- Selective naked-eye detection of Hg2+ through an efficient turn-on photoinduced electron transfer fluorescent probe and its real applications
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A simple molecular fluorescent probe 5 has been designed and synthesized by appending anthracene and benzhydryl moieties through a piperazine bridge. The probe upon interaction with different metal ions showed high selectivity and sensitivity (2 ppb) for Hg2+ through fluorescence "turn-on" response in HEPES buffer. The significant fluorescence enhancement (～10-fold) is attributable to PET arrest due to complexation with nitrogen atoms of the piperazine unit and Hg2+ in 1:2 stoichiometry, in which a naked-eye sensitive fluorescent blue color of solution changed to a blue-green (switched-on). As a proof of concept, promising prospects for application in environmental and biological sciences 5 have been utilized to detect Hg 2+ sensitively in real samples, on cellulose paper strips, in protein medium (like BSA), and intracellularly in HeLa cells. Moreover, the optical behavior of 5 upon providing different chemical inputs has been utilized to construct individual logic gates and a reusable combinational logic circuit. The combinational circuit (switch ON mode; OR logic gate) is easily resettable to the original position (switch OFF mode; INHIBIT logic gate) by applying reset chemical inputs (OH- and PO43-) with great reproducibility.
- Srivastava, Priyanka,Razi, Syed S.,Ali, Rashid,Gupta, Ramesh C.,Yadav, Suresh S.,Narayan, Gopeshwar,Misra, Arvind
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Read Online
- Indirect reduction of CO2and recycling of polymers by manganese-catalyzed transfer hydrogenation of amides, carbamates, urea derivatives, and polyurethanes
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The reduction of polar bonds, in particular carbonyl groups, is of fundamental importance in organic chemistry and biology. Herein, we report a manganese pincer complex as a versatile catalyst for the transfer hydrogenation of amides, carbamates, urea derivatives, and even polyurethanes leading to the corresponding alcohols, amines, and methanol as products. Since these compound classes can be prepared using CO2as a C1 building block the reported reaction represents an approach to the indirect reduction of CO2. Notably, these are the first examples on the reduction of carbamates and urea derivatives as well as on the C-N bond cleavage in amides by transfer hydrogenation. The general applicability of this methodology is highlighted by the successful reduction of 12 urea derivatives, 26 carbamates and 11 amides. The corresponding amines, alcohols and methanol were obtained in good to excellent yields up to 97%. Furthermore, polyurethanes were successfully converted which represents a viable strategy towards a circular economy. Based on control experiments and the observed intermediates a feasible mechanism is proposed.
- Liu, Xin,Werner, Thomas
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p. 10590 - 10597
(2021/08/20)
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- Design, synthesis, and molecular docking study of new piperazine derivative as potential antimicrobial agents
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Herein, we describe the successful design and synthesis of seventeen new 1,4-diazinanes, compounds commonly known as piperazines. This group of piperazine derivatives (3a-q) were fully characterized by 1H NMR, 13C NMR, FT-IR, and LCMS spectral techniques. The molecular structure of piperazine derivative (3h) was further established by single crystal X-ray diffraction analysis. All reported compounds were evaluated for their antibacterial and antifungal potential against five bacterial (Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) and two fungal strains (Candida albicans and Cryptococcus neoformans). The complete bacterial screening results are provided. As documented, piperazine derivative 3e performed the best against these bacteria. Additionally, data obtained during molecular docking studies are very encouraging with respect to potential utilization of these compounds to help overcome microbe resistance to pharmaceutical drugs, as explicitly noted in this manuscript.
- Patil, Mahadev,Noonikara Poyil, Anurag,Joshi, Shrinivas D.,Patil, Shivaputra A.,Patil, Siddappa A.,Bugarin, Alejandro
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- Synthesis and evaluation of potent and selective MGL inhibitors as a glaucoma treatment
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Monoacylglycerol lipase (MGL) inhibition provides a potential treatment approach to glaucoma through the regulation of ocular 2-arachidonoylglycerol (2-AG) levels and the activation of CB1 receptors. Herein, we report the discovery of new series of carbamates as highly potent and selective MGL inhibitors. The new inhibitors showed potent nanomolar inhibitory activity against recombinant human and purified rat MGL, were selective (>1000-fold) against serine hydrolases FAAH and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Protein-based 1H NMR experiments indicated that inhibitor 2 rapidly formed a covalent adduct with MGL with a residence time of about 6 h. This interconversion process “intrinsic reversibility” was exploited by modifications of the ligand's size (length and bulkiness) to generate analogs with “tunable’ adduct residence time (τ). Inhibitor 2 was evaluated in a normotensive murine model for assessing intraocular pressure (IOP), which could lead to glaucoma, a major cause of blindness. Inhibitor 2 was found to decrease ocular pressure by ～4.5 mmHg in a sustained manner for at least 12 h after a single ocular application, underscoring the potential for topically-administered MGL inhibitors as a novel therapeutic target for the treatment of glaucoma.
