Original article
Synthesis and in vitro urease inhibitory activity of N,N′-disubstituted thioureas

https://doi.org/10.1016/j.ejmech.2014.01.001Get rights and content

Highlights

  • Synthesis of N,N'-disubstituted thiourea derivatives.

  • In vitro urease inhibitory activity.

  • Thirteen compounds found to be the most active.

  • Structure–activity relationship has been established.

Abstract

Thiourea derivatives (138) were synthesized and evaluated for their urease inhibition potential. The synthetic compounds showed a varying degree of in vitro urease inhibition with IC50 values 5.53 ± 0.02–91.50 ± 0.08 μM, most of which are superior to the standard thiourea (IC50 = 21.00 ± 0.11 μM). In order to ensure the mode of inhibition of these compounds, the kinetic study of the most active compounds has been carried out. Most of these inhibitors were found to be mixed-type of inhibitors, except compounds 13 and 30 which were competitive, while compound 19 was identified as non-competitive inhibitor with Ki values between 8.6 and 19.29 μM.

Graphical abstract

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Compounds 138 showed a varying degree or urease inhibitory activities with IC50 values in the range of 5.53 ± 0.02–91.50 ± 0.08 μM, most of which are superior compared to the standard.

Introduction

Urease (urea amidohydrolase EC 3.5.1.5) is a nickel-containing enzyme that catalyzes the hydrolysis of urea to ammonia and CO2 or carbamate [1]. A variety of ureases are found in bacteria, fungi, higher plants and in soil as a soil enzyme [2] Activity of urease (E.C 3.5.1.5) has been shown to be an important virulence determinant in the pathogenesis of many clinical conditions which are detrimental for human and animal health as well as for agriculture. In agriculture, high urease activity causes significant environmental and economic problems by releasing abnormally large amounts of ammonia into the atmosphere during urea fertilization [3]. Moreover, it induces plant damage primarily by depriving plants of their essential nutrients and secondarily by ammonia toxicity, increasing the pH of the soil [4].

Urease has been implicated to play a role in the pathogenesis of many bacteria such as Helicobacter pylori, Proteus mirabilis and Brucella abortus [5]. Urease has been identified as an immunogenic modulator in several pathogen-induced inflammatory reactions [6]. It is also known to be a major cause of pathologies induced by Helicobacter pylori which allows the bacteria to survive at the low pH of the stomach during colonization and therefore plays an important role in the pathogenesis of gastric and peptic ulcers which may lead to cancer, Since urease is not only damaging for humans, but also for animals and in agriculture, various strategies based on urease inhibition were considered as treatment approaches for infections caused by urease-producing bacteria [7], [8].

Moreover, H. pylori are recognized as a major risk factor for recurrent gastroduodenal inflammatory diseases and gastric adenocarcinoma [9]. Ureases play an important role in protecting the H. pylori from the effects of gastric acid [10]. Medically, ureases are important virulence factors implicated in the pathogenesis of many clinical conditions such as pyelonephritis, hepatic coma, peptic ulceration, and the formation of infection-induced urinary stones and reactive arthritis [11].

Thiourea is an organic compound with the molecular formula CSN2H4. It is a versatile reagent in synthetic chemistry. Thioureas are related to thioamides and can be prepared from ammonium thiocyanate, but more commonly by the reaction of phenyl isothiocyanate with alkyl or aryl amines. They are important building blocks in the synthesis of heterocycles [12]. Thioureas manifest important multiple biological effects and are the basis for target-oriented synthesis. Moreover, ureas and thioureas evaluate their plant growth-regulating activity mainly on the herbicidal, root growth inhibitory and stimulatory and cytokinin-like activities [13]. Thioureas and ureas (symmetrical or unsymmetrical) have attracted much attention as drug candidates against a variety of diseases due to their bioactivities and broad spectrum as pesticides and in pharmacological activities [14], [14](a). A variety of thiourea derivatives and their metal complexes exhibit analgesic, anti-inflammatory [15], anticancer, antitumor [16], antiplatelet [17] antimalarial [18], and antimicrobial activities [19], [20]. Thiourea derivatives also possess anti-HCV [21], anti-HIV, antituberculosis, and antileukemic activity [22]. Fluorinated thioureas constitute a novel class of potent influenza virus neuraminidase inhibitors [23].

In continuation of our research work on urea and thiourea derivatives as potential lead compounds in our drug discovery program and keeping in mind the urease inhibitory activity of thiourea [24], we have synthesized a variety of thioureas and screened them for their urease inhibitory properties.

Section snippets

Chemistry

We have previously reported the synthesis of unsymmetrically-substituted N,N′-diaryl thioureas and urea derivatives in excellent yields and their in vitro bioactivities determined as cytotoxic, phytotoxic, acetylcholinesterase, butyrylcholinesterase [14a], and anti-glycation activities [14b]. Along with that we have being working on sulfur containing compounds [25], as well as hydrazones in search lead molecules [26]. In the present study thirty-eight unsymmetrically N,N-diaryl-substituted

Conclusion

Summarizingly, a series of substituted thiourea derivatives have been synthesized successfully in appreciable yields and evaluated for their in vitro urease inhibition potential. SAR studies carried out to investigate the role of substitutions by functional groups attached to the thiourea bridge which exert imperative influence on the urease inhibitory potential. It is also concluded that substituents having the lone pair of electrons and are appropriately oriented from the thiourea center and

General experimental

Melting points were determined on a Büchi 434 melting point apparatus and are uncorrected. NMR was performed on Bruker AV 300, 400, and 500 MHz instruments, respectively. CHN analyses were determined on a Carlo Erba Strumentazion-Mod-1106, Italy, instrument. Infrared (IR) spectra were recorded on a JASCO IR-A-302 spectrometer. Electron impact mass spectra (EI MS) were recorded on a Finnigan MAT-311A, Germany, spectrometer. Thin layer chromatography (TLC) was performed on precoated silica gel

Acknowledgment

The authors are thankful to the Organization for Prohibition of Chemical Weapons (OPCW), The Netherlands, and Higher Education Commission (HEC) Pakistan for their financial support for projects No. L/ICA/ICB/173681/12 and 20-1910, respectively.

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