- Staphylococcus aureus rnpa inhibitors: Computational-guided design, synthesis and initial biological evaluation
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Antibiotic resistance is spreading worldwide and it has become one of the most important issues in modern medicine. In this context, the bacterial RNA degradation and processing machinery are essential processes for bacterial viability that may be exploited for antimicrobial therapy. In Staphylococcus aureus, RnpA has been hypothesized to be one of the main players in these mech-anisms. S. aureus RnpA is able to modulate mRNA degradation and complex with a ribozyme (rnpB), facilitating ptRNA maturation. Corresponding small molecule screening campaigns have recently identified a few classes of RnpA inhibitors, and their structure activity relationship (SAR) has only been partially explored. Accordingly, in the present work, using computational modeling of S. aureus RnpA we identified putative crucial interactions of known RnpA inhibitors, and we used this information to design, synthesize, and biologically assess new potential RnpA inhibitors. The present results may be beneficial for the overall knowledge about RnpA inhibitors belonging to both RNPA2000-like thiosemicarbazides and JC-like piperidine carboxamides molecular classes. We evaluated the importance of the different key moieties, such as the dichlorophenyl and the piperidine of JC2, and the semithiocarbazide, the furan, and the i-propylphenyl ring of RNPA2000. Our efforts could provide a foundation for further computational-guided investigations.
- Suigo, Lorenzo,Chojnacki, Michaelle,Zanotto, Carlo,Sebastián-Pérez, Victor,Morghen, Carlo De Giuli,Casiraghi, Andrea,Dunman, Paul M.,Valoti, Ermanno,Straniero, Valentina
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- Mononuclear copper(i) complexes of triphenylphosphine and: N, N ′-disubstituted thioureas as potential DNA binding chemotherapeutics
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In this work, nine new mixed-ligand complexes with the general formula [CuBr(TPP)2Tu1-9] were synthesized. The copper(i) complexes of triphenylphosphine (TPP) and different N,N′-disubstituted thioureas (Tu) were characterized via spectroscopic techniques including Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (1H, 13C, and 31P NMR), and single-crystal X-ray diffraction (SC-XRD). The complexes were synthesized via the direct reaction of bromo(tris(triphenylphosphine)copper(i)) [BrCu(PPh3)3] precursor and thiourea ligand solution under ambient conditions. Complexes 1, 2 and 3 crystallized in a triclinic system with the P1 space group. Each complex is mononuclear, and the copper atom is tetrahedrally attached to two TPP groups through the phosphorous atom, one thiourea molecule through the sulfur atom and one bromine atom. The synthesized compounds were docked with a DNA macromolecule to predict their binding site and it was found that all molecules showed favorable binding to the DNA minor grooves. The DNA interaction studies of the representative complexes demonstrated their efficient DNA binding affinities. Based on the docking and DNA interaction results, complex 7 was found to be the best binder with a docking affinity of 382.2 kJ mol-1 and binding constant of 3.96 × 104 M-1. This compound tends to interact with the minor groove through the bromine atom positioning the side triphenylphosphine rings along the X-axis of the groove while keeping the 1-(2-chlorobenzyl)-3-(3-(trifluoromethyl)phenyl)thiourea ring on the outside.
- Khan, Syed Ishtiaq,Ahmad, Sajjad,Khan, Inayat Ali,Badshah, Amin,Rauf, Muhammad Khawar,Putejo, Jahangir Ali,Siddiq, Muhammad Nasir,Kausar, Samia,Altaf, Ataf Ali
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p. 8925 - 8935
(2021/06/01)
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- Synthesis of Novel Tris-1,2,4-triazole Derivatives and Their Antibacterial Activity
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Abstract: A series of novel 3,3′,3″-[1,3,5-triazine-2,4,6-triyltris(azanediyl)]tris(5-aryl-1H-1,2,4-triazole-1-carbothioamide) derivatives were designed and synthesized through reaction of new tris-thiourea derivatives with thiosemicarbazide and sodium hy
- Ghane, M.,Ghorbani, S. Shiroud,Montazeri, N.,Zeydi, M. M.
