- Chromophore-linked substrate (CLS405): Probing metallo-β-lactamase activity and inhibition
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Serine- and metallo-β-lactamases present a threat to the clinical use of nearly all β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems. Efforts to develop metallo-β-lactamase (MBL) inhibitors require suitable screening platforms to allow the rapid determination of β-lactamase activity and efficient inhibition. Unfortunately, the platforms currently available are not ideal for this purpose. Further progress in MBL inhibitor identification requires inexpensive and widely applicable assays. Herein the identification of an inexpensive and stable chromogenic substrate suitable for use in assays of clinically relevant MBLs is described. (6R,7R)-3-((4-Nitrophenoxy)methyl)-8-oxo-7-(2-phenylacetamido) -5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5,5-dioxide (CLS405) was synthesised in a three-step protocol. CLS405 was then characterised spectroscopically, and its stability and kinetic properties evaluated. With a Δλmax value of 100 nm between the parent and hydrolysis product, a higher analytical accuracy is possible with CLS405 than with commonly used chromogenic substrates. The use of CLS405 in assays was validated by MBL activity measurements and inhibitor screening that resulted in the identification of N-hydroxythiazoles as new inhibitor scaffolds for MBLs. Further evaluation of the identified N-hydroxythiazoles against a panel of clinically relevant MBLs showed that they possess inhibitory activities in the mid- to low-micromolar range. The findings of this study provide both a useful tool compound for further inhibitor identification, and novel scaffolds for the design of improved MBL inhibitors with potential as antibiotics against resistant strains of bacteria. Monitoring MBLs! Resistance to β-lactam antibiotics, mediated by metallo-β-lactamases (MBLs), is an increasing clinical problem. While compounds that target MBLs could be useful antibacterial agents, their identification is hampered by the lack of suitable assay platforms. To this end, CLS405, a chromophore-linked MBL substrate, was developed and its applicability demonstrated by the identification of N-hydroxythiazoles as potential inhibitors against a panel of clinically relevant MBLs. Copyright
- Makena, Anne,Van Berkel, Sander S.,Lejeune, Clarisse,Owens, Raymond J.,Verma, Anil,Salimraj, Ramya,Spencer, James,Brem, Juergen,Schofield, Christopher J.
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- Synthesis and evaluation of novel coumarin-oxime ethers as potential anti-tubercular agents: Their DNA cleavage ability and BSA interaction study
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As a contribution to the development of novel coumarin-oxime ether conjugates with therapeutically interesting properties, a series of coumarin-oxime ether (1a–1j) was synthesised using SN2 reaction of bromomethyl coumarins with butane-2,3-dione monoxime. Invitro anti-tuberculosis activityagainstMTBH37Rv strain was established for the coumarin-oxime ether (1a–1j). Most of the compounds exhibited significant activity with minimum inhibitory concentration (MIC)in the range of 0.04–3.12 μg mL?1. Compound (1h) was identified as a hit candidate exhibiting MIC of 0.04 μg mL?1, closer to the MIC value of Isoniazid (0.02 μg mL?1), a commercially available drug for the treatment of tuberculosis. Compound 1h also displayed a low level of toxicity in Vero cells along with a good safety profile in vitro. Compounds that showed potent anti-tubercular activity were also found to cleave DNA more efficiently and thereby exhibit nuclease activity. The most active compound (1h) was further studied to deduce the mode of interaction with model serum protein, bovine serum albumin (BSA).
- Reddy, Dinesh S.,Kongot, Manasa,Netalkar, Sandeep P.,Kurjogi, Mahantesh M.,Kumar, Rakesh,Avecilla, Fernando,Kumar, Amit
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- A facile synthesis and evaluation of new biomolecule-based coumarin-thiazoline hybrids as potent anti-tubercular agents with cytotoxicity, DNA cleavage and X-ray studies
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An efficient and rapid synthesis of coumarin-thiazoline hybrids (1a-1j) under microwave irradiation is described with high yields. The synthesized compounds were characterized using elemental and spectroscopic analysis; in addition, the structures of compounds 1a, 1b, 1e and 1h have been elucidated using single crystal X-ray diffraction techniques. All the newly synthesized compounds were screened for their in vitro anti-tubercular activity and in a DNA cleavage study, while the most active compounds were subjected to a cytotoxicity assay on Vero cell lines. Among those tested, compound 1b exhibited excellent anti-tubercular activity (MIC 0.09 μg ml-1) with a low level of cytotoxicity, suggesting that compound 1b is a promising lead for subsequent investigations in search of new anti-tubercular agents. Furthermore, a DNA cleavage study using an agarose gel electrophoresis method revealed that compounds 1b, 1d, 1f and 1i cleaved DNA more efficiently and thereby exhibit nuclease activity.
