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Carrier-mediated drug delivery systems are promising therapeutics for targeted delivery and improved efficacy and safety of potent cytotoxic drugs. Nimesulide is a multifactorial cyclooxygenase 2 nonsteroidal anti-inflammatory drug with analgesic, antipyr

Anexpeditious green synthetic approach was developed for the synthesis of α-aminophosphonates in good yields through one-pot three component reaction (Kabachnik-Fields reaction) of equimolar quantities of N-(4-amino-2-phenoxy phenyl)methanesulfonamide, di

A new class of 1,2,3-triazol derivatives derived from nimesulide was designed as potential inhibitors of PDE4B. Synthesis of these compounds was carried out via a multi-step sequence consisting of copper-catalyzed azide-alkyne cycloaddition (CuAAC) as a key step in aqueous media. The required azide was prepared via the reaction of aryl amine (obtained from nimesulide) with α-chloroacetyl chloride followed by displacing the α-chloro group by an azide. Some of the synthesized compounds showed encouraging PDE4B inhibitory properties in vitro that is >50% inhibition at 30 μM that were supported by the docking studies of these compounds at the active site of PDE4B enzyme (dock scores ～ -28.6 for a representative compound). Two of these PDE4 inhibitors showed promising cytotoxic properties against HCT-15 human colon cancer cells in vitro with IC50 ～ 21-22 μg/mL.

Nimesulide (NIM) is a nonsteroidal anti-inflammatory drug, and clinical treatment with NIM has been associated with severe hepatotoxicity. The bioactivation of nitro-reduced NIM (NIM-NH2), a major NIM metabolite, has been thought to be responsible for the hepatotoxicity of NIM. However, we found that NIM-NH2 did not induce toxic effects in primary rat hepatocytes. This study aimed to investigate other bioactivation pathways of NIM and evaluate their association with hepatotoxicity. After incubating NIM with NADPH- and GSH-supplemented human or rat liver microsomes, we identified two types of GSH conjugates: one was derived from the attachment of GSH to NIM-NH2 (NIM-NH2-GSH) and the other one was derived from a quinone-imine intermediate (NIM-OH-GSH). NIM-NH2-GSH was generated not only by the oxidative activation of NIM-NH2 but also from the reductive activation of NIM. Both NADPH and GSH could act as reducing agents. Moreover, aldehyde oxidase also participated in the reductive activation of NIM. NIM-OH-GSH was generated mainly from NIM via epoxidation with CYP1A2 as the main catalyzing enzyme. NIM was toxic to both primary human and rat hepatocytes, with IC50 values of 213 and 40 μM, respectively. Inhibition of the oxidative and reductive activation of NIM by the nonspecific CYP inhibitor 1-aminobenzotriazole and selective aldehyde oxidase inhibitor estradiol did not protect the cells from NIM-mediated toxicity. Moreover, pretreating cells with l-buthionine-sulfoximine (a GSH depletor) did not affect the cytotoxicity of NIM. These results suggested that oxidative and reductive activation of NIM did not cause the hepatotoxicity and that the parent drug concentration was associated with the cytotoxicity.

A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for

Methanol is a potential hydrogen source and C1 synthon, which finds interesting applications in both chemical synthesis and energy technologies. The effective utilization of this simple alcohol in organic synthesis is of central importance and attracts scientific interest. Herein, we report a clean and cost-competitive method with the use of methanol as both C1 synthon and H2 source for selective N-methylation of amines by employing relatively cheap RuCl3.xH2O as a ligand-free catalyst. This readily available catalyst tolerates various amines comprising electron-deficient and electron-donating groups and allows them to transform into corresponding N-methylated products in moderate to excellent yields. In addition, few marketed pharmaceutical agents (e. g., venlafaxine and imipramine) were also successfully synthesized via late-stage functionalization from readily available feedstock chemicals, highlighting synthetic value of this advanced N-methylation reaction. Using this platform, we also attempted tandem reactions with selected nitroarenes to convert them into corresponding N-methylated amines using MeOH under H2-free conditions including transfer hydrogenation of nitroarenes-to-anilines and prepared drug molecules (e. g., benzocaine and butamben) as well as key pharmaceutical intermediates. We further enable one-shot selective and green syntheses of 1-methylbenzimidazole using ortho-phenylenediamine (OPDA) and methanol as coupling partners.

For the first time the template containing structural features of more than one NSAIDs and the 1,2,3-triazole ring was explored for the identification of potential cytotoxic agents. These new and complex molecules were predicted to be effective inhibitors

Metal nanoparticles (NPs) are usually stabilized by a capping agent, a surfactant, or a support material, to maintain their integrity. However, these strategies can impact their intrinsic catalytic activity. Here, we demonstrate that the in-situ formation of copper NPs (Cu0NPs) upon the reduction of the earth-abundant Jacquesdietrichite mineral with ammonia borane (NH3BH3, AB) can provide an alternative solution for stability issues. During the formation of Cu0NPs, hydrogen gas is released from AB, and utilized for the reduction of nitroarenes to their corresponding anilines, at room temperature and under ambient pressure. After the nitroarene-to-aniline conversion is completed, regeneration of the mineral occurs upon the exposure of Cu0NPs to air. Thus, the hydrogenation reaction can be performed multiple times without the loss of the Cu0NPs’ activity. As a proof-of-concept, the hydrogenation of drug molecules “flutamide” and “nimesulide” was also performed and their corresponding amino-compounds were isolated in high selectivity and yield.