- Alapafuja, Shakiru O.,Malamas, Michael S.,Shukla, Vidyanand,Zvonok, Alexander,Miller, Sally,Daily, Laura,Rajarshi, Girija,Miyabe, Christina Yume,Chandrashekhar, Honrao,Wood, JodiAnne,Tyukhtenko, Sergiy,Straiker, Alex,Makriyannis, Alexandros
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- Reversed isoniazids: Design, synthesis and evaluation against Mycobacterium tuberculosis
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Novel reversed isoniazid (RINH) agents were synthesized by covalently linking isoniazid with various efflux pump inhibitor (EPI) cores and their structural motifs. These RINH agents were then evaluated for anti-mycobacterial activity against sensitive, isoniazid mono-resistant and MDR clinical isolates of M. tuberculosis and a selected number of compounds were also tested ex vivo for intracellular activity as well as in the ethidium bromide (EB) assay for efflux pump inhibition efficacy. The potency of some compounds against various strains of M. tuberculosis (4a–c, 7 and 8; H37Rv-MIC99 ≤1.25 μM, R5401-MIC99 ≤2.5 μM, X_61-MIC99 ≤5 μM) demonstrated the potential of the reversed anti-TB agent strategy towards the development of novel anti-mycobacterial agents to address the rapidly growing issue of resistance. Further, macrophage activity with >90% inhibition by 1a–c and 3b (MIC90 ≤13.42 μM) and inhibition of EB efflux demonstrated by these compounds are encouraging.
- Kumar, Malkeet,Singh, Kawaljit,Ngwane, Andile H.,Hamzabegovic, Fahreta,Abate, Getahun,Baker, Bienyameen,Wiid, Ian,Hoft, Daniel F.,Ruminski, Peter,Chibale, Kelly
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supporting information
p. 833 - 844
(2018/01/22)
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- Continuous-Flow Multistep Synthesis of Cinnarizine, Cyclizine, and a Buclizine Derivative from Bulk Alcohols
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Cinnarizine, cyclizine, buclizine, and meclizine belong to a family of antihistamines that resemble each other in terms of a 1-diphenylmethylpiperazine moiety. We present the development of a four-step continuous process to generate the final antihistamines from bulk alcohols as the starting compounds. HCl is used to synthesize the intermediate chlorides in a short reaction time and excellent yields. This methodology offers an excellent way to synthesize intermediates to be used in drug synthesis. Inline separation allows the collection of pure products and their immediate consumption in the following steps. Overall isolated yields for cinnarizine, cyclizine, and a buclizine derivative are 82, 94, and 87 %, respectively. The total residence time for the four steps is 90 min with a productivity of 2 mmol h-1. The incredible bulk: Bulk alcohols are converted continuously into chlorides using HCl in a microflow. A reaction network that consists of four steps and two inline separations leads to the continuous preparation of cinnarizine, cyclizine, and a buclizine derivative with yields of 82, 94, and 87 %, respectively. The total residence time for the four steps is 90 min with a productivity of 2 mmol h-1.
- Borukhova, Svetlana,Nol, Timothy,Hessel, Volker
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- Synthesis and Anticancer Activity of 1-(1H -Indol-3-yl)-2-(4-diarylmethylpiperazine-1-yl)ethane-1,2-dione Derivatives
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Several new 1-(4-diarylmethylpiperazine-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione derivatives were synthesized by acylation of 1-diarylmethylpiperazine with 2-(1H-indol-3-yl)-2-oxoacetyl chloride. Their structures were confirmed by 1H NMR, IR, mass spectra, and elemental analysis. These compounds were further evaluated for their anticancer activity, and most of them were found to have moderate-to-potent antiproliferative activities against Hela, A-549, and ECA-109 cancer cell lines in vitro.
- Jiang, Jun-Rong,Xu, Feng,Wu, Han-Gui
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- Hydrogenated acridine derivative and its application
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The invention relates to the field of chemical synthesis, and particularly relates to a compound with the general formula being Y-L-X and an application of the compound serving as a calcium channel blocking agent or/and an acetylcholinesterase inhibitor. The compound with the general formula being Y-L-X can be used for adjusting calcium homeostasis and treating cardiovascular diseases, stroke or dementia.
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Paragraph 0060; 0061; 0062; 0066
(2016/10/08)
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- CdS nanocapsules and nanospheres as efficient solar light-driven photocatalysts for degradation of Congo red dye
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CdS-1 (nanosphers) and CdS-2 (nanocapsule), were synthesized via green synthetic route without using any toxic surfactants by thermolysis of bis(4-benzhydrylpiperazine-1-carbodithioate-κ2 S, S?)cadmium(II) (1) and bis (4-benzylpipera-zine-1-carbodithioate-κ2 S, S?)cadmium(II) (2), respectively in the presence of ethylenediamine as a solvent. The nanoparticles were characterized by TEM, XRD, SEM, FT-IR UV–Visible and Fluorescence spectroscopy. The TEM results showed the formation of nanospheres (CdS-1) and nanocapsules (CdS-2) from complexes 1 and 2, respectively. Both CdS nanoparticles (NPs) have hexagonal crystal phase and a band gap value in the visible region as confirmed by the XRD and UV–Visible spectra, respectively. The photoluminescence (PL) data revealed that CdS-2 has longer recombination time of photo-injected electron hole pairs than CdS-1. The similar FT-IR spectra for both CdS NPs, and different HOMO-LUMO gap values for complexes {4.8187?eV (1) and CdS-2 4.7504?eV (2)} as predicted by DFT calculations suggest that stability of complexes play a key role in controlling morphology. Furthermore, the visible light driven photocatalytic degradation of Congo red dye was observed higher for nanocapsules than nanospheres due to a longer recombination time of photo-injected electron hole pairs.
