N-substituted Maleimides Research Articles

Synthesis , characterization and biological activity study of N-substituted sulfonamido maleimides substituted with different heterocycles

Eighteen new cyclic imides (maleimides) conncted to benzothiazole moiety through sulfonamide group were synthesized via multistep synthesis.The first step involved preparation of two maleamic acids N-phenylmaleamic acid and N-benzylmaleamic acid via reaction of maleic anhydride with aniline or benzyl amine.Dehydration of the prepared amic acids by treatment with acetic anhydride and anhydrous sodium acetate in the second step afforded N-phenylmaleimide and N- benzyl maleimide which in turn were treated with chlorosulfonic acid in the third step to afford 4-(N-maleimidyl) phenyl sulfonyl chloride and 4-(N-maleimidyl) benzyl sulfonyl chloride respectively.In the Fourth step of this work each one of the two prepared maleimidyl sulfonyl chlorides was introduced in reaction with nine substituted-2-amino benzothiazole compounds producing nine N-(4-(N-substituted benzothiazole -2-yl) sulfonamido phenyl) maleimides and nine N-(4-(N-substituted benzothiazole-2-yl)snlfonamido benzyl) maleimides.More over another new six sulfonamide phenyl and benzyl maleimides substituted with other heterocycles (pyridine and phenazone )were prepared via reaction of 4-(N-maleimidyl) phenyl and benzyl sulfonyl chlorides with heterocyclic amines including (2-amino pyridine,4-amino-pyridine,4-aminophenazone). Microbiological activity of the prepared compounds against two typs of bacteria(staphylococcus aureus and klebsiella pneumonia) and (candida albicans) fungi were evaluated and the results showed that these compounds have good antibacterial and good antifungal activities.

Synthesis and Biochemical Evaluation of Ethanoanthracenes and Related Compounds: Antiproliferative and Pro-Apoptotic Effects in Chronic Lymphocytic Leukemia (CLL).

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells, and it is the most frequent form of leukemia diagnosed in Western countries. It is characterized by the proliferation and accumulation of neoplastic B lymphocytes in the blood, lymph nodes, bone marrow and spleen. We report the synthesis and antiproliferative effects of a series of novel ethanoanthracene compounds in CLL cell lines. Structural modifications were achieved via the Diels-Alder reaction of 9-(2-nitrovinyl)anthracene and 3-(anthracen-9-yl)-1-arylprop-2-en-1-ones (anthracene chalcones) with dienophiles, including maleic anhydride and N-substituted maleimides, to afford a series of 9-(E)-(2-nitrovinyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones, 9-(E)-3-oxo-3-phenylprop-1-en-1-yl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones and related compounds. Single-crystal X-ray analysis confirmed the structures of the novel ethanoanthracenes 23f, 23h, 24a, 24g, 25f and 27. The products were evaluated in HG-3 and PGA-1 CLL cell lines (representative of poor and good patient prognosis, respectively). The most potent compounds were identified as 20a, 20f, 23a and 25n with IC50 values in the ranges of 0.17-2.69 µM (HG-3) and 0.35-1.97 µM (PGA-1). The pro-apoptotic effects of the potent compounds 20a, 20f, 23a and 25n were demonstrated in CLL cell lines HG-3 (82-95%) and PGA-1 (87-97%) at 10 µM, with low toxicity (12-16%) observed in healthy-donor peripheral blood mononuclear cells (PBMCs) at concentrations representative of the compounds IC50 values for both the HG-3 and PGA-1 CLL cell lines. The antiproliferative effect of the selected compounds, 20a, 20f, 23a and 25n, was mediated through ROS flux with a marked increase in cell viability upon pretreatment with the antioxidant NAC. 25n also demonstrated sub-micromolar activity in the NCI 60 cancer cell line panel, with a mean GI50 value of 0.245 µM. This ethanoanthracene series of compounds offers potential for the further development of lead structures as novel chemotherapeutics to target CLL.

Synthesis of Fused-Ring Pyrrolizine Derivatives via a Copper-Catalyzed Radical Cascade Cyclization

AbstractHerein, an atom-economic method for the synthesis of fused-ring pyrrolizine derivatives by a cycloaddition reaction of easily accessible N-substituted pyrrole-2-carboxaldehydes with N-substituted maleimides in the presence of di-tert-butyl peroxide has been successfully developed. A total of 23 compounds were obtained by using this method, with a maximum yield of 72%, providing a practical and efficient method for the synthesis of tricyclic pyrrolizine frameworks.