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p. 605 - 610
(2021/06/02)
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- Benzoylthioureas: Design, synthesis and antimycobacterial evaluation
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Background: New drugs and strategies to treat tuberculosis (TB) are urgently needed. In this context, thiourea derivatives have a wide range of biological activities, including anti-TB. This fact can be illustrated with the structure of isoxyl, an old anti-TB drug, which has a thiourea as a pharmacophore group. Objective: The aim of this study is to describe the synthesis and the antimycobacterial activity of fifty-nine benzoylthioureas derivatives. Methods: Benzoylthiourea derivatives have been synthesized and evaluated for their activity against Mycobacterium tuberculosis using the MABA assay. After that, a structure-activity relationship study of this series of compounds has been performed. Results and Discussion: Nineteen compounds exhibited antimycobacterial activity between 423.1 and 9.6 μM. In general, we observed that the presence of bromine, chlorine and t-Bu group at the para-position in benzene ring plays an important role in the antitubercular activity of Series A. These substituents were fixed at this position in benzene ring and other groups such as Cl, Br, NO2 and OMe were introduced in the benzoyl ring, leading to the derivatives of Series B. In general, Series B was less cytotoxic than Series A, which indicates that the presence of a substituent at benzoyl ring contributes to an improvement in both antimycobacterial activity and toxicity profiles. Conclusion: Compound 4c could be considered a good prototype to be submitted to further structural modifications in the search for new anti-TB drugs, since it is 1.8 times more active than the first line anti-TB drug ethambutol and 0.65 times less active than isoxyl.
- Abreu, Lethícia O.,Bispo, Marcelle L. F.,Brito, Tiago O.,Gomes, Karen M.,Louren?o, Maria C. S.,Macedo, Fernando,Pereira, Patricia M. L.,Tisher, Cesar A.,Yamada-Ogatta, Sueli F.,de Fátima, ?ngelo
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- Synthesis, characterization and biological activity of some dithiourea derivatives
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Novel dithiourea derivatives have been designed as HIV-1 protease inhibitors using Autodock 4.2, synthesized and characterized by spectroscopic methods and microanalysis. 1-(3-Bromobenzoyl)-3-[2-({[(3-bromophenyl)formami-do]methanethioyl}amino)phenyl]thio
- Frost, Carminita,Hoppe, Heinrich,Hosten, Eric,Isaacs, Michelle,Khanye, Setshaba D.,Krause, Jason,Lobb, Kevin,Odame, Felix,Sayed, Yasien,Tshentu, Zenixole
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p. 764 - 777
(2020/10/02)
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- Synthesis and computational study of new meta- and para-substituted ferrocenyl thioureas as potent protein kinase inhibitors and cytotoxic agents
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The present study describes the synthesis, characterization, DNA binding and in vitro biological evaluation of ferrocene-enhanced thioureas. The new complexes (N1–N6) were prepared by reacting ferrocenyl anilines (A-B) with freshly prepared isothiocyanates in dry acetone. A crystallographic study of N3 revealed a supramolecular structure involving secondary non-covalent interactions (π?H and π?π). The nature and extent of the binding of these complexes with the salmon sperm DNA (SS-DNA) were examined by cyclic voltammetry and UV–Vis spectroscopy. The complexes have strong binding to DNA with binding constants ranging from 9.83 × 103 to 5.76 × 104 M?1. The shifts in the cathodic peak potentials with the addition of DNA in the electrochemical studies of the new complexes are attributed to electrostatic interactions. This observation is an indicator of the oxidizable behavior of the complexes in the presence of DNA. The theoretically calculated energies of the frontier molecular orbitals (EHOMO and ELUMO) and the Mulliken charge distributions for the optimized structures determined by the DFT/B3LYP method correlate well with the electrochemically determined redox potentials (correlation coefficient, 0.986). The computational measurements also led to a close agreement between the calculated and observed vibrational frequencies. The new complexes proved to be good candidates for protein kinase inhibition and cytotoxicity studies.