- Khan, Azam,Zia-ur-Rehman,Rehman, Muneeb-ur-,Khan, Rajwali,Zulfiqar,Waseem, Amir,Iqbal, Azhar,Shah, Zawar Hussain
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- Chrysin-piperazine conjugates as antioxidant and anticancer agents
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Synthesis of 7-(4-bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one intermediate treating chrysin with 1,4-dibromobutane facilitated combination of chrysin with a wide range of piperazine moieties which were equipped via reacting the corresponding amines with bis(2-chloroethyl)amine hydrochloride in diethylene glycol monomethyl ether solvent. Free radical scavenging potential of prepared products was analyzed in vitro adopting DPPH and ABTS bioassay in addition to the evaluation of in vitro anticancer efficacies against cervical cancer cell lines (HeLa and CaSki) and an ovarian cancer cell line SK-OV-3 using SRB assay. Bearable toxicity of 7a-w was examined employing Madin-Darby canine kidney (MDCK) cell line. In addition, cytotoxic nature of the presented compounds was inspected utilizing Human bone marrow derived mesenchymal stem cells (hBM-MSCs). Overall, 7a-w indicated remarkable antioxidant power in scavenging DPPH+ and ABTS++, particularly analogs 7f, 7j, 7k, 7l, 7n, 7q, 7v, 7w have shown promising free radical scavenging activity. Analogs 7j and 7o are identified to be highly active candidates against HeLa and CaSki cell lines, whereas 7h and 7l along with 7j proved to be very sensitive towards ovarian cancer cell line SKOV-3. None of the newly prepared scaffolds showed cytotoxic nature toward hBM-MSCs cells. From the structure-activity point of view, nature and position of the electron withdrawing and electron donating functional groups on the piperazine core may contribute to the anticipated antioxidant and anticancer action. Different spectroscopic techniques (FT-IR, 1H NMR, 13C NMR, Mass) and elemental analysis (CHN) were utilized to confirm the desired structure of final compounds.
- Patel, Rahul V.,Mistry, Bhupendra,Syed, Riyaz,Rathi, Anuj K.,Lee, Yoo-Jung,Sung, Jung-Suk,Shinf, Han-Seung,Keum, Young-Soo
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p. 166 - 177
(2016/05/24)
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- Repurposing the antihistamine terfenadine for antimicrobial activity against staphylococcus aureus
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Staphylococcus aureus is a rapidly growing health threat in the U.S., with resistance to several commonly prescribed treatments. A high-throughput screen identified the antihistamine terfenadine to possess, previously unreported, antimicrobial activity against S. aureus and other Gram-positive bacteria. In an effort to repurpose this drug, structure-activity relationship studies yielded 84 terfenadine-based analogues with several modifications providing increased activity versus S. aureus and other bacterial pathogens, including Mycobacterium tuberculosis. Mechanism of action studies revealed these compounds to exert their antibacterial effects, at least in part, through inhibition of the bacterial type II topoisomerases. This scaffold suffers from hERG liabilities which were not remedied through this round of optimization; however, given the overall improvement in activity of the set, terfenadine-based analogues provide a novel structural class of antimicrobial compounds with potential for further characterization as part of the continuing process to meet the current need for new antibiotics.
- Perlmutter, Jessamyn I.,Forbes, Lauren T.,Krysan, Damian J.,Ebsworth-Mojica, Katherine,Colquhoun, Jennifer M.,Wang, Jenna L.,Dunman, Paul M.,Flaherty, Daniel P.
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p. 8540 - 8562
(2014/12/11)
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- Synthesis and cytotoxicity studies of novel benzhydrylpiperazine carboxamide and thioamide derivatives
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Synthesis and cytotoxic activities of 32 benzhydrylpiperazine derivatives with carboxamide and thioamide moieties were reported. In vitro cytotoxic activities of compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines by sulphorhodamine B assay. In general, 4-chlorobenzhydrylpiperazine derivatives were more cytotoxic than other compounds. In addition, thioamide derivatives (6a-g) have higher growth inhibition than their carboxamide analogs.
