biology. In this review, the literature has been surveyed to provide comprehensive coverage of the synthetic methodology of different flavins and receptors and their molecular-recognition studies. Various applications of flavin-receptor complexes have also been highlighted.

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“…The imine bond of 1 could be effectively reduced to the disubstituted hydrazine derivative (14) using an excess of borane in THF with heating. The compound was not protective at the concentrations tested.…”

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confidence: 99%

“…For example, compounds 19b and 19c were poorly soluble at assay concentrations (cLogP: 19a, 5.8; 19b, 6.0; 19c, 6.1; 1, 5.2) and did not return meaningful dose−response curves. A significantly more soluble CNH compound (22) (cLogP: 3.9−4.0) was elaborated from the S-methylation of (2,6-dimethylphenyl)thiourea, 14 20, to give 21, followed by displacement with hydrazine and condensation with 4-bromobenzaldehyde to give the hydrazinecarboximidamide, 22. Unfortunately, the bioactivity of this compound was diminished (IC 50 = 13.8 μM).…”

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confidence: 99%

Structure–Activity Relationship of Semicarbazone EGA Furnishes Photoaffinity Inhibitors of Anthrax Toxin Cellular Entry

Jung

Chamberlain

et al. 2014

ACS Med. Chem. Lett.

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EGA, 1, prevents the entry of multiple viruses and bacterial toxins into mammalian cells by inhibiting vesicular trafficking. The cellular target of 1 is unknown, and a structure− activity relationship study was conducted in order to develop a strategy for target identification. A compound with midnanomolar potency was identified (2), and three photoaffinity labels were synthesized (3−5). For this series, the expected photochemistry of the phenyl azide moiety is a more important factor than the IC 50 of the photoprobe in obtaining a successful photolabeling event. While 3 was the most effective reversible inhibitor of the series, it provided no protection to cells against anthrax lethal toxin (LT) following UV irradiation. Conversely, 5, which possessed weak bioactivity in the standard assay, conferred robust irreversible protection vs LT to cells upon UV photolysis. KEYWORDS: Photoaffinity labeling, semicarbazone, aryl azide, anthrax lethal toxin, endosomal trafficking A common mechanism by which viruses and bacterial toxins enter host cells involves trafficking from an early to a late endosome followed by release into the cytoplasm as triggered by endosomal acidification. 1−3 Inhibition of this process represents a host-targeted strategy for the development of broad-spectrum antiviral and antibacterial drugs. Recently, EGA, N 1 -(4-bromobenzylidene)-N 4 -(2,6-dimethylphenyl)-semicarbazone, 1, was identified from a high-throughput phenotypic screen to protect cells from anthrax lethal toxin (LT). 4 Further investigations showed that 1 protected cells from multiple viruses and bacterial toxins that rely on pHdependent endosomal trafficking to enter cells. Although the details of the biochemical mechanism have been studied, the cellular target(s) remain unknown. We have conducted a structure−activity relationship (SAR) study with the goal of improving the potency of 1 and developing a strategy for photoaffinity labeling and identification of the involved proteins.A series of derivatives of 1 were synthesized and tested, revealing precise requirements for activity in a tight and relatively flat structure−activity landscape. The 2,6-dimethyl substitution in the N 4 -ring as well as an unaltered semicarbazone core were shown to be optimal for activity while certain modifications to the N 1 -phenyl ring were tolerated. From the SAR, a compound more potent than the original hit was generated, namely the N 1 -2-fluoro-4-bromophenyl analogue (IC 50 = 0.4 μM), 2. In addition, three photoaffinity probes, 3−5, two of which possess low micromolar activity, were designed and synthesized. Our key finding is that the expected photochemistry of the phenyl azide moiety is a more important factor than the IC 50 of the photoprobe in achieving successful photolabeling. While 3 was the most potent inhibitor of intoxication by LT in the standard assay, it did not provide protection to the cells upon UV photolysis. Conversely 5, which possesses two fluorine atoms ortho to the azido function, was a poor inhibitor in the stand...

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Improved Procedures for the Preparation of Cycloalkyl-, Arylalkyl-, and Arylthioureas

Cited by 98 publications

References 0 publications

Synthesis, Characterization and Urease Inhibition Studies of Transition Metal Complexes of Thioureas Bearing Ibuprofen Moiety

Synthesis, Characterization and Urease Inhibition Studies of Transition Metal Complexes of Thioureas Bearing Ibuprofen Moiety

Exploring the Mechnisms of Molecular Recognition by Flavins

Structure–Activity Relationship of Semicarbazone EGA Furnishes Photoaffinity Inhibitors of Anthrax Toxin Cellular Entry

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