1440-61-5Relevant academic research and scientific papers
4,6-Diphenylpyridines as Promising Novel Anti-Influenza Agents Targeting the PA-PB1 Protein-Protein Interaction: Structure-Activity Relationships Exploration with the Aid of Molecular Modeling
Trist, Iuni M. L.,Nannetti, Giulio,Tintori, Cristina,Fallacara, Anna Lucia,Deodato, Davide,Mercorelli, Beatrice,Palù, Giorgio,Wijtmans, Maikel,Gospodova, Tzveta,Edink, Ewald,Verheij, Mark,De Esch, Iwan,Viteva, Lilia,Loregian, Arianna,Botta, Maurizio
, p. 2688 - 2703 (2016)
Influenza is an infectious disease that represents an important public health burden, with high impact on the global morbidity, mortality, and economy. The poor protection and the need of annual updating of the anti-influenza vaccine, added to the rapid emergence of viral strains resistant to current therapy make the need for antiviral drugs with novel mechanisms of action compelling. In this regard, the viral RNA polymerase is an attractive target that allows the design of selective compounds with reduced risk of resistance. In previous studies we showed that the inhibition of the polymerase acidic protein-basic protein 1 (PA-PB1) interaction is a promising strategy for the development of anti-influenza agents. Starting from the previously identified 3-cyano-4,6-diphenyl-pyridines, we chemically modified this scaffold and explored its structure-activity relationships. Noncytotoxic compounds with both the ability of disrupting the PA-PB1 interaction and antiviral activity were identified, and their mechanism of target binding was clarified with molecular modeling simulations.
Substitution of β-nitrostyrenes by electrophilic carbon-centered radicals
García-Torres, Alejandro,Cruz-Almanza, Rymundo,Miranda, Luis D.
, p. 2085 - 2088 (2004)
Various trans-β-alkylstyrenes (55-90% yield) were isolated from the free radical addition/elimination process of α-iodocarboxylic acid derivatives with β-nitrostyrenes using dilauroyl peroxide as initiator. The corresponding xanthates give low yields of the alkene under similar conditions.
Diphenylmorpholine CMPO: Synthesis, coordination behavior and extraction studies of actinides
Das, Dhrubajyoti,Sivaramakrishna, Akella,Gopakumar, Gopinadhanpillai,Brahmmananda Rao,Sivaraman,Vijayakrishna, Kari
, p. 215 - 222 (2018)
Carbamoylmethyl phosphine oxide (CMPO) derivatives are well known ligands in the separation and extraction of trivalent lanthanides and actinides from nuclear waste. The substituents of CMPO play major role in their selectivity and extractability. We report the synthesis and characterization of diphenylmorpholine carbamoylmethyl phosphine oxide (DPMCMPO) (L1) and diphenyl-N,N-diethyl carbamoylmethyl phosphine oxide (DPDECMPO) (L2) using various spectroscopic techniques, such as FT-IR, 1H, 13C, and 31P NMR. The molecular structure of DPMCMPO is confirmed by single crystal XRD analysis. The present study aims to understand the influence of substituents on ‘N’ atom of L1 (morpholine based DPMCMPO) and L2 (diethyl substituted DPDECMPO) ligands for the extraction of some selected actinide ions such as Th(IV), U(VI) and Am(III). The geometry and electronic structure of these ligands and their respective complexes with Th(NO3)4 and UO2(NO3)2 are further explored using density functional theory (DFT) calculations. The employed ligands (L1 and L2) show greater distribution values for Th(IV) over U(VI), due to strong “ligand-Th” complexation ability as suggested by DFT calculations.