- Asghar, Faiza,Lal, Bhajan,Badshah, Amin,Butler, Ian S.,Nawaz Tahir, Muhammad
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- Synthesis, carbonic anhydrase inhibitory activity and antioxidant activity of some 1,3-oxazine derivatives
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(Table presented.). A series of 1-(6-methyl-2-substituted phenyl-4-thioxo-4H-1,3-oxazin-5-yl)ethanones (3a-n) were synthesized by the reaction of benzoyl isothiocyanates with active methylene compound acetylacetone in the presence of triethyl amine in a one-pot process. The structures of the products were elucidated by elemental analyses, FT-IR, 1H NMR, 13C NMR, and mass spectroscopy. These new 1,3-oxazine derivatives were evaluated for their inhibitory activity against carbonic anhydrase II. Results for in vitro assay revealed that compound 3b having 4-methoxy phenyl moiety was the most potent inhibitor with IC50 value of 0.144 ± 0.008 μM. It exhibited higher enzyme inhibitory activity as compared to the standard acetazolamide (IC50 = 0.997 ± 0.061 μM). The compounds 3c, 3h, and 3n also displayed superior inhibitory activities compared to the rest of the synthesized oxazine derivatives. The radical scavenging activity of oxazine derivatives was also performed and it was found that compounds showed moderate antioxidant activity. Lipinski rule confirmed the therapeutic potential of the synthesized compounds. Molecular docking studies were also performed to further understand the binding affinity of these compounds with PDBID 1V9E which confirmed that the synthesized derivatives bind in the active binding site of the target protein. Based upon our results, it is proposed that compound 3b may serve as a lead structure to design more potent carbonic anhydrase inhibitors.
- Qamar, Rabia,Saeed, Aamer,Saeed, Maria,Ashraf, Zaman,Abbas, Qamar,Hassan, Mubashir,Albericio, Fernando
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p. 352 - 361
(2018/10/20)
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- Biologically active: Halo -substituted ferrocenyl thioureas: Synthesis, spectroscopic characterization, and DFT calculations
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In our search for new therapeutic agents, ferrocene-based thioureas (M1-M9) were successively synthesized and characterized by various analytical techniques like FT-IR, Raman, CHNS, AAS, and multinuclear (1H and 13C) NMR. The interac
- Asghar, Faiza,Rana, Sadaf,Fatima, Saira,Badshah, Amin,Lal, Bhajan,Butler, Ian S.
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p. 7154 - 7165
(2018/05/04)
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- Synthesis and antitumor activity of novel N-benzoyl-N'-substituted pyrimidinyl (thio)semicarbazide derivatives
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A series of substituted pyrimidinyl (thio)semicarbazide derivatives were designed and synthesized. The antitumor results showed that the activity of thiosemicarbazide compounds (series II) was generally higher than that of the corresponding semicarbazide derivatives (series I). Among them, IIk displayed higher cytotoxicity against HL-60, BGC-823 and Bel-7402 than that of adriamycin and exhibited broad in vitro cytotoxicity against 13 human tumor cell lines. Meanwhile, the cytotoxic selectivity and anti-multidrug resistance were evaluated, and IIk exhibited selective cytotoxicity against cancer cells in comparison to human normal cells and had significant anti-multidrug resistance capability. The bioassay results showed that IIk showed great promise as a potent lead compound for further antitumor discovery.
- Song, Gaopeng,Li, Jianzuo,Tian, Hao,Li, Yasheng,Hu, Dekun,Li, Ying,Cui, Zining
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p. 329 - 334
(2016/04/04)
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- Solution-phase microwave assisted parallel synthesis, biological evaluation and in silico docking studies of N,N′-disubstituted thioureas derived from 3-chlorobenzoic acid
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A facile and robust microwave-assisted solution phase parallel synthesis protocol was exercised for the development of a 38-member library of N,N′-disubstituted thiourea analogues (1–38) by using an identical set of conditions. The reaction time for synthesis of N,N′-disubstituted thiourea analogues was drastically reduced from a reported duration of 8–12 h for conventional methods to only 1.5–2.0 min. All the derivatives (1–38) were characterized by physico-analytical techniques such as elemental analysis in combination with FT-IR,1H,13C NMR and by single crystal XRD analysis have also been performed. These compounds were screened for their in vitro urease inhibition activities. Majority of compounds exhibited potent urease inhibition activities, however, the most significant activity was found for 16, with an IC50value of 1.23 ± 0.1 μM. Furthermore, the synthesized compounds were screened for their cytotoxic potential against lungs cancer cell lines. Cell culture studies demonstrated significant toxicity of the compounds on the cell lines, and the levels of toxicity were altered in the presence of various side groups. The molecular docking studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the urease enzymes. These compounds have a great potential and significance for further investigations.
