- Dithiocarbamate substituted phenothiazine derivatives: In silico experiments, synthesis, and biological evaluation
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Objective: The present study was designed to study the anticancer activity of a series of novel analogs of phenothiazine with dithiocarbamate as a side chain. Methods: A novel series of derivatives containing dithiocarbamate as a side chain at the tenth position of phenothiazine nucleus were synthesized, characterized by spectral analysis, and evaluated for their antimitotic and antioxidant activity using germinated Bengal gram seeds and 2,2-diphenyl-1-picrylhydrazyl (DPPH) method, respectively. A quantitative estimate of drug-likeness was also performed, which calculated the molecular properties and screened the molecules based on drug-likeness rules. Further, molecular docking study was performed for finding the binding affinity with tubulin protein to rationalize their anticancer activity. Results: The results revealed that the antioxidant activity of compounds 3e, 3g, 3i, 3j and standard Ascorbic acid were 10 mmol, 14 mmol, 16 mmol, 16 mmol and 35 mmol, respectively. Further compounds 3e, 3g, 3h and 3i have shown promising antimitotic activity. Compound 3i (-9 K. Cal/mol) showed the highest binding energies towards tubulin protein when compared to standard drug colchicine (-8.6 K. Cal/mol). Among all, compound 3i showed promising antimitotic and antioxidant activity, which correlated with insilico docking studies. Conclusion: Dithiocarbamate substituted phenothiazine derivatives proved to be encouraging leads as tubulin inhibitors.
- Kotha, Anusha,Md, Ashma,S., Muni Sireesha,Saritha, Jyostna T.,Vemuri, Jyothi
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- Benzylidene thiazolidinediones: Synthesis, in vitro investigations of antiproliferative mechanisms and in vivo efficacy determination in combination with Imatinib
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Thiazolidinedione (TZD) has been an interesting scaffold due to its proven antidiabetic activity and encouraging findings in anticancer drug discovery. We synthesised benzylidene thiazolidinedione derivatives which exhibited excellent antiproliferative effects in chronic myeloid leukemic cells K562 and the most active compounds 3t and 3x had GI50 value of 0.9 and 0.23 μM respectively. Both the compound was found to arrest the growth of K562 cells in G0/G1 phase in a time and dose dependent manner. Further, western blot analysis revealed that 3t and 3x could also inhibit the expression of cell proliferation markers, PCNA and Cyclin D1 and compound 3x up-regulated apoptosis markers, cleaved PARP1 and activated caspase 3, which could be a possible mechanism for the excellent antiproliferative effects exhibited by these compounds. In vitro combination studies of 3t and 3x with Imatinib found to potentiate the antitumor effects of Imatinib. Further in vivo efficacy in K562 xenografts, of 3t and 3x alone and in combination with Imatinib was found to be promising and far better than control group and combination treatment was found to be more effective as compared to only Imatinib treated or test compound treated animals. Thus, our findings suggest that these compounds are promising antitumor agents and could help to enhance the anticancer effects of Imatinib and other tyrosine kinase inhibitors, when used in combination.
- Joshi, Hardik,Patil, Vijay,Tilekar, Kalpana,Upadhyay, Neha,Gota, Vikram,Ramaa
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supporting information
(2020/10/02)
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- An Inhibitor of the Interaction of Survivin with Smac in Mitochondria Promotes Apoptosis
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Herein we report the first small molecule that disrupts the survivin-Smac interaction taking place in mitochondria. The inhibitor, PZ-6-QN, was identified by initially screening a phenothiazine library using a fluorescence anisotropy assay and then conducting a structure–activity relationship study. Mutagenesis and molecular docking studies suggest that PZ-6-QN binds to survivin similarly to the known Smac peptide, AVPI. The results of the effort also show that PZ-6-QN exhibits good anticancer activity against various cancer cells. Moreover, cell-based mechanistic studies provide evidence for the proposal that PZ-6-QN enters mitochondria to inhibit the survivin-Smac interaction and promotes release of Smac and cytochrome c from mitochondria into the cytosol, a process that induces apoptosis in cancer cells. Overall, the present study suggests that PZ-6-QN can serve as a novel chemical probe for study of processes associated with the mitochondrial survivin-Smac interaction and it will aid the discovery of novel anticancer agents.
