Β-amino Carbonyl Research Articles

New Metal Complexes with Mannich -β-amino carbonyl ligand; Preparation, spectral Characterisation and Biological Activity.

New metal complexes and a new beta-amino maniche carbonyl ligand were prepared and characterized. (((4-(tert-butyl)-2-((S)- (phenylamino) (p-tolyl) methyl)cyclohexan-1-one)) (HL) was formed from the reaction of aniline and 4-methylbesaldehyde with 4- (tert-butyl)cyclohexane-1-one at a 1:1:1 mol ratio respectively reaction of (4-methyl-2-((R)-(phenylamino)(p-tolyl) methyl)cyclohexan-1-one (HL) and MnII, CoII, NiII, CuII, ZnII and CdII metal ions in a 2:1 (L:M) ratio led to the isolation of monomeric complexes from analytical and spectroscopic techniques including; elemental microanalysis, magnetic susceptibility, conductivity, TGA, and FTIR, electronic and mass spectra and 1 H, 13C-NMR characterization data indicated to a four- and six-coordinate isolate.Complexes Many bacterial and fungal strains were tested, and the data obtained showed that these complexes are more active against a variety of organisms, under experiment, than free associations.

MicroRNA-Dependent Mechanisms Underlying the Function of a β-Amino Carbonyl Compound in Glioblastoma Cells.

Glioblastoma (GB) is an aggressive brain malignancy characterized by its invasive nature. Current treatment has limited effectiveness, resulting in poor patients' prognoses. β-Amino carbonyl (β-AC) compounds have gained attention due to their potential anticancerous properties. In vitro assays were performed to evaluate the effects of an in-house synthesized β-AC compound, named SHG-8, upon GB cells. Small RNA sequencing (sRNA-seq) and biocomputational analyses investigated the effects of SHG-8 upon the miRNome and its bioavailability within the human body. SHG-8 exhibited significant cytotoxicity and inhibition of cell migration and proliferation in U87MG and U251MG GB cells. GB cells treated with the compound released significant amounts of reactive oxygen species (ROS). Annexin V and acridine orange/ethidium bromide staining also demonstrated that the compound led to apoptosis. sRNA-seq revealed a shift in microRNA (miRNA) expression profiles upon SHG-8 treatment and significant upregulation of miR-3648 and downregulation of miR-7973. Real-time polymerase chain reaction (RT-qPCR) demonstrated a significant downregulation of CORO1C, an oncogene and a player in the Wnt/β-catenin pathway. In silico analysis indicated SHG-8's potential to cross the blood-brain barrier. We concluded that SHG-8's inhibitory effects on GB cells may involve the deregulation of various miRNAs and the inhibition of CORO1C.

Synthesis of β-Amino Carbonyl 6-(Aminomethyl)- and 6-(Hydroxymethyl)pyrazolopyrimidines for DPP-4 Inhibition Study.

Type-2 diabetes is a chronic progressive metabolic disease resulting in severe vascular complications and mortality risk. Recently, DPP-4 inhibitors had been conceived as a favorable class of agents for the treatment of type 2 diabetes due to the minimal side effects. Sitagliptin is the first medicine approved for the DPP-4 inhibitor. Its structure involved three fragments: 2,4,5-triflorophenyl fragment pharmacophore, enantiomerically β-amino carbonyl linker, and tetrahydrotriazolopyridine. Herein, we are drawn to the possibility of substituting tetrahydrotriazolopyridine motif present in Sitagliptin with a series of new fused pyrazolopyrimidine bicyclic fragment to investigate potency and safety. Two series of fused 6-(aminomethyl)pyrazolopyrimidine and 6-(hydroxymethyl) pyrazolopyrimidine derivatives containing β-amino ester or amide as linkers were successfully designed for the new DPP-4 inhibitors. Most fused 6-methylpyrazolopyrimidines were evaluated against DPP-4 inhibition and selectivity capacity. Based on research study, β-amino carbonyl fused 6-(hydroxymethyl)pyrazolopyrimidine possesses the significant DPP-4 inhibition (IC50 ≤ 59.8 nM) and presents similar with Sitagliptin (IC50 = 28 nM). Particularly, they had satisfactory selectivity over DPP-8 and DPP-9, except for QPP. β-Amino esters and amides fused 6-(hydroxymethyl)pyrazolopyrimidine were developed as the new DPP-4 inhibitors. Those compounds with a methyl group or hydrogen in N-1 position and methyl substituted group in C-3 of pyrazolopyrimidine moiety showed better potent DPP-4 inhibition (IC50 = 21.4-59.8 nM). Furthermore, they had satisfactory selectivity over DPP-8 and DPP-9 Finally, the docking results revealed that compound 9n was stabilized at DPP-4 active site and would be a potential lead drug.