Ru(II)-Catalyzed [4 + 2]-Annulation of 2-Alkenyl/Arylimidazoles with N-Substituted Maleimides and 1,4-Naphthoquinones: Access to Imidazo-Fused Polyheterocycles.

Synthesis of imidazo-fused polyheterocyclic molecular frameworks, viz. imidazo[1,2-a]pyrrolo[3,4-e]pyridines, imidazo[2,1-a]pyrrolo[3,4-c]isoquinolines, and benzo[g]imidazo[1,2-a]quinoline-6,11-diones, has been achieved by the ruthenium(II)-catalyzed [4 + 2] C-H/N-H annulation of 2-alkenyl/2-arylimidazoles with N-substituted maleimides and 1,4-naphthoquinones. The developed protocol is operationally simple, exhibits broad substrate scope with excellent functional group tolerance, and provides the desired products in moderate to good yields. The mechanistic studies suggest that the reaction involves the formation of a C-C bond through Ru-catalyzed C(sp2)-H bond activation followed by intramolecular cyclization.

New N-Substituted Maleimide Drug Polymers: Synthesis, Drug Release and Antibacterial Activity

New N-Substituted Maleimide Drug Polymers: Synthesis, Drug Release and Antibacterial Activity

Glyoxylic Acid Monohydrate-Promoted Formation of the C-SO2 Bond Starting from Maleimides/Quinones and Sodium Sulfinates.

By using glyoxylic acid monohydrate as a promoter, a wide range of substances containing a C-SO2 bond could be obtained from N-substituted maleimides or quinones and sodium sulfinates. The protocol features mild reaction conditions, short reaction time, and good atomic economics, which provides an alternative protocol for the α-sulfonylation of α,β-unsaturated ketones.

Design, Synthesis and Antifungal Evaluation of N-Substituted Maleimide Derivatives with Imidazole and 2-Methyl Imidazole Moieties

A series of N-substituted maleimide derivatives with an attached imidazole and 2-methyl imidazole heterocyclic rings were designed, synthesized and evaluated for their antifungal activity against four pathogenic fungi. 1H-NMR, 13C-NMR and mass spectra confirmed the chemical structures of all synthesized compounds. All compounds 4a-4g, 5b and 5f were initially screened for qualitative (zone of inhibition) antifungal activity against C. albicans, A. fumigatus, A. niger, and A. oryzae. The screening results indicate that most of the synthesized compounds showed significant antifungal activity against the tested fungi. Furthermore, the compounds that showed a significant zone of inhibition were selected and tested quantitatively (MIC50 and IC50) against the same pathogenic fungi species. The MIC50 and IC50 results of selected compounds were analyzed. These results strongly suggest that compound 5f has shown promising antifungal activity. Furthermore, the structure–activity relationship of compound 5f revealed that the compound substituted with the –F group possess prominent antifungal activity.

Mesoporous Mixed-Metal-Organic Framework Incorporating a [Ru(Phen)3]2+ Photosensitizer for Highly Efficient Aerobic Photocatalytic Oxidative Coupling of Amines.

[Ru(Phen)3]2+ (phen = phenanthroline) as a very classical photosensitizer possesses strong absorption in the visible range and facilitates photoinduced electron transfer, which plays a vital role in regulating photochemical reactions. However, it remains a significant challenge to utilize more adequately and exploit more efficiently the ruthenium-based materials due to the uniqueness, scarcity, and nonrenewal of the noble metal. Here, we integrate the intrinsic advantages of the ruthenium-based photosensitizer and mesoporous metal-organic frameworks (meso-MOFs) into a [Ru(Phen)3]2+ photosensitizer-embedded heterometallic Ni(II)/Ru(II) meso-MOF (LTG-NiRu) via the metalloligand approach. LTG-NiRu, with an extremely robust framework and a large one-dimensional (1D) channel, not only makes ruthenium photosensitizer units anchored in the inner wall of meso-MOF tubes to circumvent the problem of product/catalyst separation and recycling of catalysts in heterogeneous systems but also exhibits exceptional activities for the aerobic photocatalytic oxidative coupling of amine derivatives as a general photocatalyst. The conversion of the light-induced oxidative coupling reaction for various benzylamines is ∼100% in 1 h, and more than 20 chemical products generated by photocatalytic oxidative cycloaddition of N-substituted maleimides and N,N-dimethylaniline can be synthesized easily in the presence of LTG-NiRu upon visible light irradiation. Moreover, recycling experiments demonstrate that LTG-NiRu is an excellent heterogeneous photocatalyst with high stability and excellent reusability. LTG-NiRu represents a great potential photosensitizer-based meso-MOF platform with an efficient aerobic photocatalytic oxidation function that is convenient for gram-scale synthesis.