- Gurdal, Enise Ece,Durmaz, Irem,Cetin-Atalay, Rengul,Yarim, Mine
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p. 205 - 214
(2014/04/03)
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- Stereoselective synthesis of (z)-1-benzhydryl-4-cinnamylpiperazines via the wittig reaction
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A synthetic method of producing (E)- and (Z)-isomers of 1-benzhydryl-4-cinnamylpiperazines in a specific ratio from corresponding benzhydrylpiperazine is described. Of the three compounds synthesized (5a-c), the ratio of E/Z-isomers remained around 15:85. The key intermediates, 1-benzhydryl-4-(2,2-dimethoxyethyl)piperazine derivatives (3a-c), were prepared by nucleophilic substitution reaction of benzhydrylpiperazines (2a-c) with chloroacetaldehyde dimethylacetal in good yield (up to 88%). Hydrolysis of 3a-c gave the corresponding aldehydes 4a-c, which when subjected to the Wittig reaction followed by column purification to afford 1a-c (E-isomers) and 6a-c (Z-isomers) in pure form. The isolated compounds were characterized by NMR and mass spectral analysis. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.] Copyright
- Shivprakash,Reddy, G. Chandrasekara
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supporting information
p. 600 - 609
(2014/01/17)
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- Synthesis of 1-benzhydryl piperazine derivatives and evaluation of their ACE inhibition and antimicrobial activities
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This study presents the synthesis of 14 new 1,4-disubstituted piperazine derivatives from allyl bromides of Baylis-Hillman adduct and 4,4-disubstituted benzhydryl piperazines. All the synthesized compounds were further screened for in vitro ACE inhibitor and antimicrobial activities. Among the synthesized piperazine derivatives, compound 12h showed moderate ACE inhibitor activity as compared to the standard, angiotensin-converting enzyme inhibitor (Sigma). The kinetic data (K m, K i and V max values) of enzyme inhibition for compound 12h and ACE inhibitor standard were also determined. Similarly, all compounds were screened against different bacterial strains. Compounds 12a, 12b, 12d, 12h and 12i showed excellent to moderate activity against various tested bacterial strains. Compounds 12b and 12i showed broad spectrum of antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, S. aureus MLS 16, Escherichia coli, Bacillus subtilis and Klebsiella planticola, while compounds 12a, 12d and 12i showed promising activity against P. aeruginosa (MIC value of 8.96 μM), S. aureus (MIC value of 42.2 μM) and S. aureus MLS 16 (MIC value of 81.3 μM), respectively. The remaining compounds showed activity at a concentration of >491 μM.
- Santhoshi, Amlipur,Kumar, Singam Naveen,Sujitha, Pombala,Poornachandra, Yedla,Sadhu, Partha Sarathi,Kumar, C. Ganesh,Rao, Vaidya Jayathirtha
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p. 3207 - 3219
(2014/05/06)
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- A simple blue fluorescent probe to detect Hg2+ in semiaqueous environment by intramolecular charge transfer mechanism
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An efficient intramolecular charge transfer fluorescent probe bridging benzhydryl moiety and dansyl fluorophore through piperazine unit has been synthesized and characterized. The photophysical behavior of synthesized probe has been analyzed in the presence of different cations in aqueous acetonitrile solution. The probe has shown sensitivity to detect Hg2+ ion selectively over other tested cations at 20 nM level. The probable mode of binding of Hg2+ through the nitrogen and oxygen atoms of piperazine and dansyl has been established by spectral data analysis.
- Srivastava, Priyanka,Ali, Rashid,Razi, Syed S.,Shahid, Mohammad,Patnaik, Satyakam,Misra, Arvind
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p. 3688 - 3693
(2013/07/05)
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- PROCASPASE-ACTIVATING COMPOUNDS AND COMPOSITIONS
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The invention provides compounds and compositions useful for the modulation of certain enzymes. The compounds and compositions can induce of cell death, particularly cancer cell death. The invention also provides methods for the synthesis and use of the compounds and compositions, including the use of compounds and compositions in therapy for the treatment of cancer and selective induction of apoptosis in cells.
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Paragraph 0088; 0189-0190
(2013/04/24)
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- Development of small-molecule probes that selectively kill cells induced to express mutant RAS
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Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing cell lines with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibroblasts expressing HRASG12V followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRASG12V oncogene. This effort led to the identification of two novel molecular probes (PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4-23-fold selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in cancer cells.
- We?wer, Michel,Bittker, Joshua A.,Lewis, Timothy A.,Shimada, Kenichi,Yang, Wan Seok,MacPherson, Lawrence,Dandapani, Sivaraman,Palmer, Michelle,Stockwell, Brent R.,Schreiber, Stuart L.,Munoz, Benito
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supporting information; experimental part
p. 1822 - 1826
(2012/04/04)
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- Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors
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A novel series of compounds derived from the previously reported N-type calcium channel blocker NP118809 (1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one) is described. Extensive SAR studies resulted in compounds with IC50 values in the range of 10-150 nM and selectivity over the L-type channels up to nearly 1200-fold. Orally administered compounds 5 and 21 exhibited both anti-allodynic and anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain.