Catalytic hydrogenation of nitroarenes is an industrially very important and environmentally friendly process for the production of anilines; however, highly chemoselective reduction of nitroarenes decorated with one or more reducible groups in a nitroarene molecule remains a challenge. Herein, a novel hybrid non-noble iron-based nanocatalyst (named as FeS2/NSC) was developed, which was prepared from biomass as C and N source together with inexpensive Fe(NO3)3 as Fe source through high-temperature pyrolysis in a straightforward and cost-effective procedure. Comprehensive characterization revealed that single-phase pyrite FeS2 nanoparticles with precisely defined composition and uniform size were homogeneously dispersed on N,S-codoped porous carbon with large specific surface area, hierarchical porous channels, and high pore volume. The resultant catalyst FeS2/NSC demonstrated good catalytic activity for hydrogenation of functionalized nitroarenes with good tolerance of various functional groups in water as a sustainable and green solvent. Compared with bulk pyrite FeS2 and other non-noble metal-based heterogeneous catalysts reported in the literature, a remarkably enhanced activity was observed under mild reaction conditions. More importantly, FeS2/NSC displayed exclusive chemoselectivity for the reduction of nitro groups for nitroarenes bearing varying readily reducible groups.

The invention relates to a preparation method of four nimesulide derivatives with the function of treating liver malignant tumors. According to the invention, a nimesulide solution and an acid or alkaline substance are subjected to displacement reaction to generate three salts with better water solubility and more stability, which are the nimesulide derivatives, or p-aminobenzonitrile is used as asubstrate, the fourth nimesulide derivative with higher bioavailability is generated through a series of redox reactions, four novel nimesulide derivatives are successfully prepared, all the four compounds are soluble in water, the solubility is better than that of the nimesulide, and better absorption rate and bioavailability are provided, and the hepatotoxicity of the four derivatives is not obviously different from that of the nimesulide at normal dose, and only one derivative is enhanced in liver toxicity at overdose. The inhibitory effect on BEL-7402 is no less than or even stronger thanthat of nimesulide when the four derivatives are co-cultured with CIK cells. The four nimesulide derivatives can be used for preparing drugs for inhibiting human liver cancer cells.

The development of efficient and selective nanostructured catalysts for industrially relevant hydrogenation reactions continues to be an actual goal of chemical research. In particular, the hydrogenation of nitriles and nitroarenes is of importance for the production of primary amines, which constitute essential feedstocks and key intermediates for advanced chemicals, life science molecules and materials. Herein, we report the preparation of graphene shell encapsulated Co3O4- and Co-nanoparticles supported on carbon by the template synthesis of cobalt-terephthalic acid MOF on carbon and subsequent pyrolysis. The resulting nanoparticles create stable and reusable catalysts for selective hydrogenation of functionalized and structurally diverse aromatic, heterocyclic and aliphatic nitriles, and as well as nitro compounds to primary amines (>65 examples). The synthetic and practical utility of this novel non-noble metal-based hydrogenation protocol is demonstrated by upscaling several reactions to multigram-scale and recycling of the catalyst.

Human aldehyde oxidase 1 (AOX1) catalyzes the oxidation of various drugs and endogenous compounds. Recently, we found that AOX1 catalyzed the reduction of drugs such as nitrazepam and dantrolene. In this study, we aimed to clarify the substrate selectivit

Three nimesulide derivatives, N-[4-(2,5-dioxo-pyrrolidin-1-yl)-2-phenoxyphenyl] methanesulfonamide (2), N-[4-(4-methanesulfonylamino-3-phenoxy phenylsulfamoyl) phenyl] acetamide (3), and 4-(4-methanesulfonylamino-3-phenoxyphenyl-carbamoyl)-butanoic acid (4), have been synthesized, and their crystal structures have been determined from laboratory powder X-ray diffraction data. The nature of intermolecular interactions in 2-4 has been analyzed through Hirshfeld surfaces and two-dimensional fingerprint plots and compared with that in the nimesulide polymorphs (1a and 1b). The crystal packing in 2-4 exhibits an interplay of N-H?O, O-H?O (in 4), C-H?O, and C-H?π (in 2) hydrogen bonds, which assemble molecules into a supramolecular framework. Hydrogen-bond based interactions in 2-4 have been complemented by calculating molecular electrostatic potential surfaces. In a competitive molecular recognition situation, the effectiveness of the -NH moiety as a hydrogen bond donor is comparable to that of the -COOH moiety in 4. Hirshfeld surface analyses of 2-4 as well as a few related nimesulide derivatives indicate that about 90% of the Hirshfeld surface areas in these compounds are due to H?H, C?H, and O?H contacts.