Photoinduced Electron Donor-Acceptor Complex-Mediated Radical Cascade Involving N-(Acyloxy)phthalimides: Synthesis of Tetrahydroquinolines.

We conceptualized a novel disconnection approach for the synthesis of fused tetrahydroquinolines that exploits a visible light-mediated radical (4 + 2) annulation between alkyl N-(acyloxy)phthalimides and N-substituted maleimides in the presence of DIPEA as an additive. The reaction proceeds through the formation of a photoactivated electron donor-acceptor complex between alkyl NHPI esters and DIPEA, and the final tetrahydroquinolines were obtained in a complete regioselective fashion. The methodology features a broad scope and good functional group tolerance and operates under metal- and catalyst-free reaction conditions. Detailed mechanistic investigations including density functional theory studies provide insight into the reaction pathway.

Synthesis, characterization and anti-breast cancer activity of some maleimide derivatives

This study included the synthesis of four compounds of maleimide derivatives. Novel compounds (K1-K4) resulted from the reaction between N-substituted maleimide and aryl hydrazide (benzohydrazide, p-toluic hydrazide or isonazide). The novel maleimide derivatives were identified using infrared spectroscopy (FT-IR), 1H- and 13 C-nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry, as well as the melting point of the preparing compounds. The MTT assay were used to examine the anti-breast cancer (MCF-7) activities of four compounds. The compounds K2 and K4 demonstrated anti-cancer activity against breast cancer cells.

Controlling the toxicity of biomass-derived difunctional molecules as potential pharmaceutical ingredients for specific activity toward microorganisms and mammalian cells.

A biomass-derived difuran compound, denoted as HAH (HMF-Acetone-HMF), synthesized by aldol-condensation of 5-hydroxyfurfural (HMF) and acetone, can be partially hydrogenated to provide an electron-rich difuran compound (PHAH) for Diels-Alder reactions with maleimide derivatives. The nitrogen (N) site in the maleimide can be substituted by imidation with amine-containing compounds to control the hydrophobicity of the maleimide moiety in adducts of furans and maleimide by Diels-Alder reaction, denoted as norcantharimides (Diels-Alder adducts). The structural effects on the toxicity of various biomass-derived small molecules synthesized in this manner to regulate biological processes, defined as low molecular weight (≤ 1000 g/mol) organic compounds, were investigated against diverse microbial and mammalian cell types. The biological toxicity increased when hydrophobic N-substitutions and C=C bonds were introduced into the molecular structure. Among the synthesized norcantharamide derivatives, some compounds demonstrated pH-dependent toxicities against specific cell types. Reaction kinetics analyses of the norcantharimides in biological conditions suggest that this pH-dependent toxicity of norcantharimides could arise from retro Diels-Alder reactions in the presence of a Brϕnsted acid that catalyzes the release of an N-substituted maleimide, which has higher toxicity against fungal cells than the toxicity of the Diels-Alder adduct. These synthetic approaches can be used to design biologically-active small molecules that exhibit selective toxicity against various cell types (e.g., fungal, cancer cells) and provide a sustainable platform for production of prodrugs that could actively or passively affect the viability of infectious cells.

New Aspects of the Reaction of Thioacetamide and N-Substituted Maleimides.

N-Arylmaleimides are universal substrates for the synthesis of various heterocyclic compounds with a wide spectrum of biological activity. However, their reactions with thioacetamides have not been comprehensively studied. We studied the reactions of thioacetamide with N-arylmaleimides under various conditions. We established for the first time that three types of products: epithiopyrrolo[3,4-c]pyridines, pyrrolo[3,4-c]pyridines and 3,3'-thiobis(1-arylpyrrolidine-2,5-diones) can be obtained in different conditions. In all cases, two maleimide molecules are involved in the reaction. 3,3'-Thiobis(1-arylpyrrolidine-2,5-diones) are the major products when the reaction is conducted at boiling in acetic acid. When thioacetamide and N-arylmaleimide are kept in dioxane at 50 °C, epithiopyrrolo[3,4-c]pyridines can be isolated, which, when heated in dioxane, in acetic acid or in methanol in the presence of catalytic amounts of sodium methoxide, are converted into pyrrolo[3,4-c]pyridines by eliminating hydrogen sulfide. The reaction of thioacetamide and N-arylmaleimide in dioxane at boiling temperature with the portioned addition of N-arylmaleimide leads predominantly to the formation of pyrrolo[3,4-c]pyridines. The reaction of thioacetamide with N-alkylmaleimides under all the above conditions leads predominantly to the formation of the corresponding sulfides. The structure of the compounds obtained was characterized by a set of spectral analysis methods and X-ray diffraction (XRD) data.