- Pajouhesh, Hassan,Feng, Zhong-Ping,Ding, Yanbing,Zhang, Lingyun,Pajouhesh, Hossein,Morrison, Jerrie-Lynn,Belardetti, Francesco,Tringham, Elizabeth,Simonson, Eric,Vanderah, Todd W.,Porreca, Frank,Zamponi, Gerald W.,Mitscher, Lester A.,Snutch, Terrance P.
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scheme or table
p. 1378 - 1383
(2010/07/06)
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- SUBSTITUTED DIBENZHYDRYLPIPERAZINES
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The present invention relates to new dibenzhydrylpiperazine modulators of histamine receptors, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 27
(2009/07/18)
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- Synthesis and in vitro antiproliferative activity of novel 1-benzhydrylpiperazine derivatives against human cancer cell lines
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In order to explore the antiproliferative effect associated with the piperazine framework, several 1-benzhydrylpiperazine derivatives 8(a-d), 9(a-d) and 10(a-h) were synthesized. Variation in the functional group at N-terminal of the piperazine led to three sets of compounds, bearing the sulfonyl, amide and thiourea, respectively. Their chemical structures were confirmed by 1H NMR, LCMS, IR and elemental analysis. The antiproliferative effect of the compounds were evaluated in vitro using the MTT colorimetric method against one normal cell line (NF-103 skin fibroblast cells) and four human cancer cell lines (MCF-7 breast carcinoma cell line, HepG-2 hepatocellular carcinoma cell line, HeLa cervix carcinoma cell line and HT-29 colon carcinoma cell line) for the time period of 24 h. Among the series, four compounds exhibited interesting growth inhibitory effects against all four cell lines.
- Kumar, C.S. Ananda,Prasad, S.B. Benaka,Vinaya,Chandrappa,Thimmegowda,Kumar, Y.C. Sunil,Swarup, Sanjay,Rangappa
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experimental part
p. 1223 - 1229
(2009/09/30)
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- Synthesis and crystal structure of 1-benzhydryl-4-methane-sulfonyl- piperazine
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The title compound, 1-benzhydryl-4-methanesulfonyl-piperazine, was synthesized by the nucleophilic substitution of 1-benzhydryl-piperazine with methyl sulfonyl chloride. The product obtained was characterized by spectroscopic techniques, and the structure was investigated by X-ray crystallography. The compound crystallizes in the monoclinic crystal class in the space group P21/c with cell parameters a=9.5820(4) A, b=16.8150(12) A, c=13.5280(8) A, =127.270(5), and V=1734.5(2)A3 for Z=4. The structure reveals that the piperazine ring is in a chair conformation. There is a large discrepancy around the bond angles of the piperazine N atoms. The geometry around the S atom is distorted tetrahedral.
- Naveen,Sridhar,Prasad, J. Shashidhara,Kumar, C. S. Ananda,Prasad, S. B. Benaka,Thimmegowda,Rangappa
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- Hybrid approach for the design of highly affine and selective dopamine D3 receptor ligands using privileged scaffolds of biogenic amine GPCR ligands
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A series of compounds containing privileged scaffolds of the known histamine H1 receptor antagonists cetirizine, mianserin, ketotifen, loratadine, and bamipine were synthesized for further optimization as ligands for the related biogenic amine binding dopamine D3 receptor. A pharmacological screening was carried out at dopamine D2 and D3 receptors. In the preliminary testing various ligands have shown moderate to high affinities for dopamine D3receptors, for example, N-(4-{4-[benzyl(phenyl)amino]piperidin-1-yl}butylnaphthalen-2-carboxamide (19a) (hD3 Ki = 0.3 nM; hD2 Ki = 703 nM), leading to a selectivity ratio of 2343.
- Sasse, Britta C.,Mach, Ulrich R.,Leppaenen, Jukka,Calmels, Thierry,Stark, Holger
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p. 7258 - 7273
(2008/03/27)
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- Synthesis and evaluation of 1-benzhydryl-sulfonyl-piperazine derivatives as inhibitors of MDA-MB-231 human breast cancer cell proliferation
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A series of novel 1-benzhydryl-sulfonyl-piperazine derivatives 7(a-e) were designed by a nucleophilic substitution reaction of 1-benzhydryl-piperazine with various sulfonyl chlorides and characterized by 1H nuclear magnetic resonance (NMR), liquid chromatography mass spectrometry (LC/MS), Fourier-transform infrared (FTIR), and elemental analysis. Our research is focused on identifying synthetically occurring chemotherapeutic substances capable of inhibiting, retarding, or reversing the process of multistage carcinogenesis. The title compounds were evaluated for their efficacy in inhibiting MDA-MB-231 breast cancer cell proliferation. Compound 1-benzhydryl-4-(4-tert-butyl-benzenesulfonyl)-piperazine (7d) showed significant inhibitory activity. Birkhaeuser 2007.
- Ananda Kumar,Nanjunda Swamy,Thimmegowda,Benaka Prasad,Yip, George W.,Rangappa
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p. 179 - 187
(2008/09/17)
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- Calcium channel blockers comprising two benzhydril moieties
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Certain piperazine substituted compounds are described which are useful in altering calcium channel activity.