- Rauf, Muhammad Khawar,Zaib, Sumera,Talib, Ammara,Ebihara, Masahiro,Badshah, Amin,Bolte, Michael,Iqbal, Jamshed
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p. 4452 - 4463
(2016/08/23)
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- Structure-Activity Relationships and Anti-inflammatory Activities of N-Carbamothioylformamide Analogues as MIF Tautomerase Inhibitors
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Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is an attractive therapeutic target for the treatment of inflammatory diseases. In our previous study, 3-[(biphenyl-4-ylcarbonyl)carbamothioyl]amino benzoic acid (compound 1) was discovered as a potent inhibitor of MIF by docking-based virtual screening and bioassays. Here, a series of analogues of compound 1 derived from similarity search and chemical synthesis were evaluated for their MIF tautomerase activities, and their structure-activity relationships were then analyzed. The most potent inhibitor (compound 5) with an IC50 of 370 nM strongly suppressed lipopolysaccharide (LPS)-induced production of TNF-α and IL-6 in a dose-dependent manner and significantly enhanced the survival rate of mice with LPS-induced endotoxic shock from 0 to 35% at 0.5 mg/kg and to 45% at 1 mg/kg, highlighting the therapeutic potential of the MIF tautomerase inhibition in inflammatory diseases.
- Zhang, Yu,Xu, Lei,Zhang, Zhiqiang,Zhang, Zhiyu,Zheng, Longtai,Li, Dan,Li, Youyong,Liu, Feng,Yu, Kunqian,Hou, Tingjun,Zhen, Xuechu
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p. 1994 - 2004
(2015/10/06)
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- Synthesis, structural characterization, DNA binding and antioxidant potency of new ferrocene incorporated acyl ureas
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In this article, we have reported the synthesis of three new ferrocene incorporated ureas namely; 1-(4-Chlorobenzoyl)-3-(4-ferrocenylphenyl)urea (P4Cl), 1-(3-Chlorobenzoyl)-3-(4-ferrocenyl phenyl)urea (P3Cl) and 1-(2-Chlorobenzoyl)-3-(4-ferrocenylphenyl)urea (P2Cl). All new compounds were unambiguously characterized by common analytical techniques (NMR, FT-IR, AAS, CHNS and molecular docking). Furthermore, single crystal XRD analysis was done for 1-(3-Chlorobenzoyl)-3-(4-ferrocenylphenyl)urea. DNA binding is a pre-requisite for a compound to be used as an antitumor agent. The DNA binding study was done by cyclic voltammetry, UV-vis spectroscopy and viscometry. The drug-DNA binding constant was found to vary in the sequence: KP2Cl (6.056 × 104 M-1) > KP4Cl (5.713 × 104 M-1) > KP3Cl (4.631 × 104 M-1). Diffusion coefficient of the drug-DNA adduct for all the compounds is lower than the free drug, indicating that drug-DNA adduct is of higher molecular weight and slow diffusing as compared to the free drug. Small binding site size of 0.440 (P3Cl), 0.585 (P4Cl) and 0.673 (P2Cl) base pairs is consistent with electrostatic interaction. All the compounds exhibited good antioxidant activities with IC50 values of 82, 136 and 54 μM for P4Cl, P3Cl and P2Cl respectively, against DPPH.