Development of Sequence-Controlled, Degradable, and Cytocompatible Oligomers with Explicit Fragmentation Pathways.

Sequence-defined and degradable polymers can mimic biopolymers, such as peptides and DNA, to undertake life-supporting functions in a chemical way. The design and development of well-structured oligomers/polymers is the most concern for the public, even to further uncover their degradation process illustrating the degraded products and their properties. However, seldom investigation has been reported on the aforementioned aspects. In this work, the alternating photo-reversible addition-fragmentation chain-transfer (photo-RAFT) single unit monomer insertion (SUMI) of different N-substituted maleimides and thermal radical ring-opening SUMI of a cyclic ketene acetal monomer (i.e., 5,6-benzo-2-methylene-1,3-dioxepane (BMDO)) is adopted, to produce two degradable pentamers owing to the conversion of the exo-methylene group of BMDO into ester bonds along the main chains of the prepared products. Moreover, the possible degraded approach of pentamers is studied by combining high-resolution mass spectrometry (HRMS) and liquid chromatography-mass spectrometry (LC-MS) for the first time. This work also sheds light on the precise structures and cytotoxicity of SUMI products and their degraded compounds, proposing a detailed and credible outlook for biomedical applications.

Use of Polymer-Supported 4-(N,N-Dimethylamino)pyridine in a Formal Conjugate Addition/Elimination Mediated by an N-Ylide Generated In Situ for the Construction of Highly Functionalized Itaconimides/Alkenes

AbstractA simple, mild, and metal-free cascade reaction has been developed for the construction of highly functionalized olefins. The approach relies on the initial formation of [3+2]-cycloadducts from a pyridinium ylide generated in situ from polymer-bound DMAP (PS-DMAP) with an N-substituted maleimide or an α,β-unsaturated β-keto ester. The cycloadduct decomposes to regenerate supported DMAP and yield a functionalized itaconimide or olefin. The method has a broad substrate scope. The alkene product has been further transformed into trisubstituted furan. PS-DMAP could be reused for five cycles.

β-Amino Acid Organocatalysts in the Asymmetric Michael Addition of Isobutyraldehyde to N-Substituted Maleimides

Asymmetric Michael additions of carbonyl compounds to N-substituted maleimides are among the most convenient reactions to prepare optically pure succinimide building blocks. Although a few β-amino acids were found to be highly efficient organocatalysts in the addition of α-branched aldehydes, the effect of their structure on the results of these reactions has not yet been investigated. In the present study, we disclose several unexpected and interesting structural effects of aliphatic and cycloaliphatic β-amino acids obtained in the enantioselective conjugate addition of isobutyraldehyde to N-benzylmaleimide. The dependence of the sense of the enantioselectivity on the bulkiness of the substituent on the β-carbon atom, the beneficial spatial arrangements of the functional groups in cis isomers with cyclohexane scaffold and the inversion of the enantioselectivity depending on the absence of a base additive observed with some trans isomers are unprecedented findings. The minor influence of the nitrogen substituent of the maleimide ring on both the reaction rate and the enantioselectivity was also evidenced using alicyclic β-amino acid prepared from an easily available terpene derivative.

Recyclization of Maleimides by Binucleophiles as a General Approach for Building Hydrogenated Heterocyclic Systems.

The building of heterocyclic systems containing hydrogenated fragments is an important step towards the creation of biologically-active compounds with a wide spectrum of pharmacological activity. Among the numerous methods for creating such systems, a special place is occupied by processes using N-substituted maleimides as the initial substrate. This molecule easily reacts in Diels-Alder/retro-Diels-Alder reactions, Michael additions with various nucleophiles, and co-polymerization processes, as have been described in numerous detailed reviews. However, information on the use of maleimides in cascade heterocyclization reactions is currently limited. This study is devoted to a review and analysis of existing literature data on the processes of recyclization of N-substituted maleimides with various C,N-/N,N-/S,N-di- and polynucleophilic agents, such as amidines, guanidines, diamines, aliphatic ketazines, aminouracils, amino- and mercaptoazoles, aminothiourea, and thiocarbomoyl pyrazolines, among others. The significant structural diversity of the recyclization products described in this study illustrates the powerful potential of maleimides as a building block in the organic synthesis of biologically-active compounds with hydrogenated heterocyclic fragments.

