Methanone Derivatives Research Articles

Design, synthesis and evaluation of new methyl piperazine derivatives as anticancer agents

BackgroundTo overcome the problem of side effects and toxicity, development of new anticancer agents is needed. Recently, piperidine salicylanilide derivatives with nanomolar epidermal growth factor receptor (EGFR) inhibitory and cytotoxicity activity have been reported. In the present study effect of replacing piperidine in reported piperidine salicylanilide with N-methyl piperazine and changing substituent’s of phenyl ring at other end on anticancer activity have been explored. A series of sixteen methyl piperazine incorporated phenyl benzamide and phenyl methanone derivatives have been synthesized and tested in a panel of three cancer cell lines (adenocarcinomic human alveolar basal epithelial cells (A-549), human colon carcinoma (HCT-116) and human pancreatic carcinoma (MIAPaCa-2)), using gefitinib as standard. Further, to study the probable mechanism, due to their structural similarity with EGFR inhibitors, docking interactions with EGFR active site were observed using Schrodinger suite.ResultThe results indicated that most of the compounds showed promising activity; out of which, compound A-11 was most active having cytotoxicity much better than that of gefitinib. It showed IC50 value of 5.71 µM against A-549 cell line, 4.26 µM against HCT-116 colon cancer line and 31.36 µM against MIAPaCa-2 cell line.ConclusionIt was found that these compounds fit well in the active site and may be exhibiting anticancer activity via EGFR inhibition.Graphical

Structure-Activity Relationship and Functional Evaluation of Cannabinoid Type-1 Receptor.

The type-1 cannabinoid receptor (CB1R) is a potential therapeutic target in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Owing to their structural diversity, it is not easy to derive general structure-activity relationships (SARs) for CB1R ligands. In this study, CB1R ligands were classified into six structural families, and the corresponding SAR was determined for their affinities for CB1R. In addition, we determined their functional activities for the activation of extracellular signal-regulated kinases (ERKs). Among derivatives of indol-3-yl-methanone, the highest ligand affinity was observed when a pentyl and a naphthalenyl group were attached to the N1 position of the indole ring and the carbon site of the methanone moiety, respectively. In the case of adamantane indazole-3-carboxamide derivatives, the presence of fluorine in the pentyl group, the substituent at the N1 position of the indazole ring, strongly increased the affinity for CB1R. For (naphthalen-1-yl) methanone derivatives, the presence of 4-alkoxynaphthalene in the methanone moiety was more beneficial for the affinity to CB1R than that of a heterocyclic ring. The functional activities of the tested compounds, evaluated through ERK assay, were correlated with their affinity for CB1R, suggesting their agonistic nature. In conclusion, this study provides valuable insight for designing novel ligands for CB1R, which can be used to control psychiatric disorders and drug abuse.

Discovery of (2-(4-Substituted phenyl)quinolin-4-yl)(4-isopropylpiperazin-1-yl)methanone Derivatives as Potent Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors.

Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an increasingly important role in the treatment of hyperlipidemia. In pursuit of potent small molecules that block the PCSK9/low-density lipoprotein receptor (LDLR) protein-protein interaction (PPI), a series of 2-phenylquinoline-4-carboxylic acid derivatives were designed and synthesized based on previously derived molecules. In the in vitro PPI inhibition test, compounds M1, M12, M14, M18 and M27 exhibited potent activities with IC50 values of 6.25 μM, 0.91 μM, 2.81 μM, 4.26 μM and 0.76 μM, respectively, compared with SBC-115337 (IC50 value of 9.24 μM). Molecular docking and molecular dynamics simulations revealed the importance of hydrophobic interactions in the binding of inhibitors to the PPI interface of PCSK9. In LDLR expression and LDL uptake assays, the tested compounds M1, M12 and M14 were found to restore LDLR expression levels and to increase the extracellular LDL uptake capacity of HepG2 cells in the presence of exogenous PCSK9. Collectively, novel small-molecule PCSK9/LDLR PPI inhibitors (especially M12) with in vitro lipid lowering ability, were discovered as lead compounds for further development of hypolipidemic drugs.