Stereoselective Construction of Less-Accessible Acyclic α,α-Disubstituted β-Ketiminonitriles via Electrophilic Cyanation of β,β-Disubstituted Enesulfinamides.

The metalloenamines, formed by NH-deprotonation of β,β-disubstituted enesulfinamides, can undergo reactions with commercially available electrophilic cyanating reagents such as tosyl cyanide (TsCN) or 3-oxo-1,2-benziodoxole-1(3H)-carbonitrile (CBX). Through the utilization of appropriate stereoisomers of enesulfinamides, this method enables the selective synthesis of any of the four stereoisomers of α,α-disubstituted β-sulfinylimino nitriles, which feature acyclic quaternary stereocenters and are typically more challenging to synthesize. These compounds can then undergo stereoselective nucleophilic addition, leading to the creation of valuable enantioenriched multisubstituted β-amino carbonyl surrogates with a high degree of structural diversity.

Enantioselective Access to β-Amino Carbonyls via Ni-Catalyzed Formal Olefin Hydroamidation.

We herein describe a Ni-catalyzed formal hydroamidation of readily available α,β-unsaturated carbonyl compounds to afford valuable chiral β-amino acid derivatives (up to >99:1 e.r.) using dioxazolones as a robust amino source. A wide range of alkyl-substituted olefins conjugated to esters, amides, thioesters, and ketones were successfully amidated at the β-position with excellent enantioselectivity for the first time. Combined experimental and computational mechanistic studies supported our working hypothesis that this unconventional β-amidation of unsaturated carbonyl substrates can be attributed to the polar-matched migratory olefin insertion of an (amido)(Cl)NiII intermediate, in situ generated from the dioxazolone precursor.

Hen egg white lysozyme encapsulated in ZIF-8 for performing promiscuous enzymatic Mannich reaction

Hen egg white lysozyme (HEWL) was exploited for the synthesis of β-amino carbonyl compounds through a direct and three-component Mannich reaction in aqueous, confirming high chemoselectivity toward imine. In order to further extend the applications of the enzyme, HEWL was encapsulated using a metal-organic framework (MOF). The reactivity, stereoselectivity, and reusability of the encapsulated enzyme were investigated. The reaction was significantly enhanced as compared to the non-encapsulated enzyme. A mutated version of the enzyme, containing Asp52Ala (D52A), lacking important catalytical residue, has lost the bacterial site activity against Micrococcus luteus (M. luteus) while the D52A variant displayed an increased rate of the Mannich reaction, indicating a different catalytical residue involved in the promiscuous reaction. Based on site-directed mutagenesis, molecular docking, and molecular dynamic studies, it was proposed that π-stacking, H-bond interactions, and the presence of water in the active site may play crucial roles in the mechanism of the reaction.

Synthesis and characterization of Ag-Au loaded SiO2 nanocomposites and study of its catalytic applicability in Mannich reaction

This study, Ag-Au/SiO2 bimetal nanocomposites were used as a heterogeneous novel catalyst for microwave-assisted stereoselective synthesis of β-amino carbonyl in Mannich reaction. For this purpose, Ag-Au bimetal nanoparticles (BNPs) was prepared with the particle size lower than 30 nm and loaded on SiO2 nanospheres. These Ag-Au/SiO2 nanocomposites were synthesized via Stober method modified with the addition of colloidal bimetal nanoparticles. The as-prepared nanocomposites were characterized by several techniques including scanning electron microscopy (HR-SEM), X-ray diffraction (XRD), transmission electron microscopy (TEM), selected area electron diffraction (SAED), atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). The catalytic performance of the synthesized Ag-Au/SiO2 for the catalysis of Mannich reaction was investigated. The present methodology found to be having several advantages, such as good yield, shorter reaction time and the reusability of the catalyst.