Direct routes to functional RAFT agents from substituted N-alkyl maleimides

Three different routes are presented for the synthesis of functional RAFT agents from N-substituted maleimides, which are then used to synthesise α,β,ω-functional RAFT polymers.

Oxathiaborolium-catalyzed enantioselective [2 + 2] cycloadditions.

The generation of sulfur-stabilized borenium cations by SnCl4, a halophilic Lewis acid, leads to the formation of oxathiaborolium pentachlorostannate, which is an excellent Lewis acid and is successfully used to catalyze the [2 + 2] cycloadditions of N-substituted maleimides and silyl enol ethers to afford cycloadducts with excellent enantioselectivities (17 examples, up to 96% ee). This efficient synthetic methodology provides a new viable and significantly efficient route to ring-fused cyclobutanes bearing quaternary stereogenic centers by combining pot, atom, and step economy to synthesize complex organic molecules.

Conjugate addition of 1,3-dicarbonyl compounds to maleimides using bifunctional primary amine‒(thio)phosphoramide organocatalysts

Asymmetric Michael additions of 1,3-dicarbonyl compounds to N-substituted maleimides were carried out using primary amine-(thio)phosphoramide bifunctional chiral organocatalysts derived from optically pure C2-symmetric 1,2-diamines. The addition of ethyl 2-fluoroacetoacetate using the 1,2-diphenylethane-1,2-diamine derived thiophosphoramide catalyst afforded various succinimides substituted with fluorine bearing quaternary carbon in high yields, good diastereomeric ratios and excellent enantiomeric excesses. Alicyclic β-ketoesters provided the diastereomerically pure Michael adducts in good yields and high enantioselectivities, whereas 2,4-pentanedione afforded products with slightly lower enantiomeric excesses. The bulkiness of the N-substituent of the maleimide ring influenced mostly the conversions. The thiophosphoramide catalyst was found also efficient in the addition of ethyl 2-fluoroacetoacetate to β-nitrostyrenes. Unprecedentedly, during this work the highly enantioselective addition of 1,3-dicarbonyl compounds to maleimides were catalyzed by a primary amine‒hydrogen-bond donor groups containing bifunctional organocatalyst. These reactions occurred through enamine intermediate, as evidenced by electrospray-ionization mass spectrometry and NMR spectroscopy.

Synthesis and kinetic characterization of hyperbolic inhibitors of human cathepsins K and S based on a succinimide scaffold

Cathepsins K and S are closely related papain-like cysteine peptidases and potential therapeutic targets for metabolic and inflammatory diseases such as osteoporosis and arthritis. Here we describe the reduction of a previously characterized succinimide (2,5-dioxopyrrolidine)-containing hyperbolic inhibitor of cathepsin K (methyl (RS)-N-[1-(4-methoxyphenyl)-2,5-dioxopyrrolidin-3-yl]glycinate), to obtain a better and more selective compound (compound 4a - methyl (2,5-dioxopyrrolidin-3-yl)glycinate), which acted as a hyperbolic mixed inhibitor/activator similar to already known allosteric effectors of cathepsin K. We then investigated the potential of the succinimide scaffold as inhibitors of cathepsins K and/or S and synthesized a library of such compounds by 1,4-addition of α-amino acid esters and related compounds to N-substituted maleimides. From the generated library, we identified the first small molecule hyperbolic inhibitors of cathepsin S (methyl ((R)-2,5-dioxopyrrolidin-3-yl)-l-threoninate (compound R-4c) and 3-{[(1S,2R,3′S)-2-hydroxycyclohexyl]amino}pyrrolidine-2,5-dione (compound (1S,2R,3′S-10)). The former acted via a similar mechanism to compound 4a, while the latter was a hyperbolic specific inhibitor of cathepsin S. Given the versatility of the scaffold, the identified compounds will be used as the basis for the development of high-affinity hyperbolic inhibitors of the individual peptidases and to explore the potential of hyperbolic inhibitors for the inhibition of cysteine cathepsins in in vitro models.