Design, synthesis, and anticancer activity of some novel 1H-benzo[d]imidazole-5-carboxamide derivatives as fatty acid synthase inhibitors

Multiple malignancies exhibit aberrant FASN expression, associated with enhanced de novo lipogenesis to meet the metabolic demands of rapidly proliferating tumour cells. Furthermore, elevated FASN expression has been linked to tumour aggressiveness and poor prognosis in a variety of malignant tumours, making FASN is an attractive target for anticancer drug discovery. Herein, we report the de novo design and synthesis of (2-(2-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperazin-1-yl)methanone derivatives as novel FASN inhibitors with potential therapeutic applications in breast and colorectal cancers. Twelve (2-(2-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperazin-1-yl)methanone derivatives (CTL) were synthesized and evaluated for FASN inhibition and cytotoxicity against colon cancer (HCT-116, Caco-2 cell lines), breast cancer (MCF-7 cell line) and normal cell line (HEK-293). Compounds CTL-06 and CTL-12 were chosen as the most promising lead molecules based on FASN inhibition and selective cytotoxicity profiles against colon and breast cancer cell lines. Compounds CTL-06 and CTL-12 demonstrate promising FASN inhibitory activity at IC50 of 3 ± 0.25 µM and 2.5 ± 0.25 µM when compared to the FASN inhibitor orlistat, which has an IC50 of 13.5 ± 1.0 µM. Mechanistic investigations on HCT-116 revealed that CTL-06 and CTL-12 treatment led to cell cycle arrest in Sub-G1/S phase along with apoptosis induction. Western blot studies indicated that CTL-06 and CTL-12 inhibited FASN expression in a dose-dependent manner. CTL-06 and CTL-12 treatment of HCT-116 cells enhanced caspase-9 expression in a dose-dependent manner, while upregulating proapoptotic marker Bax and downregulating antiapoptotic Bcl-xL. Molecular docking experiments of CTL-06 and CTL-12 with FASN enzyme revealed the mode of binding of these analogues in the KR domain of the enzyme.

Molecular properties and In silico bioactivity evaluation of (4-fluorophenyl)[5)-3-phen-(4-nitrophenyl yl-4,5-dihydro-1H-pyrazol-1-yl]methanone derivatives: DFT and molecular docking approaches

ObjectivesMolecular structures, spectroscopic properties, charge distributions, frontier orbital energies, nonlinear optical (NLO) properties and molecular docking simulations were analyzed to examine the bio-usefulness of a series of (4-fluorophenyl)[5-(4-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl]methanone derivatives. MethodsThe compounds were studied through computational methods. Equilibrium optimization of the compounds was performed at the B3LYP/6-31G(d,p) level of theory, and geometric parameters, frequency vibration, UV–vis spectroscopy and reactivity properties were predicted on the basis of density functional theory (DFT) calculations. ResultsThe energy gap (ΔEg), electron donating/accepting power (ω−/ω+) and electron density response toward electrophiles/nucleophiles calculated for M1 and M2 revealed the importance of substituent positioning on compound chemical behavior. In addition, ω−/ω+ and ΔEn/ΔEe indicated that M6 is more electrophilic because of the presence of two NO2 groups, which enhanced its NLO properties. The hyperpolarizability (β0) of the compounds ranged from 5.21 × 10−30 to 7.26 × 10−30 esu and was greater than that of urea; thus, M1–M6 were considered possible candidates for NLO applications. Docking simulation was also performed on the studied compounds and targets (PDB ID: 5ADH and 1RO6), and the calculated binding affinity and non-bonding interactions are reported. ConclusionThe calculated ω− and ω+ indicated the electrophilic nature of the compounds; M6, a compound with two NO2 groups, showed enhanced effects. Molecular electrostatic potential (MEP) analysis indicated that amide and nitro groups on the compounds were centers of electrophilic attacks. The magnitude of the molecular hyperpolarizability suggested that the entire compound had good NLO properties and therefore could be explored as a candidate NLO material. The docking results indicated that these compounds have excellent antioxidant and anti-inflammatory properties.

Synthesis of Novel Pyrazolyl and Isoxazolyl 3-(Furan-2-yl)-5-Methyl-1-(4-Nitrophenyl)-1H-Pyrazol-4-yl Derivatives via Regioselectivity of the 1,3-Dipolar Cycloaddition

The reaction of 1-(3-(furan-2-yl)-5-methyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl)ethan-1-one 1 with dimethylformamide dimethyl acetal (DMF-DMA) afforded 3-(dimethylamino)-1-(3-(furan-2-yl)-5-methyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl)prop-2-en-1-one 2. Then the treatment of enaminone 2 with the appropriate hydrazonoyl halides 3a–f in chloroform in the presence of triethylamine at reflux gave novel bipyrazolyl methanone derivatives 4a–f. The novel bipyrazole derivatives 4a–c and 4d–f reacted with hydrazine hydrate in ethanol at reflux to give the corresponding pyrazolopyridazinones 9a–c and pyrazolopyridazines 10d–f, respectively. Stirring of hydroximoyl chlorides 11a,b with enaminone 2 in chloroform in the presence of triethylamine at room temperature afforded isoxazole derivatives 12a,b. The reaction of isoxazoles 12a,b with hydrazine hydrate in refluxing ethanol gave the corresponding isoxazolopyridazines 14a,b.