Synthesis, Structural Characterisation and Biological Activity; New Metal Complexes Derived from Semicarbazone Ligand

The results of synthesizing a novel tridentate Schiff-base ligand and its metal complexes have been given. The ligand itself is described as being tridentate. The synthesis of the ligand has the following chemical formula: (E)-2-((2S)-4-(tert-butyl) -2-((S)-(phenylamino) (p-tolyl) methyl) cyclohexylidene) hydrazine -1-carboxamide was produced as a byproduct of the reaction between benzoic acid and benzoic acid between (((4-(tert-butyl)-2-((S)-(phenylamino)(p-to and (HL). The ligand was reacted with 1:1 (L:M) mole ratios of ions containing Mn(II), Co(II), Ni(II), Cu(II), Zn(II), and Cd(II), which resulted in the production of title complexes. In cases where it was necessary, physicochemical techniques were utilized to characterize both the ligand and the complexes. Examples include magnetic susceptibility and conductance measurements, microanalysis of elements, nuclear magnetic resonance (1H, 13C), mass spectrometry, Fourier transform infrared (FT-IR), electronic spectra, and more. The results of these studies demonstrated that the ions Mn (II), Co (II), Cu(II), Ni(II), Zn(II), and Cd(II) can be partitioned into four-coordinate and six-coordinate complexes, respectively. In addition, the TGA was used to investigate whether or not the ligand and specific complexes were thermally stable. Several different bacterial and fungus strains were utilized to examine the ligand and its complexes for potential antibacterial activity. According to the findings, the complexes are far more effective than the free ligand in combating a wider variety of species. Keywords: Structural study; Metal complexes; Mannich -β-amino carbonyl; Thermal stability; Staphylococcus aureus (G+).

Synthesis, Characterization, Pharmacogenomics, and Molecular Simulation of Pyridinium Type of Ionic Liquids and Their Applications.

Substituted pyridinium bromides are prepared by conventional and solvent-free greener methods. The solvent-free solid-phase (greener) method is superior to the conventional method because of its nontoxic nature, simple reaction setup procedure, and twenty times less time consumption. Column chromatography and toxic organic solvents are avoided. Substituted pyridinium salts 1-2(a-c) show excellent catalytic response in the preparation of β-amino carbonyl derivatives using the conventional approach. Pharmacokinetics is very important in target validation and in shifting a lead compound into a drug. The physicochemical properties discussed here can be used effectively in the drug designing candidate, which is a cumbersome process in clinical research. In addition, molecular simulations are demonstrated, and compounds 1-2(a-c) possess the most potent VEGFR-2 kinase protein inhibitory activities, and most interestingly, compound 2a strongly binds and regulates the VEGFR-2 kinase activity in therapeutic approaches and cancer prevention.

Thermal, spectroscopic, ADMET and toxicological studies of synthesized β-Amino carbonyl compounds

Thermal, spectroscopic, ADMET and toxicological studies of synthesized β-Amino carbonyl compounds

Microfluidics Biocatalysis System Applied for the Synthesis of N-Substituted Benzimidazole Derivatives by Aza-Michael Addition

Benzimidazole scaffolds became an attractive subject due to their broad spectrum of pharmacological activities. In this work, a methodology was developed for the synthesis of N-substituted benzimidazole derivatives from benzimidazoles and α, β-unsaturated compounds (acrylonitriles, acrylate esters, phenyl vinyl sulfone) catalyzed by lipase TL IM from Thermomyces lanuginosus in continuous-flow microreactors. Investigations were conducted on reaction parameters such as solvent, substrate ratio, reaction temperature, reactant donor/acceptor structures, and reaction time. The transformation is promoted by inexpensive and readily available lipase in methanol at 45 °C for 35 min. A wide range of β-amino sulfone, β-amino nitrile, and β-amino carbonyl compounds were efficiently and selectively synthesized in high yields (76–97%). All in all, a microfluidic biocatalysis system was applied to the synthesis of N-substituted benzimidazole derivatives, and could serve as a promising fast synthesis strategy for further research to develop novel and highly potent active drugs.

Lead modification via computational studies: Synthesis of pyrazole-containing β-amino carbonyls for the treatment of type 2 diabetes.

This article describes studies on the design, synthesis, and biological evaluation of pyrazole-containing β-amino carbonyl compounds (5a-5q) as DPP-4 inhibitors and anti-diabetic agents. In contrast, mannich reactions went smoothly with bismuth nitrate (Bi (NO3 )3 ) catalyst in the presence of ethanol and produced pyrazole-containing β-amino carbonyl compounds in good yield. Molecular docking studies of designed derivatives with DPP-4 enzyme (PDB: 2OLE), compounds 5d, 5h, 5j, and 5k showed excellent interaction. 3D QSAR and pharmacophoric model studies were also carried out. ADMET parameters, pharmacokinetic properties, and in vivo toxicity studies further confirmed that all the designed compounds were found to have good bioavailability and were less toxic. Further, these compounds were evaluated as enzyme-based in vitro DPP-4 inhibitory activity, and 5d, 5h, 5i, 5j, and 5k exhibited IC50 toward DPP-4 enzyme of 10.52, 10.41, 5.55, 4.16, and 7.5nM, respectively. The most potent compound, 5j, was further selected for in vivo anti-diabetic activity using an STZ-induced diabetic mice model, and 5j showed a significant diabetic control effect.