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- Design, synthesis, and structure-activity relationships of pyrazolo[3,4-d]pyrimidines: A novel class of potent enterovirus inhibitors
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A series of pyrazolo[3,4-d]pyrimidines were synthesized and their antiviral activity was evaluated in a plaque reduction assay. It is very interesting that this class of compounds provide remarkable evidence that they are very specific for human enteroviruses, in particular, coxsackieviruses. Some derivatives proved to be highly effective in inhibiting enterovirus replication at nanomolar concentrations. SAR studies revealed that the phenyl group at the N-1 position and the hydrophobic diarylmethyl group at the piperazine largely influenced the in vitro antienteroviral activity of this new class of potent antiviral agents. It was found that the pyrazolo[3,4-d]pyrimidines with a thiophene substituent, such as compounds 20-24, in general exhibited high activity against coxsackievirus B3 (IC50=0.063-0.089μM) and moderate activity against enterovirus 71 (IC50=0.32-0.65μM) with no apparent cytotoxic effect toward RD (rhabdomyosarcoma) cell lines (CC5025μ M).
- Chern, Jyh-Haur,Shia, Kak-Shan,Hsu, Tsu-An,Tai, Chia-Liang,Lee, Chung-Chi,Lee, Yen-Chun,Chang, Chih-Shiang,Tseng, Sung-Nien,Shih, Shin-Ru
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p. 2519 - 2525
(2007/10/03)
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- N-[4-(Methylsulfonylamino)benzyl]thiourea analogues as vanilloid receptor antagonists: Analysis of structure-activity relationships for the 'C-Region'
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We recently reported that N-(4-t-butylbenzyl)-N′-[4- (methylsulfonylamino)benzyl] thiourea (2) was a high affinity antagonist of the vanilloid receptor with a binding affinity of Ki=63 nM and an antagonism of Ki=53.9 nM in rat VR1 heterologously expressed in Chinese hamster ovary (CHO) cells (Mol. Pharmacol. 2002, 62, 947-956). In an effort to further improve binding affinity and antagonistic potency, we have modified the C-region of the lead 4-t-butylbenzyl group with diverse surrogates, such as araalkyl, alkyl, 4-alkynylbenzyl, indanyl, 3,3-diarylpropyl, 4-alkoxybenzyl, 4-substituted piperazine and piperidine. The lipophilic surrogates, arylalkyl and alkyl, conferred modest decreases in binding affinities and antagonistic potencies; the groups having heteroatoms resulted in dramatic decreases. Our findings indicate that 4-t-butylbenzyl is one of the most favorable groups for high receptor binding and potent antagonism to VR1 in this structural series.
- Lee, Jeewoo,Kang, Sang-Uk,Lim, Ju-Ok,Choi, Hyun-Kyung,Jin, Mi-Kyung,Toth, Attila,Pearce, Larry V.,Tran, Richard,Wang, Yun,Szabo, Tamas,Blumberg, Peter M.
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p. 371 - 385
(2007/10/03)
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- CALCIUM CHANNEL BLOCKERS COMPRISING TWO BENZHYDRIL MOIETIES
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Certain piperazine substituted compounds are described which are useful in altering calcium channel activity.
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- Benzofuran derivatives, pharmaceutical composition containing the same, and a process for the preparation of the active ingredient
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The present invention is a piperazinylalkylbenzofuran derivative of the formula wherein R1 represents a C1-4 alkyl group, R2 stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxyl group, Z represents a hydrogen atom, Ar′ represents a diphenylmethyl group, a pyridyl group, a partially saturated 5-membered heterocyclic group or a phenyl group, n has a value of 0 or 1, and pharmaceutically suitable acid addition salts thereof.
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- Pharmaceutically active pyrrolidine derivatives
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The present invention is related to pyrrolidine derivatives of formula (I). Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula (I) are useful in the treatment and/or prevention of premature labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor. More preferably, said compounds are useful in the treatment and/or prevention of disease states mediated by oxytocin, including premature labor, premature birth and dysmenorrhea. The present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation, wherein X is selected from the group consisting of CR6R7, NOR6, NNR6R7; A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO22—, —SO2NH—, —CH2—,B is either a group —(C═O)—NR8R9 or represents a heterocyclic residue having the formula (a) wherein Q is NR10, O or S; n is an integer selected of 0, 1 or 2; Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.
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- Pharmaceutically active pyrrolidine derivatives as bax inhibitors
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The present invention is related to new substituted pyrrolidine derivatives of formula (I). Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula (I) are useful in the treatment and/or prevention of neurodegenerative disorders, diseases associated with polygultamine tracts, epilepsy, ischemia, infertility, cardiovascular disorders renal hypoxia, hepatitis and AIDS. Said pyrrolidine derivatives display a modulatory and most notably a down-regulating-up to an inhibitory-activity with respect to the cellular death agonist Bax and/or the activation pathways leading to Bax and allows therefore to block the release of cytochrome (c). The present invention is furthermore related to novel pharmaceutically activity substituted pyrrolidine derivatives as well as to methods of their preparation, wherein X is selected from the group consisting of O, S, CRR, NOR, NNRR; A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO2-, —SO2NH—; —CH2-; B is either a group —(C═O)—NRR or represents a heterocyclic residue having the formula (II) wherein Q is NR, O or S; n is an integer selected of 0, 1 or 2; Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.