- Reddy, Dinesh S.,Hosamani, Kallappa M.,Devarajegowda, Hirihalli C.,Kurjogi, Mahantesh M.
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- Fluorescence ratiometric zinc sensors based on controlled energy transfer
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The high-fidelity detection of labile zinc is of central importance for understanding the molecular mechanisms that link zinc homeostasis and human pathophysiology. Fluorescence ratiometric sensors are most suitable for the detection and trafficking of intracellular zinc ions. Here, we report the development of fluorescence ratiometric zinc sensors (HN1 and HN2) based on two-fluorophore platforms. The sensor constructs include blue fluorescent umbelliferone and an energy-accepting chromophore that absorbs the blue fluorescence. Zinc binding was found to promote fluorescence turn-on of the umbelliferone emission by suppression of intramolecular photoinduced electron transfer, thereby facilitating resonance energy transfer to the energy acceptors. The net observables were the fluorescence ratiometric changes, the extent of which depended strongly on the chemical structures of the acceptors. Photophysical investigations, including steady-state and transient photoluminescence spectroscopy, suggested a mechanism for the fluorescent zinc response that involved a combination of the intramolecular electron transfer and the interchromophoric energy transfer. The zinc probes displayed sensing capability that is suitable for the detection of biological zinc ions, with good selectivity, pH tolerance, and appropriate Kd values. Finally, zinc detection was demonstrated by fluorescence ratiometric visualization of exogenously supplied zinc ions in live HeLa cells. The probes enabled the reliable monitoring of zinc equilibration across the cell membrane. The Royal Society of Chemistry 2012.
- Woo, Hana,You, Youngmin,Kim, Taehee,Jhon, Gil-Ja,Nam, Wonwoo
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- Design and Synthesis of Novel C4-Linked Substituted 2H-Chromen-2-one-hypoxanthine Hybrids as Potential Antimicrobial Agents: An Approach to Molecular Docking Studies
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We present here design and synthesis of very efficient, high-yielded?and simple approach of a series of C4-linked coumarin–hypoxanthine pharmacophores 1(a–j) with moderate to excellent in vitro antimicrobial activity. According to earlier studies, potential modification at C4-position of coumarin ring provided excellent bioactive molecules. All the titled compounds were characterized by spectroscopic and elemental analyses. Titled compounds have been developed via systematic tuning of coumarin ring substitutions, which are prepared from the well-known Pechmann condensation reaction. The addition of a pendent nucleobase in hypoxanthine group improved the in vitro antimicrobial activity. Computational studies were also mimicking the potent biomolecules. A good pharmacokinetic profile is suggested by theoretical calculation of absorption, distribution, metabolism, and excretion properties. Therefore, synthesis of these titled compounds provided an insight towards better antimicrobial agents.
- Naik, Soniya D.,Hosamani, Kallappa M.
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- Facile synthesis of β-ketoesters mediated by Sml2: Reformatsky reaction type selfcondensation
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α-Bromoesters are converted to β-ketoesters by treatment with samarium diiodide via self condensation under the mild conditions. The reaction appears to be initiated via the formation of samariun diiodide ester enolate for the Reformatsky reation type.
- Park, Heui Sul,Lee, In Sang,Kim, Yong Hae
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- Biscoumarin–pyrimidine conjugates as potent anticancer agents and binding mechanism of hit candidate with human serum albumin
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In our continuing efforts to develop therapeutically active coumarin-based compounds, a series of new C4–C4′ biscoumarin–pyrimidine conjugates (1a–l) was synthesized via SN2 reaction of substituted 4-bromomethyl coumarin with thymine. All compounds were characterized using spectroscopic techniques, that is, attenuated total reflection infrared (ATR-IR), CHN elemental analysis, and 1H and 13C NMR (nuclear magnetic resonance). In addition, the structure of compound 1d (1,3-bis[(7-chloro-2-oxo-2H-chromen-4-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione) was established through X-ray crystallography. Compounds 1a–l were screened for in vitro anticancer activity against C6 rat glioma cells. Among the screened compounds, 1,3-bis[(6-chloro-2-oxo-2H-chromen-4-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione (1c) was identified as the best antiproliferative candidate, exhibiting an IC50 value of 4.85 μM. All the compounds (1a–l) were found to be nontoxic toward healthy human embryonic kidney cells (HEK293), indicating their selective nature. In addition, the most active compound (1c) displayed strong binding interactions with the drug carrier protein, human serum albumin, and exhibited good solution stability at biological pH conditions. Fluorescence, UV–visible spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism of compound 1c with protein.