Metal-free photosensitized intermolecular carboimination of alkenes: a green and direct access to both β-amino acids and β-amino ketones.

β-Amino carbonyl substructures are privileged motifs in natural products and active pharmaceutical compounds. Here, we report a photoinduced metal-free and highly regioselective intermolecular carboimination method via the simultaneous introduction of amino and carbonyl groups into the CC double bond in one step, providing straightforward, green and general access to both β-amino acid and β-amino ketone motifs from readily available alkene feedstocks. The mild reaction conditions, excellent functional group tolerance and product diversity should make this a broadly applicable carboimination approach of very broad interest to organic and medicinal chemists.

Asymmetric synthesis of cyclic β-amino carbonyl derivatives by a formal [3 + 2] photocycloaddition.

Herein, a visible-light mediated strategy unlocking a family of cyclic β-amino carbonyl derivatives bearing three contiguous stereogenic centres is introduced. The overall reactivity relies on the performance of the substrate-catalyst complex to assist both the enantiocontrol and the photoredox tasks. This transformation led to an enantioselective [3 + 2] photocycloaddition between coordinated α,β-unsaturated acyl imidazoles and cyclopropylamine derivatives.

New Mannich Base (2R)-4-methyl-2-((S)(phenylamino)(p-tolyl)methyl)cyclohexan-1-one; Synthesis and Spectral Characterisation

The study includes preparation and characterisation of a new Mannich -β-amino carbonyl namely: (2R)-4-methyl-2-((S)(phenylamino)(p-tolyl)methyl)cyclohexan-1-one. was achieved from the reaction of 4-methylcyclohexan-1-one and aniline with 4-methylbenzaldehyde in a 1:1:1 mole ratio, respectively. Calcium chloride was used as catalyst and ethanol as reaction medium. A range of physico-chemical tools were used to charcteris the isolated compound. These include; FT-IR, 1H-, 13C-NMR, mass spectra, elemental analysis and melting point.

Facile Synthesis, Characterization and in Silico Docking Studies of Novel Thiazolidine-2,4-Dione-Based Mannich Base Bearing Furan/Thiophene Moiety as Promising Anti-Inflammatory Agents

Mannich bases are compounds bearing a β-amino carbonyl moiety. They are formed in the Mannich reaction that consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group by formaldehyde and a primary or secondary amine. Mannich base products are known for their curative properties such as anti-inflammatory, antibacterial, anticancer, antifungal, anthelmintic, anticonvulsant, analgesic, anti-HIV, antipsychotic, antiviral, and antimalarial activities. Further, thiazolidinedione derivatives have shown to be efficacious in inflammatory diseases as wide-ranging as psoriasis, ulcerative colitis and non-alcoholic steatohepatitis. In light of the above observations, new series of thiazolidine-2,4-dione based Mannich base derivatives were synthesized via a simple and catalyst-free procedure involving the condensation of thiazolidine-2,4-dione, formaldehyde and secondary amines in DMF solvent. The structures of the newly synthesized compounds were confirmed by their IR, 1H-NMR, and Mass spectra. The synthesized compounds were tested for their in silico anti-inflammatory activity by Docking studies against COX-2 enzyme (PDB: 1CX2). Compounds 4a and 4b showed good in silico anti-inflammatory properties comparable to that of standard drug Diclofenac and may be considered as promising candidates for the development of new anti-inflammatory agents.