Achieving dual-state emission and high-contrast mechanochromic luminescence based on donor-acceptor type phenothiazine methanone derivatives

The development of fluorescent materials that can achieve dual-state emission (DSE) and high-contrast mechanochromic luminescence has attracted more and more attention. However, such materials are very rare, and there are no clear molecular design principles to follow. In current work, two novel DSE emitters are designed and synthesized by modifying phenothiazine and benzene or naphthalene rings on both sides of the methanone. Their photophysical properties in both dilute solution and the solid state are studied and compared. Optical researches have shown that D-A type phenothiazine methanone derivatives exhibit well-defined ICT (intramolecular charge transfer) characteristics. At the same time, they show intense luminescent efficiencies in both solution (ΦPTZ-CO-B = 0.645; ΦPTZ-CO-NA = 0.624) and solid states (ΦPTZ-CO-B = 0.386; ΦPTZ-CO-NA = 0.357), indicating their DSE properties. It is noteworthy that compounds PTZ-CO-B and PTZ-CO-NA exhibit significant fluorescence response to mechanical force, and the emitting wavelengths are red-shifted by 33 nm and 46 nm, respectively. XRD patterns and DSC curves confirm that the mechanochromism results from reversible changes in stacking pattern. The current work develops materials that can achieve DSE emission and high-contrast mechanochromism, laying the foundation for the development of such materials.

Design and Development of Triazole Derivatives as Prospective Anticancer Agents: A Review.

In recent years, there has been a crucial need for the design and development of novel anticancer drugs that can lessen the serious health problems and unwanted side effects associated with currently used anticancer drugs. The triazole nucleus is well-recognized to possess numerous pharmacological activities, including anticancer, as revealed by various investigations on anticancer drugs and the latest research findings. The aim of this review article is to summarise the anticancer potential of 1, 2, 3-triazole, 1, 2, 4-triazole and heterocycle-fused triazole derivatives against several human cancer cell lines, compiling research articles published between 2010 and 2021. Data were collected from PubMed, Google scholar and Research Gate using keywords "anticancer activity of 1, 2, 3-triazole derivatives", "anticancer activity of 1, 2, 4-triazole derivatives" and "anticancer activity of heterocycle- fused triazole derivatives" and reviewed comprehensively. This review examines the anticancer potential of 1,2,3-triazole coupledoleanolic acid/dithiocarbamate/ pyrido[ 2,3-d] pyrimidine derivatives, 1,2,3-triazole linked pyrimidine/1,4-naphthoquinone hybrids, and 1,2,4-triazole substituted methanone derivatives, acridine-based 1,2,4-triazole derivatives, 1,2,4-thiadiazol coupled with 1,2,4- triazole and 5-ene-thiazolo[3,2-b][1,2,4]triazole-6(5H)-one derivatives against several human cancer cell lines. This review highlights the key findings in the area of cancer therapy. Triazole derivatives possess anticancer activity against various human cancer cell lines, and hence the triazole core may act as a lead molecule for the synthesis of novel anticancer drugs.

Homolytic aromatic substitution of acyl radicals: Oxidative coupling of 2-methylquinolines with quinoxalines

Oxidative coupling of 2-methylquinolines with quinoxalines via a TBHP ( t-butyl hydroperoxide) and TFA (trifluoroacetic acid) mediated Minisci reaction affords quinolin-2-yl(quinoxalin-2-yl)methanone derivatives. This approach provides a simple and efficient method to construct various acyl derivatives in moderate to good yields (45%–92%) without any metal catalyst. Mechanistically, homolytic aromatic substitution (HAS) of acyl radicals mediated by TBHP is crucial for the construction of the quinolin-2-yl(quinoxalin-2-yl)methanone products.

D-A-D’ type phenothiazine modified bisarylic methanone derivatives exhibiting fluorescent response to mechanical force and reversible tricolor switching

Two D-A-D′ type bisarylic methanone derivatives PTZ-BZ-Cz and PTZ-BZ-TPA, which consisted of two different electron donors and the same electron acceptor were designed and synthesized. Theoretical calculations revealed that both possessed asymmetric donor-acceptor structures and highly distorted spatial conformations. Optical researches illustrated that both exhibited an evident intramolecular charge transfer (ICT) characteristics and effective emission in the solid state. Interestingly, the mechanochromic behaviors were found. The XRD indicated that the reason for the mechanochromic phenomenon was crystalline-to-amorphous transition. It should be noted that PTZ-BZ-Cz exhibited high contrast and tricolor switching mechanochromic properties under external force stimuli. This novel phenomenon is very interesting for the development of mechanochromic materials that can simultaneously achieve high-contrast and multicolor switching. The current work provided a basis for the design of organic molecules featuring both high contrast and multicolor switching.