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- Process for producing piperazinesulfonamide derivatives and salts thereof
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A process for advantageously preparing a piperazinesulfonamide derivative represented by the general formula (III): wherein R1 is hydrogen atom, a straight or branched chain alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro group or amino group; R2 is a phenyl group which may have as substituents on its phenyl ring 1 to 3 groups selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro group and amino group, 2-pyridyl group, 3-pyridyl group or 4-pyridyl group; each of R3 and R4 is independently hydrogen atom, a straight or branched chain alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a phenyl group which may be substituted; and Y is an alkylene group having 1 to 12 carbon atoms, and a salt thereof.
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- Synthesis of trimethylhydroquinone derivatives as anti-allergic agents with anti-oxidative actions
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A novel series of trimethylhydroquinone derivatives was synthesized and evaluated for their anti-lipid peroxidation activity in rat liver microsomes, inhibition of rat basophilic leukemia-1 (RBL-1) cell 5-lipoxygenase and 48 h homologous passive cutaneous anaphylaxis (PCA) activity in rats, 4-[4-[4- (Diphenylmethyl)-1-piperazinyl]butoxy]-2,3,6-trimethylphenol (9c) exhibited the ability to inhibit Fe3+-ADP induced NADPH dependent lipid peroxidation (IC50=5.3x 10-7 M), 5-lipoxygenase ((IC50=3.5x10-7 M) and PCA reaction (57% inhibition at 100 mg/kg p.o.).
- Kawasaki, Nobuhide,Miyataka, Hideki,Nishiki, Mayumi,Matsumoto, Hitoshi,Inagaki, Naoki,Nagai, Hiroichi,Satoh, Toshio
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p. 177 - 181
(2007/10/03)
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- Phenol compound having antioxidative activity and the process for preparing the same
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Disclosed are a phenol compound represented by the formula (1): STR1 wherein R0 represents H, alkyl or alkyloxy; R1 represents alkyl; R2 represents alkyl or alkyloxy; OR3 represents OH; R4 represents H, lower alkyl or acyl, each of the above substituents may be substituted; W represents O, S or NR7 ; where R7 represents H, alkyl, aryl, OH or alkyloxy, a group of the formula (2): STR2 represents an amino which may be mono- or di-substituted or heterocyclic group containing N atom, or a pharmaceutically acceptable salt thereof, and a process for preparing the same.
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- Structure-activity relationship of newly synthesized quinoline derivatives for reversal of multidrug resistance in cancer
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The effect of 24 newly synthesized quinoline derivatives on tumor cell multidrug resistance (MDR) was examined in vitro. At low concentrations, these compounds enhanced the accumulation of [3H]vincristine in K562/ADM cells and reversed tumor cell MDR. The results of the structure-activity relationship analysis indicate that in highly active compounds the two aryl rings in the hydrophobic moiety deviate from a common plane, so they are capable of interacting with hydrogen bond donors of P-170 glycoprotein (P- gp) via π-hydrogen-π interactions. Other major structural features which influence the MDR-reversing activities of these compounds are a quinoline nitrogen atom and a basic nitrogen atom in piperazine. Furthermore, in highly active compounds, the distance between the hydrophobic moiety and the basic nitrogen atom (an atom connected to 2-hydroxypropoxyquinoline) must be at least 5 A?. Several compounds were found to reverse vincristine resistance in K562/ADM cells in vitro, and compound 16 (MS-209) was selected for clinical studies.
- Suzuki, Tsuneji,Fukazawa, Nobuyuki,San-nohe, Kunio,Sato, Wakao,Yano, Osamu,Tsuruo, Takashi
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p. 2047 - 2052
(2007/10/03)
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- Amphoteric drugs. I. Synthesis and antiallergic activity of [4-(diphenylmethoxy)piperidino]-, [4-(diphenylmethyl)piperazinyl]- and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives
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A simple method of transforming classical antihistaminics into nonsedative antiallergic agents with strong effects in rat models is described. Various [4-(diphenylmethoxy)piperidinol - (series A), [4-(diphenylmethyl)piperazinyl]- (series B) and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives (series C) were synthesized and examined for antiallergic activities and effects on the central nervous system (CNS), in comparison with the corresponding N-methyl derivatives (1a-c). N-Alkylcarboxylic acids (5a-c) showed stronger inhibitory effects on compound 48/80-induced lethality in rats than the corresponding N-methyl derivatives (1a-c). In particular, N-alkylcarboxylic acids (5a) in series A exhibited approximately 100-fold stronger inhibitory effects than 1a, and were the least effective in prolonging the sleeping time on hexobarbital-induced anesthesia in mice in all series. As a result of chemical modification in series A, it was found that introduction of a methyl group at the para-position on one benzene ring in the (diphenylmethoxy)piperidine system effectively reduced CNS side-effects without reducing antiallergic activity. (+)-3-[4-[(4-Methylphenyl)phenylmethoxy] piperidinol propionic acid ((+)-51), an optically active isomer of 51, exhibited a stronger antiallergic effect (ED50 = 0.17 mg/kg, p.o.) than ketotifen and terfenadine in the 48 h homologous passive cutaneous anaphylaxis (PCA) test, and moreover exhibited no CNS side-effects, such as prolongation of the sleeping time on hexobarbital-induced anesthesia, at an oral dose of 30 mg/kg. Compound (+)-51 was thus proved to be a promising candidate as a nonsedative antiallergic agent.