- Asghar, Faiza,Badshah, Amin,Hussain, Raja Azadar,Sohail, Manzar,Akbar, Kamran,Butler, Ian Sydney
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p. 131 - 139
(2015/09/07)
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- Design, syntheses and evaluation of benzoylthioureas as urease inhibitors of agricultural interest
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Urea is one of the most used nitrogen fertilizers worldwide. However, occurrence of urea hydrolysis to ammonia and carbon dioxide on soil surface, catalyzed by soil ureases, considerably reduces nitrogen availability to crops. In this study, we describe the design, synthesis and screening of sixty five benzoylthioureas (BTUs) for their ability to inhibit purified jack bean and soil ureases. BTUs were readily obtained in one pot, two steps synthesis with no need of cumbersome procedures for product purification. In vitro assays revealed BTUs 11, 12, 14, 19-22 and 37 as the most active jack bean urease inhibitors. Such BTUs were found to be able to bind to both catalytic and allosteric sites of urease, acting therefore as mixed-type inhibitors. Out of 28 compounds that effectively inhibited soil ureases activity, BTUs 3, 6, 10, 12, 16, 19 and 22 were determined to be more potent than the reference inhibitor N-(butyl) thiophosphoric triamide (NBPT; 40%). The other 22 BTUs were as potent as NBPT on soil ureases. The temperature-tolerance of BTUs, along with their ability to inhibit soil ureases, makes of this class of compounds potential additive for urea-based fertilizers.
- Brito, Tiago O.,Souza, Aline X.,Mota, Yane C. C.,Morais, Vinicius S. S.,De Souza, Leandro T.,De Fátima, ?ngelo,Macedo, Fernando,Modolo, Luzia V.
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p. 44507 - 44515
(2015/06/02)
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- Straightforward Approach Toward Dihydrothiazoles via Intramolecular Bromocyclization
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An intramolecular bromonium ion-assisted cyclization with sulfur as an internal nucleophile is described. Starting from benzoyl chlorides, this method provides an easy procedure for the synthesis of dihydrothiazole derivatives in moderate to good yields.
- Sadat-Ebrahimi, Seyed Esmail,Ganjizadeh Zarj, Marzieh,Moghimi, Setareh,Yahya-Meymandi, Azadeh,Mahdavi, Mohammad,Arab, Saman,Shafiee, Abbas,Foroumadi, Alireza
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p. 2142 - 2147
(2015/09/01)
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- Design, synthesis, molecular docking studies and in vitro screening of ethyl 4-(3-benzoylthioureido) benzoates as urease inhibitors
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Thioureas are exceptionally versatile building blocks towards the synthesis of wide variety of heterocyclic systems, which also possess extensive range of pharmacological activities. The substituted benzoic acids were converted into corresponding acid chlorides, these acid chlorides were then treated with potassium thiocyanate in acetone and then the reaction mixture was refluxed for 1-2 h afford ethyl 4-(3-benzoylthioureido)benzoates thioureas in good yields. All the newly synthesized compounds were evaluated for their urease inhibitory activities and were found to be potent inhibitors of urease enzyme. Compounds 1f and 1g were identified as the most potent urease inhibitors (IC50 0.21 and 0.13 μM, respectively), and was 100-fold more potent than the standard inhibitors. Further molecular docking studies were carried out using the crystal structure of urease to find out the binding mode of the inhibitors with the enzyme.
