Original article
Solution-phase microwave assisted parallel synthesis of N,N′-disubstituted thioureas derived from benzoic acid: Biological evaluation and molecular docking studies

https://doi.org/10.1016/j.ejmech.2013.10.012Get rights and content

Highlights

  • A series of N,N′-disubstituted thioureas have been synthesized.

  • The compounds have been characterized by elemental analyses, 1H & 13C NMR, FT-IR and single crystal X-ray diffraction.

  • Compound 11 was very potent inhibitor with IC50 of 1.67 μM against Jack bean urease.

  • A molecular docking study of the derivatives with the enzyme was performed.

Abstract

An efficient and facile microwave-assisted solution phase parallel synthesis for a 26-member library of N,N′-disubstituted thiourea analogs were accomplished successfully. The reaction time for synthesis of analogs was drastically reduced from a reported 8–12 h to only 10 min. Compounds were more than 95% pure, as characterized by modern analytical techniques, i.e. 1H & 13C NMR and FT-IR. The solid phase structural analysis has also been performed by single crystal XRD analysis. Synthesized compounds were preliminary screened for their in vitro urease inhibition and antifungal activity. Most of the compounds were found to be potent inhibitors of urease. However, the most significant activity was found for 11 with IC50 of 1.67 μM. The docking scores correlate with the IC50 values of inhibitors.

Graphical abstract

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N,N′-disubstituted thioureas derivatives were synthesized by microwave assisted parallel synthesis and screened for urease inhibitory activity. Molecular docking studies were performed to study the binding mode of inhibitors.

Introduction

N,N′-Disubstituted thioureas being versatile precursors, have been subjected to a various structural modifications in order to prepare a variety of their derivatives with different biological aspects. Some of N,N′-disubstituted thioureas themselves are remarkable owing to their pharmacological and biological importance. In vitro studies have revealed that various classes of thioureas are useful as potential antimalarial and anticancer agents [1], TRPV1 receptor antagonists [2], herbicides [3], insecticides [4], plant-growth regulators [5] and antihypertensive activity [6]. Thioureas may react with other reagents having different functionalities to yield active compounds of biological significance. For instance thioureas condense with a-halocarbonyl compounds to afford 2-amino-1,3-thiazoles [7] and benzothiazoles can be prepared from arylthioureas in the presence of bromine [8]. The use of thioureas to make iminothiazolines [9], thiohydantoins [10], 1,3,5-triazines [11], and 2-amino-oxazolidines [12] has also been described.

N,N′-Disubstituted thioureas are commonly synthesized by the reaction of amines with alkali metal thiocyanates in the presence of a strong acid [6], aroyl isothiocyanates with amines followed by basic hydrolysis [13], isothiocyanates with ammonia or amines [14], unsubstituted thioureas with primary alkyl amines at high temperature [15] and synthesis of mono- and N,N′-disubstituted thioureas by the debenzoylation of N-substituted and N,N′-disubstituted-N′-benzoylthioureas with hydrazine hydrate under solvent-free conditions [16]. In recent decades, several new methods have also been reported for the preparation of substituted thioureas [17]. However, these protocols have some disadvantages, namely, high reaction temperature, long reaction time, the use of noxious reagents and large quantity of solvents. The development of mild, efficient, and environmental friendly methods are still awaited. The microwave assisted organic synthesis has received considerable attention in present days that helped the chemists to increase the purity of the resulting products with enhanced chemical yield and shorten the reaction time. A mild and efficient microwave assisted synthesis of N,N′-di- and trisubstituted thioureas have been reported [18], [19], [20]. The reported solvents free synthesis, however, have some reservations regarding purity of the products due to the presence of inorganic by-products. These are because of difficulties in ensuring the uniform heating and molecular activities in the viscous phase. So the development of pure and inexpensive novel small drug like agents is a prerequisite to thwart the menace of multi-drug resistant targets. In continuation to our previously published work on N,N′-disubstituted thioureas and their coordination chemistry [21], we report here the microwave assisted solution-phase parallel synthesis of N,N′-disubstituted thioureas and their urease inhibition both in vitro & in virtual, DPPH radical scavenging and antifungal activities because of their inherent biological significance.

Section snippets

Chemistry

Microwave assisted solution-phase parallel synthesis of N,N′-disubstituted thioureas was performed using a microwave oven which was house modified especially for organic synthesis. A small library of twenty six candidates (126) was developed and characterized successfully. The purity of the compounds was checked by TLC with Merck Kieselgel GF 254 Plates, elemental analysis, and their structures were investigated by 1H and 13C NMR spectroscopy. The synthesis of benzoyl isothiocyanate was

Conclusion

A series of N,N′-disubstituted thiourea analogs were prepared using facile microwave-assisted solution phase parallel synthesis. The synthesized compounds were evaluated for in vitro urease inhibitory activity. Most of the compounds exhibited excellent urease inhibition, compound 11 showed potent urease inhibitory activity with an IC50 value 1.67 ± 0.51 μM. The binding patterns of the inhibitors were found by molecular docking studies. The proposed scaffold of compound 11 offers the possibility

Materials and methods

All experiments were carried out under the specified conditions. Solvents were distilled from the drying agents, stored over molecular sieves 4 Å and degassed before use. Microwave syntheses were carried out using a Dawlance DW-293S domestic microwave oven with variable power settings. The experiments were carried out in standard Pyrex capable glassware chamber (20 mL). The temperature of the reaction mixtures was monitored directly by a microwave-transparent fluoroptic probe.

NMR spectra were

Acknowledgments

The M. Khawar Rauf is thankful to the Quaid-i-Azam University, Islamabad, Pakistan for the grant of funds for Post-doctoral Fellowship. This study was financially supported by COMSTECH-TWAS and German-Pakistani Research Collaboration Programme to JI.

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