A novel benzothiazole derivative SKLB826 inhibits human hepatocellular carcinoma growth via inducing G2/M phase arrest and apoptosis
Lei, Qian,Zhang, Lidan,Xia, Yong,Ye, Tinghong,Yang, Fangfang,Zhu, Yongxia,Song, Xuejiao,Wang, Ningyu,Xu, Ying,Liu, Xiaowei,Yu, Luoting
, p. 41341 - 41351 (2015)
Hepatocellular carcinoma is the fifth most common cancer and durable responses in conventional treatments are limited so researchers have been devoted to developing new anti-HCC agents. Benzothiazole derivatives are known for various biological activities and have received considerable attention in cancer therapy, hence we designed and synthesized a novel potent benzothiazole compound 2-chloro-N-(2-(2-(2-morpholino-2-oxoethyl)thio)-2,3-dihydrobenzo[d]thiazol-6-yl)acetamide (SKLB826) and further investigated the biological activities against cancer. The results suggested that SKLB826 showed growth inhibition against a broad spectrum of human cancer cells, especially human HCC cell lines, in a dose-dependent manner and induced G2/M phase arrest via down-regulating the CDK1, cyclinA2 and cdc25c protein levels. SKLB826 could also induce apoptosis of HCC cells via decreasing the expression of Bcl-2 and increasing the levels of BAX and cleaved caspase-3, 9. Moreover, after treatment with SKLB826, the change of ROS level and ΔΨm suggested that SKLB826 might induce apoptosis through an intrinsic mitochondrial apoptotic pathway. Furthermore, SKLB826 could suppress tumor growth in the HepG2 xenograft model without inducing any notable major organ-related toxicity, suggesting that SKLB826 may be a potential candidate for HCC therapy.
Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors
Brullo, Chiara,Massa, Matteo,Villa, Carla,Ricciarelli, Roberta,Rivera, Daniela,Pronzato, Maria Adelaide,Fedele, Ernesto,Barocelli, Elisabetta,Bertoni, Simona,Flammini, Lisa,Bruno, Olga
, p. 3426 - 3435 (2015)
Abstract A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity.
TRICHLOROETHYLENE IN ORGANIC SYNTHESIS: II. REACTION OF TRICHLOROETHYLENE WITH SECONDARY AMINES
Pielichowski, Jan,Popielarz, Roman
, p. 2671 - 2676 (1984)
In a novel reaction, trichloroethylene reacts with secondary aliphatic amines in the presence of aqueous solution of NaOH and catalytic quantity of benzyltriethylammonium chloride to give the corresponding N,N,N',N'-tetraalkylsubstituted glycinamides.The following glycinamides were obtained with high yield: (N-morpholine)acetic acid morpholide, N-(piperidineacetyl)piperidine, N,N,N',N'-tetra-n-butylglycinamide and N,N,N',N'-tetraethylglycinamide.Mechanism of the reaction is discussed.
Synthesis, in vitro skin permeation studies, and PLS-analysis of new naproxen derivatives
Weber,Steimer,Mannhold,Cruciani
, p. 600 - 607 (2001)
Purpose. To synthesize new naproxen (01) derivatives with amide or ester structures or with a combination of the two (02-15). To compare their physicochemical properties with naproxen esters (16-22) and their respective skin permeation behavior. To study structure-permeation relationships via partial least squares (PLS)-analysis. Methods. Stability, aqueous, and octanol solubility were determined. Lipophilicity and further 53 chemical descriptors were computed. A suitable in-vitro skin permeation model was developed to compare maximal flux (Jmax) of derivatives. Based on these flux data, PLS-analysis was performed to derive structure-permeation relationships. Results. None of the new derivatives showed an improved flux in comparison to naproxen. This result can be explained by PLS-analysis: skin permeation increases with the solubility both in water and in octanol. For a good permeation, an optimized molecule should exhibit a small volume with a spherical shape. The surface area should be large in relation to volume, as indicated by the rugosity parameter. A clear separation between the hydrophobic and the hydrophilic domain (= high amphiphilic moment) is favorable. Lipophilicity is inversely correlated with skin permeation. Conclusions. PLS-analysis is a valuable tool to derive significant, internally predictive quantitative models for structure-permeation relationships of naproxen derivatives in the above described skin permeation assay.