Design, synthesis and biological evaluation of glycolamide, glycinamide, and β-amino carbonyl 1,2,4-triazole derivatives as DPP-4 inhibitors

Through modification of the skeleton of Sitagliptin and Vildagliptin, we successfully synthesized and built-up four series of 1,2,4-triazole derivatives, containing N,O-disubstituted glycolamide, N,N′-disubstituted glycinamide, β-amino ester, and β-amino amide as linkers, for the development of new dipeptidyl peptidase 4 (DPP-4) inhibitors. The synthetic strategy for glycolamides or glycinamides involved convenient two-steps reaction: functionalized transformation of 2-chloro-N-(2,4,5-triflurophenyl)acetamide 9 (hydroxylation or amination) and esterification or amidation of 1,2,4-triazole-3-carboxylic acid. On the other hand, the one-pot synthesis procedure, including substitution and deprotection, was developed for the preparation of β-amino carbonyl 1,2,4-triazoles from (1H-1,2,4-triazol-3-yl)methanol 12 or (1H-1,2,4-triazol-3-yl)methanamine 13 and Boc-(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyric acid 14. All of glycolamides, glycinamides, and β-amino carbonyl 1,2,4-triazoles were also evaluated against DPP-4 inhibitory activity. Based on the SAR study of DPP-4 inhibitory capacity, β-amino ester 5n and β-amino amide 1,2,4-triazoles 6d and 6p possessed the significant inhibition of DPP-4 (IC50 < 51.0 nM), particularly for compound 6d (IC50 = 34.4 nM). The selectivity evaluation indicated compound 5n and 6p had excellent selectivity over QPP, DPP-8, and DPP-9. In addition, the docking results revealed compounds 5n and 6p provided stronger π–π stacking interaction with residue Phe357 than 1,5-disubstituted 1,2,4-triazole 6d and Sitagliptin 1. In summary, compounds 5n and 6p could be promising lead compounds for further development of DPP-4 inhibitor.

One-pot synthesis of β-amino carbonyl compounds under solvent free condition by using alum doped nanopolyaniline catalyst

Alum doped nanopolyaniline (NDPANI), an efficient and reusable green catalyst for synthesis of β-amino carbonyl compounds has been developed. Mannich type reaction of various amines, aldehydes and ketones is carried out to synthesize the desire β-amino carbonyl compounds with excellent yield under solvent free condition. The advantages of this catalyst are inexpensive, reusability, easy preparation and stable. The reaction condition represents an advanced over established method in terms of avoiding solvent, mild reaction condition, clean reaction profile and simple workup.

In vitro anticancer activity of thiazole based β-amino carbonyl derivatives against HCT116 and H1299 colon cancer cell lines; study of pharmacokinetics, physicochemical, medicinal properties and molecular docking analysis

The present study describes the synthesis and anticancer evaluation of certain substituted rac-(2S)-2-[(R)-[(4-substitutedphenyl){[4-(4-substitutedphenyl)-1,3-thiazol-2-yl]amino}methyl]cyclohexanone derivatives. The in vitro anti-cancer assay indicating substituted β-amino carbonyl derivatives 4g and 4r are particularly active in both tests (HCT116 and H1299). The 4f, 4o , and 4t are the least functioning; 4m and 4n are marginally active; 4b and 4c are more cytotoxic when the growth inhibition percent is compared with standard drugs Camptothecin (CPT.), Acyclovir (ACV), Cisplatin (CDDP.), Vinblastine (VBL) and Trichothecene (TCT.). Among them, 2-((4- p -tosylthiazol-2-ylamino)(4-hydroxyphenyl)methyl) cyclohexanone 4u exhibits selective cytotoxicities for IC 50 µg/mL against HCT116 and H1299, respectively. Simulation of virtually designed 21 compounds has been studied for active binding sites of Crystal Structure of the Cancer Genomic DNA Mutator APOBEC3B (PDB ID- 5CQD) enzyme using molecular modelling of protein-ligand interactions. The in-depth sequencing studies reveal that the involvement of APOBEC3B in cancer mutagenesis. For comparison, the binding behaviour of known standard drugs has also studied. The new SwissADME web utensil that gives free access to a pool of quick yet reliable analytical models is presented for physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry. Among them, in-house capable technique, for example, BOILED-Egg, iLOGP, and Bioavailability Radar, are readily available on the web.

Cover Picture: Asymmetric Oxidative Mannich Reactions (Adv. Synth. Catal. 3/2021)

The inside cover picture illustrates the impact of the different approaches for the development of asymmetric oxidative Mannich reactions to synthesize chiral β-amino carbonyl compounds, very important building blocks in organic synthesis and in the pharmaceutical chemistry, which have been described in the last years. Details can be found in the review by J. R. Pedro, C. Vila and co-workers. (J. Rostoll-Berenguer, G. Blay, J. R. Pedro, C. Vila, Adv. Synth. Catal. 2021, 363, 602–628; DOI: 10.1002/adsc.202001017).