Anilines are important feedstock for the synthesis of a variety of chemicals such as dyes, pigments, pharmaceuticals and agrochemicals. The chemoselective catalytic reduction of nitro compounds represents the most important and prevalent process for the manufacture of functionalized anilines. Consequently, the development of selective catalysts for the reduction of nitro compounds in the presence of other reducible groups is a major challenge and is crucial. In this regard, herein we show that the cobalt oxide (Co3O4-NGr@C) based nano-materials, prepared by the pyrolysis of cobalt-phenanthroline complexes on carbon constitute highly selective catalysts for the transfer hydrogenation of nitroarenes to anilines using formic acid as a hydrogen source. Applying these catalysts, a series of structurally diverse and functionalized nitroarenes have been reduced to anilines with unprecedented chemo-selectivity tolerating halides, olefins, aldehyde, ketone, ester, amide and nitrile functionalities.

Nanoscaled iron oxides on carbon were modified with nitrogen-doped graphene (NGr) and found to be excellent catalysts for the chemoselective transfer hydrogenation of nitroarenes to anilines. Under standard reaction conditions, a variety of functionalized and structurally diverse anilines, which serve as key building blocks and central intermediates for fine and bulk chemicals, were synthesized in good to excellent yields.

The present invention is related to a compound conjugating a drug with a glycosaminoglycan, such as hyaluronic acid (HA), where the drug is useful for the treatment of diseases such as inflammation, auto-immune disease, allergy, infection and preferably c

Production of anilines - key intermediates for the fine chemical, agrochemical, and pharmaceutical industries - relies on precious metal catalysts that selectively hydrogenate aryl nitro groups in the presence of other easily reducible functionalities. Herein, we report convenient and stable iron oxide (Fe2O3) - based catalysts as a more earth-abundant alternative for this transformation. Pyrolysis of iron-phenanthroline complexes on carbon furnishes a unique structure in which the active Fe2O 3 particles are surrounded by a nitrogen-doped carbon layer. Highly selective hydrogenation of numerous structurally diverse nitroarenes (more than 80 examples) proceeded in good to excellent yield under industrially viable conditions.

Novel succinimide derivatives based on nimesulide were designed as potential anticancer agents and their synthesis was carried out using a straightforward and atom economic method. The key step of this methodology involved an Aza-Michael addition of several nitrogen nucleophiles to the corresponding N-aryl maleimide derivatives prepared efficiently from nimesulide via a two-step process. A number of compounds containing-NHX (X = Ar, NHCOR, NHAr etc) at the C-3 of the succinimide were prepared in good yields. A number of compounds synthesized were tested for their cytotoxicity in vitro against human colon cancer cell lines and some of them showed promising activities.

Crystal structures of two nimesulide derivatives, C13H 14O3N2S (2) and C21H 16O5N2S (3), have been determined from X-ray powder diffraction data and their electronic structures were calculated at the DFT level. The optimized molecular geometries of 2 and 3 correspond closely to that obtained from the crystallographic analysis. Intermolecular hydrogen bonds and π..π stacking interactions form supramolecular assembly in both compounds. The HOMO-LUMO energy gap (>2.2 eV) indicates a high kinetic stability of both compounds. Although the compound 2 does not exhibit any anti-inflammatory activity, 3 can induce 34% edema inhibition in rat paws.

The frst synthesis of nimesulide-based novel cyclic imides has been accomplished via the reaction of an amine prepared from nimesulide with appropriate anhydrides in the presence of sodium acetate. Using this process a variety of N-substituted cyclic imides was prepared in good yields in glacial acetic acid. Some of the compounds synthesized showed anti-infammatory activities when tested in vivo.

Synthesis of a series of compounds structurally related to the anti-inflammatory agent nimesulide has been accomplished via Pd-catalyzed C-C bond forming reactions. Thus 4-iodo derivative, prepared from nimesulide, participated in Sonogashira (copper-free

Due to a continuing effort to develop new antiviral agents, a series of 1-[4-(methanesulfonamido)-3-phenoxyphenyl]-3-alkyl/aryl thioureas 3a-i have been synthesized by the reaction of alkyl/aryl isothiocyanates with 4-amino-2-phenoxymethanesulfonanilide.

The biomimetic reduction of anti-inflammatory drug, nimesulide (1) with sodium borohydride catalyzed by 5,10,15,20-tetraarylporphyrinatoiron(III) chlorides [TAPFe(III)Cl] has been studied in organic solvents under anaerobic and aerobic conditions.

The present work reports the synthesis of a series of compounds structurally related to the antiinflammatory and antihistaminic agent nimesulide (I), in which the p-nitrophenyl moiety has been replaced by pyridine (1a-c) and pyridine N-oxide (2a-c). In addition, two compounds (3a, 4a) have been synthesized in which the p-nitro group of I was substituted by a cyano and a 1H-tetrazol-5-yl group, respectively. Representative 1a and 2a were also modified by replacing the methanesulfonamido group with an acetamido group (5a, 6a). The pharmacological evaluation of compounds 1-6 in comparison to I, indicates that such modifications are detrimental to the activity. Moreover 3a and 4a caused bronchoconstriction and hypotension, thus behaving as histaminic-like rather then antihistaminic agents.