Methanamine Derivatives Research Articles

Crystal structure determination and Hirshfeld surface analysis of N-acetyl-N-3-meth-oxy-phenyl and N-(2,5-di-meth-oxy-phen-yl)-N-phenyl-sulfonyl derivatives of N-[1-(phenyl-sulfon-yl)-1H-indol-2-yl]methanamine.

Two new [1-(phenyl-sulfon-yl)-1H-indol-2-yl]methanamine derivatives, namely, N-(3-meth-oxy-phen-yl)-N-{[1-(phenyl-sulfon-yl)-1H-indol-2-yl]meth-yl}acetamide, C24H22N2O4S, (I), and N-(2,5-di-meth-oxy-phen-yl)-N-{[1-(phenyl-sulfon-yl)-1H-indol-2-yl]meth-yl}benzene-sulfonamide, C29H26N2O6S2, (II), reveal a nearly orthogonal orientation of their indole ring systems and sulfonyl-bound phenyl rings. The sulfonyl moieties adopt the anti-periplanar conformation. For both compounds, the crystal packing is dominated by C-H⋯O bonding [C⋯O = 3.312 (4)-3.788 (8) Å], with the structure of II exhibiting a larger number, but weaker bonds of this type. Slipped π-π inter-actions of anti-parallel indole systems are specific for I, whereas the structure of II delivers two kinds of C-H⋯π inter-actions at both axial sides of the indole moiety. These findings agree with the results of Hirshfeld surface analysis. The primary contributions to the surface areas are associated with the contacts involving H atoms. Although II manifests a larger fraction of the O⋯H/H⋯O contacts (25.8 versus 22.4%), most of them are relatively distal and agree with the corresponding van der Waals separations.

Discovery, synthesis, and anti-cancer evaluation of 10-Pterostilbene methylamine hydrochloride derivatives as potential COX-2 and Topo I dual inhibitors

A series of (E)-N-benzyl-1-(2, 4-dimethoxy-6-(4 methoxystyryl) phenyl) methanamine (DMPM) derivatives (D1-D25) were successfully synthesized in the form of hydrochloride, and characterized by spectroscopic techniques. The structure of D15 was further confirmed by X-ray single crystal diffraction, where D15 existed in the form of a dimer constructed by intermolecular hydrogen bonds between the active hydrogen of –NH2+− and Cl−, and the –CH=CH– in the molecule was identified as E configuration. Compounds were evaluated for their anti-cancer properties toward HepG2, Eac-109 and MDA-MB-231 cell lines in vitro. Meanwhile, bioactive compound's toxicity against L02 cell lines were also tested. Sixteen compounds (D2, D5-D8, D10, D13, D16-D23, and D25) exhibited significant cytotoxicity against tested cancer cells with IC50 values ranging from 4.13 to 36.77 μM/L. Their toxicity toward normal human liver cells was lower than that of Cisplatin. Among them, D10, D20 and D25 showed more potent anti-cancer abilities than others. Especially, D20 manifested anti-cancer effects comparable to Cisplatin on all tested cancer cell lines. SAR revealed that –OCH2CH(CH3)2 or –O(CH2)3CH3 substitution (R1) on the benzene ring of Pterostilbene is key factors in enhancing biological activities, while –OCH3, –Cl or –F substitution (R2) on another benzene ring is beneficial for improving anti-cancer abilities, and –OCH3 may be the most favorable modifying groups for enhancing skeleton's activities. Bioactive compounds displayed excellent inhibitory effects on COX-2 at nanomolar concentrations. D20 (IC50 (COX-2) = 69.92 nm/L) was identified as the most promising COX-2 inhibitor, meanwhile, it also exhibited significant Topo I inhibitory ability at 20 μM/L. In addition, D20 effectively docked to COX-2 (PDB: 5KIR) and Topo I protein (PDB: 1TBI) with affinity of -9.0 and -5.7 kcal/mol, respectively. As a potential COX-2 and Topo I dual inhibitor, D20 induced ROS-mediate mitochondria dysfunction and altered the expression of apoptosis related proteins such as Bcl-2, Bax, Caspase3/9, and P53, leading to significant apoptosis in HepG2 cells. Moreover, D20 markedly up-regulated P21, reduced the level of CDK4 or Cyclin D1, and caused G1 phase arrest on HepG2 cancer cell lines.

Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma.

Coactivator-associated arginine methyltransferase 1 (CARM1), an important member of type I protein arginine methyltransferases (PRMTs), has emerged as a promising therapeutic target for various cancer types. In our previous study, we have identified a series of type I PRMT inhibitors, among which ZL-28-6 (6) exhibited increased activity against CARM1 while displaying decreased potency against other type I PRMTs. In this work, we conducted chemical modifications on compound 6, resulting in a series of (2-(benzyloxy)phenyl)methanamine derivatives as potent inhibitors of CARM1. Among them, compound 17e displayed remarkable potency and selectivity for CARM1 (IC50 = 2 ± 1 nM), along with notable antiproliferative effects against melanoma cell lines. Cellular thermal shift assay and western blot experiments confirmed that compound 6 effectively targets CARM1 within cells. Furthermore, compound 17e displayed good antitumor efficacy in a melanoma xenograft model, indicating that this compound warrants further investigation as a potential anticancer agent.

Synthesis and in vitro anticancer activity of novel 1,4-dimethyl-9-H-carbazol-3-yl) methanamine derivatives against human glioma U87 MG cell line

Glioblastoma Multiforme (GBM) is most aggressive type of brain tumor in adults. 1,4-dimethyl carbazoles exhibits significant anticancer activities in literature. In this research article, we synthesized a series of novel 1,4-dimethyl-9-H-carbazol-3-yl)methanamine and its derivatives (13-24) and evaluated their in vitro cytotoxicity activities against human glioma U87 MG cell line using MTT assay for 24 h phase time period. All final carbazole derivatives were well confirmed by NMR and HRMS spectroscopy techniques. In series, few compound (15-17) found excellent in vitro anticancer activity (IC50) values 18.50 µM, 47 µM and 75 µM respectively against human glioma U87MG cell line compare to standard drugs used in brain cancer such as Carmustine (IC50 = 18.24 µM) and Temozolomide (IC50 = 100 µM) respectively. Among these derivatives, compound 15 was found to have the most potent cytotoxic effect on tested glioma cell line. This study supported that 1,4-dimethyl-9-H-carbazol-3-yl)methanamine derivatives found significant anticancer potential against human glioma U87MG cell line.

Synthesis of New Amino-Functionalized Porphyrins:Preliminary Study of Their Organophotocatalytic Activity.

The design, synthesis, and initial study of amino-functionalized porphyrins as a new class of bifunctional catalysts for asymmetric organophotocatalysis is described. Two new types of amine-porphyrin hybrids derived from 5,10,15,20-tetraphenylporphyrin (TPPH2), in which a cyclic secondary amine moiety is covalently linked either to a β-pyrrolic position (Type A) or to the p-position of one of the meso phenyl groups (Type B), were prepared by condensation, reductive amination, or amidation reactions from the suitable porphyrins (either formyl or methanamine derivatives) with readily available chiral amines. A preliminary study of the possible use of Type A amine-porphyrin hybrids as asymmetric, bifunctional organophotocatalysts was performed using the chiral, imidazolidinone-catalyzed Diels-Alder cycloaddition between cyclopentadiene 28 and trans-cinnamaldehyde 29 as a benchmark reaction. The yield and the stereochemical outcome of this process, obtained under purely organocatalytic conditions, under dual organophocatalysis, and under bifunctional organophotocatalysis, were compared.

Design, synthesis and evaluation of antitumor activity of selective PRMT6 inhibitors

PRMT6 is a member of the protein arginine methyltransferase family, which is involved in a variety of physiological processes and plays an important role in the occurrence and development of tumors. Due to the high homology of type Ⅰ PRMTs and the two close binding sites of the SAM pocket and the substrate pocket, selective PRMT6 inhibitors have rarely been reported. In this study, a series of (5-phenylpyridin-3-yl)methanamine derivatives were designed and synthesized, which could form hydrogen bonding interactions with the unique Glu49 of PRMT6, thereby improving the selectivity of the compounds for PRMT6. Among them, a25 had the best activity and selectivity, with more than 25-fold selectivity for PRMT1/8 and more than 50-fold selectivity for PRMT3/4/5/7, which was superior to these reported SAM competitive and substrate competitive PRMT6 inhibitors. Importantly, a25 could significantly inhibit the proliferation of various tumor cells and effectively induce apoptosis of cancer cells. Our data clarified that a25 is a promising selective PRMT6 inhibitor for cancer therapy which is worthy of further evaluation.