- Iwasaski,Sakaguchi,Ohashi,Takahara,Ogawa,Yasuda,Koshinaka,Kato,Ito,Sawanishi
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p. 2276 - 2284
(2007/10/02)
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- 2,6-di,2,4,6-, 2,5,6-tri and 2,4,5,6-tetra-substituted pyrimidines, their pharmaceutically acceptable salts, pharmaceutical compositions containing same and their use in the treatment of neurological diseases
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2,6-di-, 2,4,6-, 2,5,6-tri- or 2,4,5,6-tetra-substituted pyrimidines, and 2,6-di-substituted pyridines. These compounds are useful for treatment of neurological diseases.
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- TRICYCLIC ANALOGUES OF THE ANTIALLERGIC AGENT OXATOMIDE: 1-(3-(4-(10,11-DIHYDRO-5H-DIBENZOCYCLOHEPTENE-5-YL)-1-PIPERAZINYL)PROPYL)-1,3-DIHYDRO-2H-BENZIMIDAZOL-2-ONE AND THE RELATED 6,11-DIHYDRODIBENZOTHIEPIN, 4,9-DIHYDROTHIENO-2-BENZOTHIEPIN, AND ...
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11-Chloro-6,11-dihydrodibenzothiepin and its 2-methyl derivative VI were transformed via the 11-(4-(ethoxycarbonyl)-1-piperazinyl) compounds IVc and Vc to 11-(1-piperazinyl) compounds IVb and Vb.Their reactions with 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one (II) afforded the title compounds IVa and IVb.Similar reactions and sequences in the series of 10,11-dihydro-5H-dibenzocycloheptene, 4,9-dihydrothieno-2-benzothiepin, and 10,11-dihydrodibenzothiepin led to further oxatomide (Ia) analogues IIIa and VIIa-XIa.In the test of passivecutaneous anaphylaxis in rats, compound VIIIa was more active than Ia, and IVa had similar activity like Ia.
- Jilek, Jiri,Holubek, Jiri,Svatek, Emil,Metys, Jan,Frycova, Hana,et al.
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p. 870 - 883
(2007/10/02)
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- Synthesis of some N-benzhydrylpiperazine derivatives as calcium antagonists
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The preparation of a series of 24 N-benzhydrylpiperazine derivatives is described. Their efficacy as calcium antagonists was examined with reference to changes in the permeability of the cell membrane to extracellular and intracellular calcium. Compounds 14, 15, 17 and 19 were the most powerful when compared with known calcium antagonists such as cinnarizine, flunarizine, and aligeron ([1-diphenylmethyl)-4-(2-propenyl)]-piperazine), and were selected for further study.
- Gubert,Braso,Sacristan,Ortiz
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p. 1103 - 1107
(2007/10/02)
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- New xanthine derivatives with potent and long lasting anti-bronchoconstrictive activity
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Twenty eight new derivatives of 8-aminoalkyl substituted xanthine have been synthesized.They all have demonstrated a potent anti-bronchoconstrictive effect in the guinea pig and some of them have a very long duration of action (>48 h).Among them, one compound: 1-methyl 3-isobutyl 8-(4-benzhydryl piperazino ethyl)xanthine (57) (S 9795) has been selected for clinical trials in asthmatic patients because of its long duration of action, its lack of CNS stimulating effects and its inhibiting action on mast cell degranulation and phosphodiesterase activity.Keywords - 8-aminoalkyl substituted xanthines / benzhydryl piperazine / piperidine / ethylenediamine / anti-bronchoconstrictors / phosphodiesterase inhibitors / asthma
- Regnier, Gilbert L.,Guillonneau, Claude G.,Duhault, Jacques L.,Tisserand, Francoise P.,Saint-Romas, Guy,Holstorp, Sophie M.
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p. 243 - 250
(2007/10/02)
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- 2,3-Dihydro-3-[4-(substituted)-1-piperazinyl]-1H-isoindol-1-ones
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Pyrazinoisoindolone derivatives of the formula STR1 wherein R1 is lower alkyl, phenyl, diphenylmethyl, pyridinyl, pyrimidinyl, pyrazinyl or pyrazinyl substituted with a lower alkyl, lower alkoxy or halo; and R2 is hydrogen, lower alkyl or di(lower)alkylamino(lower)alkyl are useful as antihypertensive agents.
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