Fluorescent indolo[2,3-b]quinoxalin-2-yl(phenyl)methanone dyes: photophysical, AIE activity, electrochemical, and theoretical studies

Herein, we have synthesized four indolo[2,3-b]quinoxalin-2-yl)(phenyl)methanone derivatives by cyclocondensation. The photophysical studies of dyes in various solvents and neat solid film exhibit typical electronic spectra with inbuilt intramolecular charge transfer (ICT) (λmax: 397–490 nm) confirming donor–acceptor architecture. Herein, dyes fluoresce in the blue-orange region (λEmax: 435–614) on excitation at their ICT maxima in toluene, ethyl acetate, chloroform, DMSO, and neat solid film. Two dyes, which exhibit good emission intensity in all mediums, were studied for aggregation-induced emission (AIE) effect. Electrochemical studies indicate the dyes possess relatively low lying LUMO (− 3.65 to − 3.98 eV) comparable to reported n-type/electron-transporting materials. The HOMO and LUMO energy levels were evaluated by DFT and TD-DFT calculations. TGA analysis shows the dyes exhibit good thermal stability. The characteristic optoelectronic properties and thermal stability signify these dyes are potential candidates for their application in optoelectronics.Graphical abstract

Rh(III)-Catalyzed Tandem Reaction Access to (Quinazolin-2-yl)methanone Derivatives from 2,1-Benzisoxazoles and α-Azido Ketones.

A Rh(III)-catalyzed tandem reaction for the synthesis of (quinazolin-2-yl)methanone derivatives has been explored from 2,1-benzisoxazoles and α-azido ketones. The transformation involves Rh(III)-catalyzed denitrogenation of α-azido ketones, aza-[4 + 2] cycloaddition, ring opening, and dehydration aromatization processes. Notably, the aza-[4 + 2] cycloaddition of an imine rhodium complex intermediate with 2,1-benzisoxazoles is the key to this reaction.

Cs2CO3-Promoted [3 + 2] Cyclization of Chalcone and N-Tosylhydrazone

Cs2CO3-promoted [3 + 2] cyclization of chalcone and N-tosylhydrazones has been developed, a series of novel (4,5-diaryl-1H-pyrazol-3-yl)(aryl)methanone derivatives were synthesized with a wide range of substrates, good tolerance of functional groups and by a one-pot three-component reaction of chalcone, aryl formaldehyde, and TsNHNH2. In addition, the gram-scale synthesis of the product and further transformations were also investigated.

Structure based drug discovery, docking modelling, synthesis and anticonvulsant pharmacological activity of new quinoline derivatives

Novel series of (2-(substituted-phenyl) quinoline-4-yl) (3-(substituted phenyl)-5-phenyl-1H-pyrazol-1-yl) methanone derivatives was carried out docking, modelling and synthesized. The chemical structures of synthesized derivatives were determined by their IR, 1HNMR, MS analysis data, correlate with docking modelling binding affinity and anticonvulsant activity by using mice in MES model. The synthesized derivatives anticonvulsant activity(3-(5-chlorophenyl)-5-phenyl-1H-pyrazol-1-yl) (2-(2-chlorophenyl) quinoline-4yl) methanone(4a) have showed greater as compared to other derivatives according to 25,50 and 100mg/ml concentration as compared to Phenytoin std. drug.

Design, synthesis, and mechanochromic luminescence of twisted donor–acceptor bisarylic methanone derivatives

Two bisarylic methanone derivatives, DBF-BZ-POZ and DBF-BZ-PTZ, which have phenoxazine or phenothiazine as electron donors and carbonyl group as electron acceptor are presented. Both molecules have highly distorted molecular conformation and exhibit obvious intramolecular charge transfer (ICT), effective solid-state emissions, and high-contrast mechanofluorochromic (MFC) properties. Both DBF-BZ-POZ and DBF-BZ-PTZ have good solid-state luminescence, efficiencies that reach 33.5% and 38.9%, respectively. The fluorescence colors of the as-prepared powders for both molecules are bright blue-green. The colors change to bright yellow with external mechanical stimulation and red shifts of 104 and 82 nm are observed in the photoluminescence (PL) spectra. Moreover, the MFC behavior of DBF-BZ-POZ and DBF-BZ-PTZ are reversible when their ground samples are subjected to fuming with the DCM vapor. Powder X-ray diffraction results indicate that the MFC phenomenon of DBF-BZ-POZ and DBF-BZ-PTZ may be attributed to crystalline-to-amorphous transitions in the material. The red shifts observed in the PL spectra after the material is ground are due to the smaller band gap induced by the planar intramolecular charge transfer (PICT) and the increased π-π interactions, the increase of exciton coupling, as well as the increased orbital overlap between neighboring molecules.