Synthesis and antidepressant activity of novel 1-(1-benzoylpiperidin-4-yl) methanamine derivatives selectively targeting SSRI/5-HT1A

A series of novel 1-(1-benzoylpiperidin-4-yl) methanamine derivatives were synthesized and evaluated for the serotonin reuptake inhibitory abilities and binding affinities to the 5-HT1A receptor. The metabolic stabilities of these compounds were measured in vitro using human or mouse liver microsomes and the antidepressant activities were explored In vivo using the forced swimming test (FST) and tail suspension test (TST) in mice. The results indicated that the compound 12a exhibited strongest serotonin reuptake inhibition (IC50 = 8.2 nM) and marked 5-HT1A receptor affinity (Ki = 0.069 nM), which were significantly superior to lead compounds Ⅰ and Ⅱ. Meanwhile, compound 12a showed good metabolic stability in vitro and exhibited potential antidepressant-like effects in the FST and TST in mice.

Enantioselective synthesis of 2-indolyl methanamine derivatives through disulfonimide-catalyzed Friedel-Crafts C2-alkylation of 3-substituted indoles with imines.

An asymmetric Friedel-Crafts C2-alkylation between 3-substituted indoles and imines catalyzed by chiral BINOL-derived disulfonimides (DSIs) has been developed. This reaction tolerated a wide range of 3-substituted indoles and imines, affording a series of chiral 2-indolyl methanamine derivatives in good yields with good to excellent enantioselectivities (up to 98% ee). This is a useful protocol for the direct synthesis of 2-indolyl methanamine derivatives. It is worth noting that increasing the temperature in this reaction could result in a better enantioselectivity, making it different from the other common organocatalytic systems.

Design, synthesis and biological evaluation of mono- and bisquinoline methanamine derivatives as potential antiplasmodial agents

Several classes of antimalarial drugs are currently available, although issues of toxicity and the emergence of drug resistant malaria parasites have reduced their overall therapeutic efficiency. Quinoline based antiplasmodial drugs have unequivocally been long-established and continue to inspire the design of new antimalarial agents. Herein, a series of mono- and bisquinoline methanamine derivatives were synthesised through sequential steps; Vilsmeier-Haack, reductive amination, and nucleophilic substitution, and obtained in low to excellent yields. The resulting compounds were investigated for in vitro antiplasmodial activity against the 3D7 chloroquine-sensitive strain of Plasmodium falciparum, and compounds 40 and 59 emerged as the most promising with IC50 values of 0.23 and 0.93 µM, respectively. The most promising compounds were also evaluated in silico by molecular docking protocols for binding affinity to the {001} fast-growing face of a hemozoin crystal model.

Iodoarene-Catalyzed Oxyamination of Unactivated Alkenes to Synthesize 5-Imino-2-Tetrahydrofuranyl Methanamine Derivatives

Reported here is the room-temperature metal-free iodoarene-catalyzed oxyamination of unactivated alkenes. In this process, the alkenes are difunctionalized by the oxygen atom of the amide group and the nitrogen in an exogenous HNTs2 molecule. This mild and open-air reaction provided an efficient synthesis to N-bistosyl-substituted 5-imino-2-tetrahydrofuranyl methanamine derivatives, which are important motifs in drug development and biological studies. Mechanistic study based on experiments and density functional theory calculations showed that this transformation proceeds via activation of the substrate alkene by an in situ generated cationic iodonium(III) intermediate, which is subsequently attacked by an oxygen atom (instead of nitrogen) of amides to form a five-membered ring intermediate. Finally, this intermediate undergoes an SN2 reaction by NTs2 as the nucleophile to give the oxygen and nitrogen difunctionalized 5-imino-2-tetrahydrofuranyl methanamine product. An asymmetric variant of the present alkene oxyamination using chiral iodoarenes as catalysts also gave promising results for some of the substrates.

Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential “signaling fingerprints” that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of “serotonergic syndrome”. Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.

From Receptor Selectivity to Functional Selectivity: The Rise of Biased Agonism in 5-HT1A Receptor Drug Discovery.

Despite extensive efforts to design serotonin 5-HT1A receptor compounds, there are currently no clinically available selective agonists to explore the therapeutic potential of activating this receptor. Commonly used drugs targeting 5-HT1A receptors, such as buspirone or other azapirone compounds, possess only limited selectivity over cross-reacting sites, act as partial agonists for 5-HT1A receptor activation, and are metabolically labile, generating active metabolites. In addition, drug discovery has been hampered by the multiplicity of 5-HT1A receptor subpopulations, expressed in different brain regions, that are coupled to distinct molecular signaling mechanisms and mediate a wide variety of physiological responses, both desired and undesired. In this context, advances in 5-HT1A receptor drug discovery have attracted attention of novel 'biased agonists' that are selective, efficacious and preferentially target the brain regions that mediate therapeutic activity without triggering side effects. The prototypical first-in-class compound NLX-101 (a.k.a. F15599; 3-chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin- 1-yl]methanone), preferentially activates 5-HT1A receptors in cortical regions and exhibits potent, rapidacting and sustained antidepressant-like and procognitive properties in animal models. Here the background has been reviewed that led to the discovery of the class of 1-(1-benzoylpiperidin-4- yl)methanamine derivatives, including NLX-101, as well as recent advances in discovery of novel 5-HT1A receptor biased agonists, notably aryloxyethyl derivatives of 1‑(1-benzoylpiperidin-4yl)methanamine which show promising pharmacological activity both in vitro and in vivo. Overall, the results suggest that opportunities exist for innovative drug discovery of selective 5-HT1A receptor biased agonists that may open new avenues for the treatment of CNS disorders involving dysfunction of serotonergic neurotransmission.

Enantioselective Friedel-Crafts Reaction of Indoles with N-Tosylimines Employing Takemoto's Organocatalyst

The asymmetric Friedel-Crafts reaction of indoles with imines provides a direct approach for the enantioselective construction of 3-indolyl methanamine derivatives. In this paper, a series of thiourea/ urea-tertiary amine derivatives have been used to catalyze the asymmetric F-C reaction of indoles with N-tosylimines. The effect of solvent, temperature and catalyst loading amount were investigated. the optimized conditions were determined to be toluene as the solvent with a 5 mol% loading of Takemoto's catalyst 1c at rt. A wide range of substituted indoles and imines were evaluated to explore the scope and general applicability of this reaction. The enantioselectivities were obviously affected by the position of the substituents on the phenyl ring of imines. 4- electron-donating substituted imines appeared to favor higher enantioselectivities. Moreover, indoles containing either electron-donating groups or electron-withdrawing groups were then investigated for the reaction with imines. In all cases, high yields and excellent enantioselectivities could be achieved. Of all the different substrates, the reaction of the 5-OMe substituted indole with 4-chloride substituted imine afforded an optimal yield and enantiomeric excess. Under the screened optimal condition, optically active 3-indolyl-methanamines were obtained in good yields (70-90%) with high enantioselectivities (up to 98%ee). The catalyst type and the substrate scope were broadened in this methodology.

Discovery of (5-Phenylfuran-2-yl)methanamine Derivatives as New Human Sirtuin 2 Inhibitors.

Human sirtuin 2 (SIRT2), a member of the sirtuin family, has been considered as a promising drug target in cancer, neurodegenerative diseases, type II diabetes, and bacterial infections. Thus, SIRT2 inhibitors have been involved in effective treatment strategies for related diseases. Using previously established fluorescence-based assays for SIRT2 activity tests, the authors screened their in-house database and identified a compound, 4-(5-((3-(quinolin-5-yl)ureido)methyl)furan-2-yl)benzoic acid (20), which displayed 63 ± 5% and 35 ± 3% inhibition against SIRT2 at 100 μM and 10 μM, respectively. The structure-activity relationship (SAR) analyses of a series of synthesized (5-phenylfuran-2-yl)methanamine derivatives led to the identification of a potent compound 25 with an IC50 value of 2.47 μM, which is more potent than AGK2 (IC50 = 17.75 μM). Meanwhile, 25 likely possesses better water solubility (cLogP = 1.63 and cLogS = −3.63). Finally, the molecular docking analyses indicated that 25 fitted well with the induced hydrophobic pocket of SIRT2.

Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT1A Receptor-Biased Agonists with Robust Antidepressant-like Activity

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of serotonin 5-HT1A receptors. The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca2+ mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5-HT1A receptor affinity, >1000-fold selectivity versus noradrenergic α1, dopamine D2, serotonin 5-HT2A, histamine H1, and muscarinic M1 receptors, and favorable druglike properties (CNS-MPO, Fsp3, LELP). The lead structure, (3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone (17, NLX-204), displayed high selectivity in the SafetyScreen44 panel (including hERG channel), high solubility, metabolic stability, and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes, or P-glycoprotein. Preliminary in vivo studies confirmed its promising pharmacokinetic profile. 17 also robustly stimulated ERK1/2 phosphorylation in rat cortex and showed highly potent (MED = 0.16 mg/kg) and efficacious antidepressant-like activity, totally eliminating immobility in the rat Porsolt test. These data suggest that the present 5-HT1A receptor-biased agonists could constitute promising antidepressant drug candidates.

Synthesis, Characterization and Antibacterial Activity of Some Schiff Bases Prepared from 3-Hydroxy-2-naphthaldehyde and Phenyl Methanamine Derivatives

Synthesis, Characterization and Antibacterial Activity of Some Schiff Bases Prepared from 3-Hydroxy-2-naphthaldehyde and Phenyl Methanamine Derivatives

Cu(OTf)2andN-Sulfinylprolinamide Catalyzed Friedel-Crafts Reaction of Indoles withN-Sulfonylaldimines

3-Indolyl methanamine derivatives have attracted much attention due to their multiple potent bioactivities. The Friedel-Crafts reaction between indole and N-sulfonylaldimine is a major method for preparation of 3-indolyl methanamine derivatives, however, abundant bisindolyl methane will be formed during the reaction. 3-Indolylmethanamine derivatives were selectively synthesized in 65-93% yields by the Friedel-Crafts amidoalkylation reaction of indoles and N-sulfonylaldimines utilizing Cu(OTf)2 and N-sulfinylprolinamide as catalysts. This method exhibited several features such as broad substrate applicability, mild reaction condition and simple operation.

ChemInform Abstract: AgF‐Mediated Dialkylation of Activate Alkenes: An Efficient Access to Nitrile‐Containing Spirooxindoles.

A novel Ag-mediated dialkylation reaction of alkenes was disclosed, in which AgF was essential to activate CH bond of acetonitrile. This reaction provided an efficient way to nitrile-containing spirooxindoles from readily available (1H-indol-3-yl)methanamine derivatives.

AgF‐Mediated Dialkylation of Activate Alkenes: An Efficient Access to Nitrile‐Containing Spirooxindoles

AbstractA novel Ag‐mediated dialkylation reaction of alkenes was disclosed, in which AgF was essential to activate CH bond of acetonitrile. This reaction provided an efficient way to nitrile‐containing spirooxindoles from readily available (1H‐indol‐3‐yl)methanamine derivatives.

Design, synthesis, and evaluations of antifungal activity of novel phenyl(2H-tetrazol-5-yl)methanamine derivatives

Fungal infections pose a continuous and serious threat to human health and life. The intrinsic resistance has been observed in many genera of fungi. Many fungal infections are caused by opportunistic pathogens that may be endogenous (Candida infections) or acquired from the environment (Cryptococcus and Aspergillus infections). So, new therapeutic strategies are needed to combat various fungal infections. Fluconazole shows good antifungal activity with relatively low toxicity and is preferred as first line antifungal therapy, but it has suffered from severe drug resistance. So, there is a need to design novel analogues by modification of fluconazole-like structure. A novel series of phenyl(2H-tetrazol-5-yl)methanamine derivatives were synthesized by reaction of α-amino nitrile with sodium azide and ZnCl2 in presence of isopropyl alcohol. They were evaluated for antifungal activity against Candida albicans and Aspergillus niger and subjected to docking study against 1EA1.