- Park, Seong-Hyun,Shin, Insu,Park, Sang-Hyun,Kim, Nam Doo,Shin, Injae
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supporting information
p. 4035 - 4041
(2019/08/02)
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- Phenothiazines nitric oxide donor, its preparation and use
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The invention discloses a kind of phenothiazine-containing nitric oxide donor compounds with the structure of a formula I. In the formula I, n is equal to 0, 1 or 2, R1 is hydrogen, halogens, C1-C4 branched or linear alkyl, or halogenated C1-C4 branched or linear alkyl, and R2 is hydrogen or C1-C4 branched or linear alkyl. The invention also discloses a preparation method of the compounds, and discloses a pharmaceutical composition taking the compounds as an active composition, and application of the compounds as anti-tumor medicines, especially to prepare medicines for treating breast cancer, lung cancer and stomach cancer.
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Paragraph 0047-0050
(2018/04/20)
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- Inhibitory effect of phenothiazine- and phenoxazine-derived chloroacetamides on Leishmania major growth and Trypanosoma brucei trypanothione reductase
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A number of phenothiazine-, phenoxazine- and related tricyclics-derived chloroacetamides were synthesized and evaluated in vitro for antiprotozoal activities against Leishmania major (L. major) promastigotes. Several analogs were remarkably potent inhibitors, with antileishmanial activities being comparable or superior to those of the reference antiprotozoal drugs. Furthermore, we explored the structure-activity relationships of N-10 haloacetamides that influence the potency of such analogs toward inhibition of L. major promastigote growth in vitro. With respect to the mechanism of action, selected compounds were evaluated for time-dependent inactivation of Trypanosoma brucei trypanothione reductase. Our results are indicative of a covalent interaction which could account for potent antiprotozoal activities.
- Marcu, Ana,Schurigt, Uta,Müller, Klaus,Moll, Heidrun,Krauth-Siegel, R. Luise,Prinz, Helge
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supporting information
p. 436 - 443
(2015/12/24)
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- Design of new phenothiazine-thiadiazole hybrids via molecular hybridization approach for the development of potent antitubercular agents
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A new library of phenothiazine and 1,3,4-thiadiazole hybrid derivatives (5a-u) was designed based on the molecular hybridization approach and the molecules were synthesized in excellent yields using a facile single-step chloro-amine coupling reaction between 2-chloro-1-(10H-phenothiazin-10-yl)ethanones and 2-amino-5-subsituted-1,3,4-thiadiazoles. The compounds were evaluated for their in vitro inhibition activity against Mycobacterium tuberculosis H37Rv (MTB). Compounds 5g and 5n were emerged as the most active compounds of the series with MIC of 0.8 μg/mL (~1.9 μM). Also, compounds 5a, 5b, 5c, 5e, 5l and 5m (MIC = 1.6 μg/mL), and compounds 5j, 5k and 5o (MIC = 3.125 μg/mL) showed significant inhibition activity. The structure-activity relationship demonstrated that an alkyl (methyl/npropyl) or substituted (4-methyl/4-Cl/4-F) phenyl groups on the 1,3,4-thiadiazole ring enhance the inhibition activity of the compounds. The cytotoxicity study revealed that none of the active molecules are toxic to a normal Vero cell line thus proving the lack of general cellular toxicity. Further, the active molecules were subjected to molecular docking studies with target enzymes InhA and CYP121.
