The nitro-reduced metabolite of nimesulide: Crystal structure, spectroscopic characterization, ESI-QTOF mass spectrometric analysis and antibacterial evaluation

doi:10.1016/j.molstruc.2017.12.085

Journal of Molecular Structure

Volume 1157, 5 April 2018, Pages 469-475

https://doi.org/10.1016/j.molstruc.2017.12.085 Get rights and content

Highlights

•
The nitro-reduced metabolite of nimesulide (NMS-NH₂) was synthesized and characterized.
•
Single-crystal X-ray structure of NMS-NH₂ is presented and compared to powder diffraction data.
•
NMS-NH₂ was further characterized in solution by a combination of NMR experiments.
•
MS and FTIR data are also provided here.
•
NMS-NH₂ showed low antibacterial activity over P. aeruginosa, while NMS was inactive.

Abstract

Here we present a synthetic procedure, spectroscopic characterization and single-crystal X-ray structure for the nitro-reduced metabolite of the anti-inflammatory drug nimesulide, hereby referred to as NMS-NH₂. The nitro-reduced metabolite was synthesized using the Béchamp reduction (iron powder under acidic media), leading to the conversion of the nitrobenzene group of nimesulide to an aniline. Mass spectrometry, infrared and nuclear magnetic resonance spectroscopies data are also provided for NMS-NH₂, and discussed in comparison to nimesulide. NMS-NH₂ was also evaluated in terms of its antibacterial activities, considering that the free single bond NH₂ group could allow the compound to act as a dihydropteroate synthase inhibitor. NMS-NH₂ had a modest antibacterial activity against P. aeruginosa (5.0 mg mL⁻¹), which was not observed for NMS.

Graphical abstract

Introduction

Nimesulide, or N-(4-nitro-2-phenoxyphenyl) methanesulfonamide (NMS, C₁₃H₁₂N₂O₅S) is a non-steroidal anti-inflammatory agent, which acts by inhibiting the COX-2 enzyme [1]. The nitro-reduced analog NMS-NH₂ (4-amino-2-phenoxy-methanesulfonanilide, C₁₃H₁₄N₂O₃S) has been identified as one of the metabolites of nimesulide in urine [2,3], as consequence of a hepatic metabolic pathway [4]. Nimesulide derivatives and metabolites have been studied in terms of their molecular structures and biological activities, mostly regarding their anti-inflammatory properties [5,6].

Despite being a sulfonamide, the structure of nimesulide differs from that of the traditional antibacterial ones. Classical sulfonamides with antibacterial activities have a SO₂ single bond NH group bound to an aromatic ring and a free NH₂ group in the para position [7]. Some representative examples include sulfadiazine, sulfameter and sulfathiazole [8,9]. These compounds are mostly used as antibacterial agents and act as inhibitors of the dihydropteroate synthase (DHPS) enzyme due to structural similarity with the natural substrate para-aminobenzoic acid (PABA) [7]. Inhibition of DHPS hinders the biosynthesis of bacterial folate. NMS-NH₂ could also act as an antibacterial agent by inhibition of the dihydropteroate synthase enzyme, considering the presence of the free single bond NH₂ group.

Many synthetic routes are available for reducing a nitro group to the corresponding amine, including catalytic hydrogenation using Raney nickel [10] and palladium-on-carbon [11,12]. For the reduction of NMS we selected a method that works under mild reaction conditions and relies on iron powder under acidic media (Béchamp reduction) [13].

In this context, we present here a synthetical procedure, single-crystal X-ray structure and preliminary antibacterial assays for the nitro-reduced metabolite (NMS-NH₂, see Fig. 1) of the anti-inflammatory drug nimesulide.

Section snippets

Materials

Nimesulide (NMS) was purchased from Sigma-Aldrich Laboratories (99%) and was used without further purification.

Synthesis of NMS-NH₂

The nitro reduction of NMS to NMS-NH₂ was performed using an adaptation of a published method by the following procedure [13]: 7.20 mmol of NMS were dissolved in 12.0 mL of ethanol/water 2:1 at 70 °C. After the dissolution of NMS, 7.32 mmol of iron powder were added, followed by 0.20 mL of concentrated hydrochloric acid (HCl). The reaction was carried out with stirring at 70 °C. After

Crystal structure

The structure of NMS-NH₂ had been previously solved and refined by powder methods by Bhattacharya et al. (Cambridge Structural Database entry OPEKOK) [11]. Even though a state-of-the-art powder techniques were used by the authors, in many cases single-crystal diffraction yields more accurate results [[19], [20], [21]]. For this reason, in this paper we present a brief discussion of the structure, highlighting differences between the one solved by powder methods and the one presented herein,

Conclusions

In this paper we presented the synthesis and single-crystal X-ray structure of the nitro-reduced metabolite of the anti-inflammatory drug NMS. The disorder of the phenoxy group led to two sites in the single-crystal structure of NMS-NH₂, with occupancies of 0.517 (19) and 0.483 (19). Bond lengths and angles are consistent with those found in an earlier study, where the structure of NMS-NH₂ was solved by powder diffraction [11]. NMR data including ¹H, ¹³C and DEPT-135, in addition to {¹³C,¹

Funding information

Conselho Nacional de Desenvolvimento Científico e Tecnológico (scholarship No. 140466/2014–2 to Raphael E. F. de Paiva; Grant No. 442123/2014-0 to Pedro P. Corbi); Fundação de Amparo à Pesquisa do Estado de São Paulo (scholarship No. 2012/21955–6 to Julia H. B. Nunes; scholarship No. 2015/20882–3 to Douglas H. Nakahata; grant No. 2015/09833-0 to Wilton R. Lustri; grant No. 2015/25144-4 to Pedro P. Corbi).

Acknowledgments

The authors are also grateful to Prof. Marcos A. Ribeiro for fruitful discussions about X-ray crystallographic refinements.

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¹: These authors contributed equally to this work.

View full text

The nitro-reduced metabolite of nimesulide: Crystal structure, spectroscopic characterization, ESI-QTOF mass spectrometric analysis and antibacterial evaluation

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials

Synthesis of NMS-NH2

Crystal structure

Conclusions

Funding information

Acknowledgments

J. Chromatogr. B

J. Pharmaceut. Biomed. Anal.

J. Mol. Struct.

J. Mol. Catal. A Chem.

Chem. Phys. Lett.

Tetrahedron

J. Mol. Struct.

Polyhedron

Org. Biomol. Chem.

Synthesis of NMS-NH₂