- Reddy, Dinesh S.,Kongot, Manasa,Singh, Vishal,Siddiquee, Md. Abrar,Patel, Rajan,Singhal, Nitin K.,Avecilla, Fernando,Kumar, Amit
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- Target-Directed Azide-Alkyne Cycloaddition for Assembling HIV-1 TAR RNA Binding Ligands
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The highly conserved HIV-1 transactivation response element (TAR) binds to the trans-activator protein Tat and facilitates viral replication in its latent state. The inhibition of Tat–TAR interactions by selectively targeting TAR RNA has been used as a strategy to develop potent antiviral agents. Therefore, HIV-1 TAR RNA represents a paradigmatic system for therapeutic intervention. Herein, we have employed biotin-tagged TAR RNA to assemble its own ligands from a pool of reactive azide and alkyne building blocks. To identify the binding sites and selectivity of the ligands, the in situ cycloaddition has been further performed using control nucleotide (TAR DNA and TAR RNA without bulge) templates. The hit triazole-linked thiazole peptidomimetic products have been isolated from the biotin-tagged target templates using streptavidin beads. The major triazole lead generated by the TAR RNA presumably binds in the bulge region, shows specificity for TAR RNA over TAR DNA, and inhibits Tat–TAR interactions.
- Dash, Jyotirmayee,Dutta, Debasish,Paul, Raj,Paul, Rakesh
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- Coumarin tethered cyclic imides as efficacious glucose uptake agents and investigation of hit candidate to probe its binding mechanism with human serum albumin
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A series of novel coumarin-cyclic imide conjugates (1a–1j) were designed and synthesized to evaluate their glucose uptake activity by insulin resistant liver hepatocyte carcinoma (HepG2) cells through 2-NBDG uptake assay. Compounds (1a–1j) were characterised using various analytical methods such as 1H NMR, 13C NMR, IR, GC–MS, elemental and single-crystal X-ray diffraction techniques. Compounds (1a–1j) exhibited 85.21 – 65.80% of glucose uptake and showed low level of cytotoxicity towards human embryonic kidney cells (HEK-293) indicating good selectivity and safety profile. Compound 1f was identified as a hit candidate exhibiting 85.21% of glucose uptake which was comparable with standard antidiabetic drug Metformin (93.25% glucose uptake). Solution stability study under physiological pH conditions ≈ (3.4 – 8.7), indicates that compound 1f is sufficiently stable at varied pH conditions and thereby compatible with bio-physiological environments. Interaction of 1f with human serum albumin (HSA) were also studied which quantifies that compound 1f binds with HSA efficiently through facile binding reaction in solution. Fluorescence, UV–vis spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism of compound 1f with protein.
- Reddy, Dinesh S.,Kongot, Manasa,Singh, Vishal,Maurya, Neha,Patel, Rajan,Kumar Singhal, Nitin,Avecilla, Fernando,Kumar, Amit
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- A Novel Minor Groove Binder as a Potential Therapeutic Agent for Myotonic Dystrophy Type 1
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Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder that is inherited in an autosomal dominant manner. DM1 originates in a (CTG?CAG) repeat expansion in the 3’-UTR of the dystrophia myotonic protein kinase (DMPK) gene on chromosome 19. One of the transcripts, r(CUG)exp, is toxic in various ways. Herein we report a rationally designed small molecule with a thiazole peptidomimetic unit that can serve as a minor groove binder for the nucleic acid targets. This peptide unit linked to two triaminotriazine recognition units selectively binds to d(CTG)exp to inhibit the transcription process, and also targets r(CUG)exp selectively to improve representative DM1 pathological molecular features, including foci formation and pre-mRNA splicing defects in DM1 model cells. As such, it represents a new structure type that might serve as a lead compound for future structure-activity optimization.