- Ramprasad, Jurupula,Nayak, Nagabhushana,Dalimba, Udayakumar
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- Design and synthesis of tacrine-phenothiazine hybrids as multitarget drugs for Alzheimer's disease
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Tacrine is well-known drug for Alzheimer's disease as an acetylcholinesterase inhibitor. Rember is a bright and promising AD drugs targeting tau protein, and it is currently in Phase III clinical trials. Phenothiazine, the key pharmacophore of Rember, can prevent tau filament formation. In this work, several tacrine-phenothiazine hybrids (T1-T26) were designed for inhibiting acetylcholinesterase and tau protein involved in Alzheimer's disease. After initial screening with the help of computational chemistry software and Molegro Virtual Docker, three molecules (T5, T18, and T22) were selected for further synthesis and biological evaluation. Next, T5, T18, and T22 were synthesized and evaluated for their acetylcholinesterase and tau hyperphosphorylation inhibition. All the tested compounds had better acetylcholinesterase inhibitory activity compared with tacrine. Among them, compound T5 was found to be the most potent compound with IC50 89 nM. Meanwhile, T5 markedly prevented tau hyperphosphorylation induced by okadaic acid in N2α cell. Its P-tau level was decreased with 39.5 % inhibition when tested at 10-5 M, lower than that Rember (55.7 %). Besides acetylcholinesterase and tau hyperphosphorylation inhibition, T5 can also interact with fibrill beta amyloid using surface plasmon resonance, the data of KD were 5.51 × 10-8 M. All the above results indicated that tacrine-phenothiazine hybrids are potential multitarget directed ligands targeting acetylcholinesterase, tau protein, and beta amyloid.
- Hui, Ai-Ling,Chen, Yan,Zhu, Shi-Jing,Gan, Chang-Sheng,Pan, Jian,Zhou, An
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p. 3546 - 3557
(2014/06/24)
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- Synthesis and biological evaluation of 1-(3-chloro-2-oxo-4-phenylazetidin- 1-yl)-3-(2-oxo-2-(10H-phenothiazin-10-yl)ethyl)urea derivatives
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A new series of eleven novel 1-(3-chloro-2-oxo-4-phenylazetidin-1yl)-3-(2- oxo-2-(10H-phenothiazin-10-yl)ethyl)urea derivatives were synthesized by cyclocondensation of various Schiff bases of phenothiazine with chloroacetyl chloride in the presence of triethylamine. Various Schiff bases of phenothiazine were synthesized by condensation of 4-(2-oxo-2-(10H-phenothiazin-10-yl)ethyl semicarbazide with various aryl aldehydes. The synthesized compounds were characterized by IR, MASS and 1H NMR spectral data and evaluated for in vitro antimicrobial, antitubercular, antioxidant and anticancer activities by disc diffusion method, MIC method, REMA, DPPH, FRAP and MTT assay method, respectively. All synthesized compounds showed moderate-to-significant anti-bacterial and anti-fungal activity and compound 4d, 4g, 4h and 4k showed good antioxidant activity with EC50 value of 55, 57, 56 and 47 μg/ml tested by DPPH method. The compounds 4j at a concentration of 10 μg/ml showed inhibition against the growth of Mycobacterium tuberculosis and 4f showed significant activity against human cervical cancer cell line with IC50 values of 18.26 μM.
- Rajasekaran,Devi, K. Sheeja
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p. 2578 - 2588
(2013/07/26)
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- New farnesyltransferase inhibitors in the phenothiazine series
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The biological screening of the chemical library of our Organic Chemistry Department, carried out on an automated fluorescence-based FTase assay, allowed us to discover that a phenothiazine derivative (1d) was an inhibitor of farnesyltransferase. Three new series of human farnesyltransferase inhibitors, based on a phenothiazine scaffold, were synthesized with protein farnesyltransferase inhibition potencies in the low micromolar range. Ester derivative 9d was the most active compound in these series. Four synthesized compounds were evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel. The modest results obtained in this preliminary investigation showed that mixing the phenothiazine and the 1,2,3-triazole motif in the structure of a single compound can lead to new scaffolds in the field of farnesyltransferase inhibitors.
- Belei, Dalila,Dumea, Carmen,Samson, Alexandrina,Farce, Amaury,Dubois, Joelle,Bicu, Elena,Ghinet, Alina
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scheme or table
p. 4517 - 4522
(2012/08/07)
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- A facile and efficient method for the selective deacylation of N-arylacetamides and 2-chloro-Narylacetamides catalyzed by SOCl2
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Thionyl chloride efficiently and selectively promoted the deacylation of N-arylacetamides and 2-chloro-N-arylacetamides, under anhydrous conditions, without effecting the ester group, aminosulfonyl group, or benzyloxyamide group. This method, which has been successfully applied to a variety of substrates including different N-arylacetamides and 2-chloro-N-arylacetamides, has the attractive advantages of inexpensive reagents, satisfactory selectivity, excellent yields, short reaction time, and convenient workup. This new method can probably be used to selectively deacylate between aromatic amides and alkyl amides. Springer Science+Business Media B.V. 2011.