- Saeed, Aamer,Khan, Muhammad Siraj,Rafique, Hummera,Shahid, Mohammad,Iqbal, Jamshed
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- New aminobenzenesulfonamide-thiourea conjugates: Synthesis and carbonic anhydrase inhibition and docking studies
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A variety of 1-substituted-3-(3-aminosulfonylphenyl)thioureas (3a-k) and two new 1-aroyl-3-(4-aminosulfonylphenyl)thiourea derivatives (5a and 5b) were synthesized by reaction of 3-aminobenzenesulfonamide and 4- aminobenzenesulfonamide respectively with f
- Zaib, Sumera,Saeed, Aamer,Stolte, Karin,Fl?rke, Ulrich,Shahid, Mohammad,Iqbal, Jamshed
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p. 140 - 150
(2014/04/17)
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- Synthesis, biological evaluation and docking study of 3-aroyl-1-(4- sulfamoylphenyl)thiourea derivatives as 15-lipoxygenase inhibitors
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A series of 3-aroyl-1-(4-sulfamoylphenyl)thiourea derivatives containing sulfonamide moiety were designed and synthesized as 15-lipoxygenase (15-LOX) inhibitors. Most synthesized compounds showed potent activity against soybean 15-LOX with IC50
- Mahdavi, Mohammad,Shirazi, Maryam Shahzad,Taherkhani, Raana,Saeedi, Mina,Alipour, Eskandar,Moghadam, Farshad Homayouni,Moradi, Alireza,Nadri, Hamid,Emami, Saeed,Firoozpour, Loghman,Shafiee, Abbas,Foroumadi, Alireza
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p. 308 - 313
(2014/06/24)
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- Synthesis of new N-[3-(Benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene] substituted benzamides
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A series of novel N -[3-(2-benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)- ylidene] substituted benzamides (2a-k) were efficiently synthesized by heterocyclization of the corresponding 1-(benzo[d]thiazol-2-yl)-3-aroylthioureas (1a{k). The cyclization was achieved by the reaction of α-bromoacteone produced in situ using bromine in dry acetone in the presence of triethylamine. TUeBITAK.
- Saeed, Aamer,Rafique, Hummera
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p. 909 - 916
(2013/12/04)
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- Novel and efficient cyclization procedure for the synthesis of 2,5-disubstituted-1,3,4-thiadiazoles without using any ring-closing reagents
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A novel method for the synthesis of 2,5-disubstituted-1,3,4-thiadiazoles via direct ring closure of 1,6-disubstituted-2,5-dithioureas in dimethylformanide without using any ring-closing reagents has been accidentally discovered. Repeated and extended experiments confirmed that this is a very simple and efficient way to synthesize these kinds of fine chemicals. A series of novel 2,5-disubstituted-1,3,4-thiadiazoles have been synthesized via this method in good yields.
- Lin, Qi,Zhang, You-Ming,Li, Man-Lin,Wei, Tai-Bao
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p. 3251 - 3260
(2012/09/10)
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- SAR analysis of a series of acylthiourea derivatives possessing broad-spectrum antiviral activity
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A series of acylthiourea derivatives were designed, synthesized, and evaluated for broad-spectrum antiviral activity with selected viruses from Poxviridae (vaccinia virus) and two different genera of the family Bunyaviridae (Rift Valley fever and La Cross
- Burgeson, James R.,Moore, Amy L.,Boutilier, Jordan K.,Cerruti, Natasha R.,Gharaibeh, Dima N.,Lovejoy, Candace E.,Amberg, Sean M.,Hruby, Dennis E.,Tyavanagimatt, Shanthakumar R.,Allen III, Robert D.,Dai, Dongcheng
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scheme or table
p. 4263 - 4272
(2012/07/17)
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- Synthesis, characterization of some new 1-aroyl-3-(4-aminosulfonylphenyl) thioureas and crystal structure of 1-(3,4,5-trimethoxybenzoyl)- 3-(4-aminosulfonylphenyl)thiourea
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A small library of novel 1-aroyl-3-(4-aminosulfonylphenyl)thiourea derivatives was synthesized by the reaction of sulfanilamide with substituted aroyl isothiocyanates in dry acetonitrile. The scope of the reaction was indicated by the synthesis of 1-undecanoyl-3-(4-aminosulfonylphenyl)thiourea, an acyl derivative involving alkanoyl isothiocyanate. All the compounds have been characterized by analytical and spectroscopic methods and in one case by single-crystal X-ray diffraction data.
- Saeed, Aamer,Mumtaz, Amara,Ishida
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experimental part
p. 45 - 54
(2012/01/06)
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- A novel series of 2,5-disubstituted 1,3,4-thiadiazoles as potential anticonvulsant agent
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In pursuit for better antiepileptic drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-thiadiazoles as anticonvulsant pharmacophore, a series of novel N-({5-[(6-methyl-1-benzofuran-3-yl)methyl]-1,3,4-thiadiazol-2-yl}carbamothioyl)-2/3/4-substitutedbenzamide were designed, synthesized and evaluated for their anticonvulsant activity. The findings of the present studies confirmed that the pharmacophore model with four binding sites is crucial for anticonvulsant activity. Structure-activity relationships among synthesized compounds were also established.