Triazole-estradiol analogs: A potential cancer therapeutic targeting ovarian and colorectal cancer
Alotaibi, Faez,Halaweish, Fathi,Halaweish, Hossam,Iram, Surtaj,Kasten, Abigail,Kyeremateng, Jennifer,Ostlund, Trevor
, (2021/12/27)
1,2,3-triazoles have continuously shown effectiveness as biologically active systems towards various cancers, and when used in combination with steroid skeletons as a carrier, which can act as a drug delivery system, allows for a creation of a novel set of analogs that may be useful as a pharmacophore leading to a potential treatment option for cancer. A common molecular target for cancer inhibition is that of the Epidermal Growth Factor Receptor/Mitogen Activated Protein Kinase pathways, as inhibition of these proteins is associated with a decrease in cell viability. Estradiol-Triazole analogs were thus designed using a molecular modeling approach. Thirteen of the high scoring analogs were then synthesized and tested in-vitro on an ovarian cancer cell line (A2780) and colorectal cancer cell line (HT-29). The most active compound, Fz25, shows low micromolar activity in both the ovarian (15.29 ± 2.19 μM) and colorectal lines (15.98 ± 0.39 μM). Mechanism of action studies proved that Fz25 moderately arrests cells in the G1 phase of the cell cycle, specifically inhibiting STAT3 in both cell lines. Additionally, Fz57 shows activity in the colorectal line (24.19 ± 1.37 μM). Inhibition studies in both cell lines show inhibition against various proteins in the EGFR pathway, namely EGFR, STAT3, ERK, and mTOR. To further study their effects as therapeutics, Fz25 and Fz57 were studied against drug efflux proteins, which are associated with drug resistance, and were found to inhibit the ABC transporter P-glycoprotein. We can conclude that these estradiol-triazole analogs provide a key for future studies targeting protein inhibition and drug resistance in cancer.
De novo Design of SARS-CoV-2 Main Protease Inhibitors
Dovala, Dustin,Fischer, Christian,Nomura, Daniel K.,Peitsinis, Zisis,Spradlin, Jessica N.,Trauner, Dirk,Yang, Chao,Zhang, Yingkai,Rühmann, Klaus-Peter,Vep?ek, Nynke A.
supporting information, (2021/10/16)
The COVID-19 pandemic prompted many scientists to investigate remedies against SARS-CoV-2 and related viruses that are likely to appear in the future. As the main protease of the virus, M Pro, is highly conserved among coronaviruses, it has emerged as a prime target for developing inhibitors. Using a combination of virtual screening and molecular modeling, we identified small molecules that were easily accessible and could be quickly diversified. Biochemical assays confirmed a class of pyridones as low micromolar noncovalent inhibitors of the viral main protease.
Microwave-assisted synthesis, structural characterization and assessment of the antibacterial activity of some new aminopyridine, pyrrolidine, piperidine and morpholine acetamides
Abdulghani, Saba S.,Alsamarrai, Abdulmajeed S. H.
, (2021/06/14)
A series of new acetamide derivatives 22–28 of primary and secondary amines and para-toluene sulphinate sodium salt have been synthesized under microwave irradiation and assessed in vitro for their antibacterial activity against one Gram-positive and two Gram-negative bacterial species such as S. pyogenes, E. coli, and P. mirabilis using the Mueller-Hinton Agar diffusion (well diffusion) method. The synthesized compounds with significant differences in inhibition diameters and MICs were compared with those of amoxicillin, ampicillin, cephalothin, azithromycin and doxycycline. All of the evaluated acetamide derivatives were used with varying inhibition concentrations of 6.25, 12.5, 37.5, 62.5, 87.5, 112.5 and 125 μg/mL. The results show that the most important antibacterial properties were displayed by the synthetic compounds 22 and 24, both of bear a para-chlorophenyl moiety incorporated into the 2-position moiety of acetamide 1. The molecular structures of the new compounds were determined using the FT-IR and1H-NMR techniques.