- Wang, Gong-Bao,Wang, Lin-Fa,Li, Chao-Zhang,Sun, Jing,Zhou, Guang-Ming,Yang, Da-Cheng
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experimental part
p. 77 - 89
(2012/05/20)
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- Synthesis and antifungal activity of some substituted phenothiazines and related compounds
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Several phenothiazines and related compounds were synthesized and their antifungal activity was evaluated in vitro. The results observed for α-chloro-N-acetyl phenothiazine led us to choose this compound as a lead in the search of antifungal agents.
- Sarmiento, Gabriela P.,Vitale, Roxana G.,Afeltra, Javier,Moltrasio, Graciela Y.,Moglioni, Albertina G.
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experimental part
p. 101 - 105
(2011/02/25)
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- Synthesis and primary cytotoxicity evaluation of new 5-benzylidene-2,4- thiazolidinedione derivatives
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In the present work, ten novel derivatives (3a-3j) of 5-benzylidene-2,4- thiazolidinediones were synthesized and their structures were determined by analytical and spectral (FTIR, 1H NMR, 13C NMR) methods. The newly synthesized compounds were evaluated for their antiproliferative activity at Tata Memorial's Advanced Center for Treatment, Research and Education in Cancer (ACTREC), India, in a panel of 7 cancer cell lines using four concentrations at 10-fold dilutions. Sulforhodamine B (SRB) protein assay was used to estimate cell stability or growth. Though the compounds showed varying degrees of cytotoxicity in the tested cell lines, most marked effect was observed by compound 3e in MCF7 (breast cancer), K562 (leukemia) and GURAV (nasopharyngeal cancer) cell lines with log10 GI50 values of -6.7, -6.72 and -6.73 respectively.
- Patil, Vijay,Tilekar, Kalpana,Mehendale-Munj, Sonali,Mohan, Rhea,Ramaa
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experimental part
p. 4539 - 4544
(2010/10/19)
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- Synthesis and antimicrobial activity of some new N-acyl substituted phenothiazines
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A series of 2-substituted N-acylphenothiazines were synthesized by using imides, N-carboxymethyl imides and the structures of these newly synthesized compounds were confirmed by spectral and elemental analyses. All new compounds were tested for their antibacterial and antifungal activities. Some compounds showed promising antibacterial and antifungal activities.
- Bansode, Tanaji N.,Shelke, Jayant V.,Dongre, Vaijanath G.
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experimental part
p. 5094 - 5098
(2010/01/06)
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- Synthesis of 2′-aryl-3-N10-[(acetylamino)-1-3-thiazolidin- 4-ones] and 5′-arylidine-2-aryl-3-N10-[(acetylamino)-1,3- thiazolidin-4-ones] and their antimicrobial and diuretic activities
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Thirty-nine new phenothiazino-4-oxo-thiazolidines and their 5-arylidines were synthesized and evaluated for their antimicrobial and diuretic activity. The structure of all the products was corroborated by IR, 1H NMR, mass spectra and elemental analysis. Some of the newly synthesized compounds show promising antimicrobial and diuretic activity.
- Yadav, Ritu,Jain, Vikrant,Srivastava,Srivastava, Soumya,Srivastava
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experimental part
p. 537 - 543
(2010/07/06)
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- Synthesis of N-alkaloidacyl derivatives of phenothiazine
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Compounds in which cytisine, anabasine, D-pseudoephedrine, and L-ephedrine fragments are linked to the phenothiazine nitrogen atom via acyl group were synthesized. These compounds are potential drugs, and their activity was confirmed by computer prediction using PASS software.
- Kulakov,Ainabaev,Nurkenov,Gazaliev
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p. 263 - 267
(2008/09/19)
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- Synthesis of new N-acylphenothiazinic derivatives with potential activity in chemotherapy
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An array of cycloimonium derivatives 3-6 has been synthesized by alkylation of a variety of azaheterocycles (3-methylisoquinoline, pyrrolopyridine and triazole) with N-(chloroacetyl)-phenothiazine. The azamethine ylide derived from 3-methylisoquinolinium salt 3 has been involved in [1,3] cycloaddition reactions with acetylenic or olefinic dipolarophiles to provide the adducts 7-9. All the synthesized compounds were identified by IR, 1H and 13C NMR spectroscopy.