- Rajak, Harish,Behera, Chinmay K.,Pawar, Rajesh S.,Singour, Pradeep K.,Kharya, Murli Dhar
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p. 1149 - 1152
(2011/10/08)
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- Aroylguanidine-based factor Xa inhibitors: The discovery of BMS-344577
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We report the design and synthesis of a novel class of N,N′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC50 = 4 nM, EC2×PT = 7 μM). However, the potent CYP3A4 inhibition activity (IC50 = 0.3 μM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC50 = 9 nM, EC2×PT = 2.5 μM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
- Shi, Yan,Li, Chi,O'Connor, Stephen P.,Zhang, Jing,Shi, Mengxiao,Bisaha, Sharon N.,Wang, Ying,Sitkoff, Doree,Pudzianowski, Andrew T.,Huang, Christine,Klei, Herbert E.,Kish, Kevin,Yanchunas Jr., Joseph,Liu, Eddie C.-K.,Hartl, Karen S.,Seiler, Steve M.,Steinbacher, Thomas E.,Schumacher, William A.,Atwal, Karnail S.,Stein, Philip D.
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scheme or table
p. 6882 - 6889
(2010/07/03)
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- Synthesis and crystal structure of some novel 2-aroylimino-3-aryl-4-phenyl- 1,3-thiazolines
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An efficient synthesis of some novel 2-aroylimino-3-aryl-4-phenyl-1,3- thiazolines was carried out by base-catalyzed cyclization of 1-aroyl-3-arylthioureas with acetophenone in the presence of bromine. The structures were confirmed by spectroscopic data,
- Saeed, Aamer,Zaman, Sabah,Bolte, Michael
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p. 2185 - 2199
(2008/09/21)
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- Synthesis and bioactivity study of 2,5-bismercapto-1,3,4-thiadiazole heterocyclic derivatives
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A series of acylhydrazone compounds 3a-i and acylthiosemicarbazides 4a-h containing thiadiazole rings have been synthesized conveniently in high yields. Some heterocyclic derivatives 5 are prepared by the method of dehydration of compounds 4. Structure of all these compounds have been confirmed by elemental analysis, IR, 1H and 13C NMR. The bioassay result indicates that some compounds have relatively low antibacterial activity and other compounds have bioactivity for improving plant growth.
- Li, Man-Lin,Zhang, You-Ming,Wei, Tai-Bao
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p. 544 - 549
(2008/09/18)
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- The synthesis of 1-(1-phenyl-1H-tetrazole-5-ylthiol)-acetyl-4-aroyl- thiosemicarbazides and 2-aroylamino-5-(1-phenyl-1H-tetrazole-5-ylthiolmethylene) - 1,3,4-thiadiazoles
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A series of 1-(1-phenyl-1H-tetrazole-5-ylthiol)acetyl-4- aroylthiosemicarbazides were synthesized in good to excellent yields under phase transfer catalytic conditions. By the cyclization of compounds 3a-i in concentrated H2SO2 at 0°
- Wei, Tai-Bao,Li, Man-Lin,Lin, Qi,Liu, Hong,Zhang, You-Ming
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p. 1583 - 1592
(2007/10/03)
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- Reaction of stable trialkylsilyl esters with Ph3P(SCN)2: A novel method for the preparation of acyl and aroyl isothiocyanates under neutral condition
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An efficient, mild and novel method is described for one-pot conversion of stable triisopropylsilyl- and tert-butyldimethylsilyl carboxylates to their corresponding acyl- or aroyl isothiocyanates using in-situ generation of Ph3P(SCN)2 at room temperature under neutral condition. This method has also been applied for the high yield preparation of 2-thioxo-3,4-dihydro-2H-1,3-benzoxazine-4-one, which has fungicidal and bactericidal activities.
- Iranpoor,Firouzabadi,Shaterian
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p. 3653 - 3657
(2007/10/03)
-