- Li, Ke,Krueger, Sarah B.,Zimmerman, Steven C.
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- Synthesis of Substituted 3(2H)-Furanones Using Alkylative Intramolecular Cyclization of Sulfonium Salts
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The facile alkylative intramolecular cyclization of 3-alkoxycarbonyl-2-oxopropyldiphenylsulfonium salts is described. This simple method can be readily applied to the synthesis of a novel family of 4-alkylated 3(2H)-furanones in moderate to high yields under mild conditions via a one-pot process.
- Inagaki, Sho,Ukaku, Mika,Chiba, Akira,Takahashi, Fumi,Yoshimi, Yasuharu,Morita, Toshio,Kawano, Tomikazu
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- Imidazo[1,2-a]pyridin-2-ylacetic acid and two pairs of isomorphous ML 2(H2O)2 dihydrates (M = Ni, Co and Mn, Cd) based on its anion: Syntheses, crystal structures and properties
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Imidazo[1,2-a]pyridin-2-ylacetic acid (HL, 1) and four ML 2(H2O)2·2H2O (M = Ni (2), Co (3), Mn (4), Cd (5)) complexes formed by its anion were synthesized, structurally characterized by single-crystal X-ray diffraction and investigated in terms of their thermal stability. In addition, magnetic properties of 2-4 are reported and the NIR-Vis-UV spectra of 2 and 3 are discussed in details. The crystal of 1 comprises 2D hydrogen bonded networks held in the crystal lattice by weak C-H.
- Dylong, Agnieszka,Sowa, Micha?,Goldeman, Waldemar,?lepokura, Katarzyna,Duczmal, Marek,Wojciechowska, Agnieszka,Matczak-Jon, Ewa
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- A LABORATORY SYNTHESIS OF 4-HYDROXY-2-(5H)-FURANONE (β-TETRONIC ACID)
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A "one pot"-fashioned preparation of 4-hydroxy-2(5H)-furanone (β-tetronic acid) was conducted in 30-40percent overall yield starting from ethyl acetoacetate.
- Momose, Takefumi,Toyooka, Naoki,Takeuchi, Yumi
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- Phosphine-Mediated Iterative Arene Homologation Using Allenes
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A PPh3-mediated multicomponent reaction between o-phthalaldehydes, nucleophiles, and monosubstituted allenes furnishes functionalized non-C2-symmetric naphthalenes in synthetically useful yields. When the o-phthalaldehydes were reacted with 1,3-disubstituted allenes in the presence of PPh2Et, naphthalene derivatives were also obtained in up to quantitative yields. The mechanism of the latter transformation is straightforward: aldol addition followed by Wittig olefination and dehydration. The mechanism of the former is a tandem γ-umpolung/aldol/Wittig/dehydration process, as established by preparation of putative reaction intermediates and mass spectrometric analysis. This transformation can be applied iteratively to prepare anthracenes and tetracenes using carboxylic acids as pronucleophiles.
- Zhang, Kui,Cai, Lingchao,Jiang, Xing,Garcia-Garibay, Miguel A.,Kwon, Ohyun
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- A click chemistry approach for the synthesis of mono and bis aryloxy linked coumarinyl triazoles as anti-tubercular agents
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A series of mono and bis-triazole coumarin hybrids 6aeu and 9aef respectively have been synthesized using 4-(azidomethyl)-2H-chromen-2-ones 5aei and aryl propargyl ethers 2aec/8 employing Click chemistry modified protocol for Azide-Alkyne cycloadditions(CuAAC). Anti-tubercular screening showed moderate activity for mono aryloxy compounds 6aeu with MIC 50-100 μg/mL, whereas the bis compounds 9aef were more effective with MICs between 0.2 and 12.5 μg/mL. Molecular modeling and 3DQSAR measurements using CoMFA and Topomer CoMFA further supported the observed results. The bis compound 9b showed excellent activity with MIC value as low as 0.2 μg/mL.
- Anand, Ashish,Naik, Reshma J.,Revankar, Hrishikesh M.,Kulkarni, Manohar V.,Dixit, Sheshagiri R.,Joshi, Shrinivas D.