- Bacu, Elena,Belei, Dalila,Couture, Axel,Grandclaudon, Pierre
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p. 253 - 259
(2008/02/13)
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- Synthesis of pyrrolo[1,2-b]pyridazine derivatives engrafted on N-acylphenothiazine
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A variety of saturated and unsaturated pyrrolo[1,2-b]pyridazine derivatives of N-acylphenothiazine 5-7, 9, 10 has been efficiently synthesized by cyclocondensation of olefinic or acetylenic dipolarophiles with azomethine ylide 4 derived from pyridazinhim salt 3 linked to N-acetylphenothiazine. The inactivation of the intermediate ylide 4 through [3+3] dipolar cycloaddition reaction delivered the polyazacyclic dimers 11 and 12.
- Bacu, Elena,Belei, Dalila,Couture, Axel,Grandclaudon, Pierre
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p. 887 - 894
(2008/04/18)
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- Structure-activity relationships for inhibition of human cholinesterases by alkyl amide phenothiazine derivatives
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A number of phenothiazine N-alkyl amide derivatives were synthesized in order to examine the structure-activity relationships for inhibition of human acetylcholinesterase and butyrylcholinesterase. Several lines of evidence indicate that inhibition of butyrylcholinesterase (BuChE) is important in the treatment of certain dementias. Further testing of this concept requires inhibitors that are both BuChE-selective and robust. N-alkyl derivatives (2, 3, 4) of phenothiazine (1) have previously been found to inhibit only BuChE in a mechanism involving π-π interaction between the phenothiazine tricyclic ring system and aromatic residues in the active site gorge. To explore features of phenothiazines that affect the selectivity and potency of BuChE inhibition, a series of N-carbonyl derivatives (5-25) was synthesized and examined for the ability to inhibit cholinesterases. Some of the synthesized derivatives also inhibited AChE through a different mechanism involving carbonyl interaction within the active site gorge. Binding of these derivatives takes place within the gorge, since this inhibition disappears when the molecular volume of the derivative exceeds the estimated active site gorge volume of this enzyme. In contrast, BuChE, with a much larger active site gorge, exhibited inhibition that increased directly with the molecular volumes of the derivatives. This study describes two distinct mechanisms for binding phenothiazine amide derivatives to BuChE and AChE. Molecular volume was found to be an important parameter for BuChE-specific inhibition.
- Darvesh, Sultan,McDonald, Robert S.,Penwell, Andrea,Conrad, Sarah,Darvesh, Katherine V.,Mataija, Diane,Gomez, Geraldine,Caines, Angela,Walsh, Ryan,Martin, Earl
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p. 211 - 222
(2007/10/03)
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- N-Homolupinanoyl and N-(ω-lupinylthio)alkanoyl derivatives of some tricyclic systems as ligands for muscarinic M1 and M2 receptor subtypes
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A set of N-homolupinanoyl- and N-(ω-lupinylthio)alkanoyl derivatives of tricyclic systems (as phenothiazine, iminodibenzyl and dihydropyridobenzodiazepinone) has been prepared and tested for affinity for rat muscarinic M1 and M2 receptor subtypes labeled with [3H]pirenzepine and [3H]AF-DX 384. Good affinity for both M1 and M2 subtypes was displayed by most compounds, often with nanomolar Ki values, which for lupinylthiopropionyl- and lupinylthiobutyryl-phenothiazines (13-16) were comparable to those of pirenzepine and methoctramine, respectively. However, only moderate selectivity for one or the other subtype was seen.
