The nitro-reduced metabolite of nimesulide: Crystal structure, spectroscopic characterization, ESI-QTOF mass spectrometric analysis and antibacterial evaluation
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 SO2NH 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 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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These authors contributed equally to this work.