Synthesis and biological evaluation of (4-Fluorophenyl)(1-(5-phenyl-1,3,4-oxadiazol-2-yl)indolizin-3-yl)methanone derivatives as anticancer and antimicrobial agents

A novel series of (4-Fluorophenyl (1-(5-phenyl-1,3,4-oxadiazol-2-yl)indolizin-3-yl)methanone derivatives 9(a-n) were synthesized by the coupling reaction of 3-(4-fluorobenzoyl)indolizine-1-carboxylic acid and substituted benzohydrazide followed by intramolecular cyclization. The structures of the compounds were characterized by 1H NMR, 13C NMR, LCMS, FT-IR, and elemental analyses. The compounds 9(a-n) anti-cancer activity was evaluated against the MCF-7 cell line (HTB-22, Homo sapiens, Breast carcinoma). Compound 9j (IC50 = 21.57 μM), and 9n (IC50 = 8.52 μM) exhibited the most potent cytotoxicity activity compared with standard drug doxorubicin (IC50= 25.71). The antibacterial activity was evaluated against Staphylococcus aureus ATCC 6538 and Escherichia coli ATCC 8739. The compounds ZOI=16mm) and 9i (ZOI=18 mm) exhibited moderate antibacterial activity compared with standard drug ciprofloxacin. The antifungal activity was evaluated against Candida albicans ATCC 10231. Most compounds exhibited moderate antifungal activity compared with the standard drug Itraconazole.

Structure Based Drug Discovery, Docking, Modelling, Synthesis and Anticancer Screening of Some Novel Quinoline Derivatives

A new series of (2-(substituted-phenyl) quinoline-4-yl) (3-(substituted phenyl)-5-phenyl-1H-pyrazol-1-yl) methanone derivatives was carried out docking modelling and synthesized. Purity was checked by TLC and chemical structures of synthesized compounds were elucidated by their IR, 1HNMR, MS analysis data. The synthesized compounds were screened for anticancer activity by using cell line MCF-7 (Human breast cancer cell line) correlate with docking modelling.

Synthesis of 5-aryl-3,3'-bis-indolyl and bis-7-aza-indolyl methanone derivatives from 5-bromo-7-azaindoles via sequential methylenation using microwave irradiation, CAN oxidation, and Suzuki coupling reactions.

A catalyst-free and green chemical method has been developed for the methylenation of indole and N-methyl-7-aza indoles with aqueous formaldehyde afforded respective N,N'-dimethyl-3,3'-bis-7-azaindolylmethanes under microwave irradiation in excellent yield. Subsequent oxidation of the products thus obtained, using one electron chemical oxidant CAN afforded N,N'-dimethyl-3,3'-bis-7-azaindolylmethanone derivatives in excellent yield. This resulted in methanone derivatives with halogen substitution at the aryl ring which when subjected to Suzuki coupling with aryl boronic acids furnished highly functionalized fluorescent biaryl derivatives. Plausible mechanisms, characterization including XRD, and evaluation of photophysical properties of the Suzuki coupled products are described.

Theoretical and experimental insights into the properties of donor–σ–acceptor type derivatives of quinoxaline and methanone containing different donor moieties

A strategy of fused electron accepting moieties was employed to synthesise a series of donor-substituted quinoxaline–methanone derivatives as red TADF emitters.

Structure Based Drug Discovery, Docking, Modelling, Synthesis and Anticancer Screening of Some Novel Quinoline Derivatives

A new series of (2-(substituted-phenyl) quinoline-4-yl) (3-(substituted phenyl)-5-phenyl-1H-pyrazol-1-yl) methanone derivatives was carried out docking modelling and synthesized. Purity was checked by TLC and chemical structures of synthesized compounds were elucidated by their IR, 1HNMR, MS analysis data. The synthesized compounds were screened for anticancer activity by using cell line MCF-7 (Human breast cancer cell line) correlate with docking modelling.