- Tasso, Bruno,Sparatore, Anna,Sparatore, Fabio
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p. 669 - 676
(2007/10/03)
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- Regioselective cleavage reaction of the aromatic methylenedioxy ring. VI. Synthesis of phenothiazine analogues by using the cleavage reaction with sodium methoxide-thiols in dimethyl sulfoxide and evaluation of their biological activities
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The reactions of aromatic methylenedioxy compounds containing electron- withdrawing groups with sodium methoxide-thiols in dimethyl sulfoxide gave 3- and 4-hydroxybenzene derivatives in good yield by regioselective attack of the thiolate ions on the methylenedioxy ring. The formation mechanism and the reactivity of thiolate ions in the cleavage reaction of the methylenedioxy ring are discussed. Various biologically active compounds, 32a, 32d, 36b, 38h, 41b and 44-47, were prepared from the 4-hydroxybenzene derivatives and their Ca2+ antagonistic activities were evaluated. Among these compounds, 2-(2-bromophenylthiomethoxy)-10-(2-diethylaminoacetyl)-3-methoxyphenothiazi ne (46) showed the most potent Ca2+ antagonistic activity. Biological activity could be conveniently evaluated by measurement of the peak height of the vanadyl ion (+4 oxidation ion) signal produced by redox reaction between the phenothiazine derivatives and vanadate ion +5 oxidation ion) with ESR spectroscopy.
- Imakura,Konishi,Uchida,Sakurai,Kobayashi,Haruno,Tajima,Yamashita
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p. 500 - 511
(2007/10/02)
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- Studies on some 10-[2-(N,N-disubstituted thiocarbamoylthio)acetyl]phenothiazine derivatives
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Nineteen 10-[2-(N,N-disubstituted thiocarbamolythio)acetyl]phenothiazine derivatives have been synthesized by the reaction of 10-chloroacetylphenothiazine with potassium salt of N,N-disubstituted dithiocarbamic acid derivatives. The structures of the compounds have been elucidated by UV, IR, 1H-NMR spectra and microanalysis. The anticholinergic activity of the compounds was determined by assessing the inhibition of acetylcholine using atropine sulfate as a control. Results are discussed in relation to the activity and structure of the synthesized compounds.
- Palaska,Sarac,Safak,Erdogan,Erol,Alpan
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p. 1453 - 1455
(2007/10/02)
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- Synthesis and Biological Activity of Some New 10-phenothiazines
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Fourteen 10-phenothiazines (IV) have been synthesized via condensation of 10-hydrazino-acetylphenothiazine with substituted benzalacetophenones.These compounds inhibit 33-86percent in vitro activity of rat brain pyruvate oxidase and afford protection against pentylenetetrazol induced seizures in albino mice.However, their anticonvulsant properties are found to be independent of their pyruvate oxidase inhibitory activity.
- Jaiswal, Neelam,Jaiswal, R. K.,Barthwal, J. P.,Kishor, K.
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p. 252 - 253
(2007/10/02)
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- Anticonvulsant activity and selective inhibition of nicotinamide adenine dinucleotide dependent oxidations by 10 (2 arylimino 3 acetylamino 4 thiazolidonyl)phenothiazines
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Several 10 (1 acetyl 4 arylthiosemicarbazido) phenothiazines and their corresponding cyclized 10 (2 arylimino 3 acetylamino 4 thiazolidonyl) phenothiazines were synthesized and characterized by their sharp melting points and elemental analyses. All compounds inhibited nicotinamide adenine dinucleotide (NAD) dependent oxidation of pyruvate and α ketoglutarate selectively, whereas NAD independent oxidation of succinate remained unaltered. All phenothiazine derivatives exhibited anticonvulsant activity, which was reflected by the 20 to 60% protection observed against pentylenetetrazol induced convulsions in mice. The ability of substituted thiosemicarbazido phenothiazines to inhibit cellular respiratory activity was reduced considerably by cyclization to the corresponding substituted thiazolidino phenothiazines. On the other hand, cyclization generally resulted in increased anticonvulsant activity. Thus, the anticonvulsant activity possessed by these substituted phenothiazines bore no relationship with their ability to inhibit selectively the NAD dependent oxidations. Selective inhibition of NAD dependent oxidation of pyruvate and α ketoglutarate in isolated rat brain mitochondria by some 10 (1 acetyl 4 arylthiosemicarbazido) phenothiazines was concentration dependent and competitive in nature.
- Singh,Ali,Auyong,Parmar,De Boer
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p. 391 - 396
(2007/10/04)
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