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- Design, synthesis, molecular docking, anti-proliferative and anti-TB studies of 2H-chromen-8-azaspiro[4.5]decane-7,9-dione conjugates
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In this work, a series of new 8-[(substituted 2-oxo-2H-chromen-4-yl)methyl]-8-azaspiro[4.5]decane-7,9-dione derivatives (1a - 1l) is synthesized and characterized by 1H NMR, 13C NMR, FT-IR, GC-MS and elemental analysis. In addition, the structure of compound 1k has been elucidated using single crystal X-ray diffraction techniques. The synthesized compounds are screened for their anticancer and anti-TB activity. Preliminary anticancer results showed that compounds (1a- 1l) exhibit moderate to potent activity against MDA-MB-231, A549, HT-29 and Hela cancer cell lines. Compound 1f exhibited the most potent activity against MDA-MB-231cell line with IC50 value of 9.05 μM concentration, compound 1g and 1h showed potent activity against A549 cell line with IC50 value of 7.05 and 13.31 μM concentration respectively. Compound 1j showed good cytotoxicity against Hela cell line with IC50 of 16.14 μM, whereas, compound 1l is found to be moderately active against HT-29 cell line with IC50 of 18.07 μM. Anti-tubercular activity revealed that compound 1c, 1d, 1g, 1h and 1j have significant activity against MTBH37Rv strain with MIC 0.78, 1.56, 0.19, 0.39 and 0.78 μg/mL respectively. Further, to investigate the mechanism of anti-TB activity and detailed intermolecular interactions between the synthesized compounds, molecular docking studies are performed.
- Mane, Smita G.,Reddy, Dinesh S.,Katagi, Kariyappa S.,Kumar, Amit,Munnolli, Ravindra S.,Kadam, Nikhil S.,Akki, Mahesh C.,Nagarajaiah,Joshi, Shrinivas D.
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- Green synthesis of therapeutically active 1,3,4-oxadiazoles as antioxidants, selective COX-2 inhibitors and their in silico studies
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A modest, competent and green synthetic procedure for novel coumarinyl-1,3,4-oxadiazolyl-2-mercaptobenzoxazoles 8i-t has been reported. Analysis of the docked (PDB ID: 5IKR; A-Chain) poses of the compounds illustrated that they adopt identical conformations to the extremely selective COX-2 inhibitor. The biological outcomes as well as computational study suggested that the compounds originated to have elevated resemblance towards COX-2 enzyme than COX-1. The compounds 8i, 8l, 8q, 8r, 8s and 8t emerged as most potent and selective COX-2 inhibitors in contrast with Mefenamic acid. The selectivity index of 8l, 8n and 8r was respectively found to be 33.95, 20.25 and 24.98 which manifested their high selectivity against COX-2. Interestingly, the compounds which were active as COX-2 inhibitors were also active as antioxidant agents.
- Nesaragi, Aravind R.,Kamble, Ravindra R.,Dixit, Shruti,Kodasi, Barnabas,Hoolageri, Swati R.,Bayannavar, Praveen K.,Dasappa, Jagadeesh Prasad,Vootla, Shyamkumar,Joshi, Shrinivas D.,Kumbar, Vijay M.
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- Microwave facilitated one-pot three component synthesis of coumarin-benzoxazole clubbed 1,2,3-triazoles: Antimicrobial evaluation, molecular docking and in silico ADME studies
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4-((4-((Benzo[d]oxazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)methyl)-2H-chromen-2-ones 7k–z were synthesized by conventional as well as microwave irradiation method in order to obtain antimicrobial agents. The present green synthetic protocol explores facile work up procedure with excellent yields (82–92%) and purity. Docking studies exhibited strong binding interactions with enzyme N-myristoyl transferase (PDB ID: 4CAW) with excellent C-score values. Compounds 7k–z were screened for their in vitro antimicrobial activities. The compounds 7w and 7 y exhibited excellent antimicrobial results for all the tested microorganisms at MICs ranging from 3.12 to 6.25 μg/ml in comparison with the marketed drugs.
- Nesaragi, Aravind R.,Kamble, Ravindra R.,Bayannavar, Praveen K.,Metre, Tukaram V.,Kariduraganavar, Mahadevappa Y.,Margankop, Sheetal B.,Joshi, Shrinivas D.,Kumbar, Vijay M.
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p. 3460 - 3472
(2021/10/02)
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- Diastereoselective Synthesis of Z-Alkenyl Disulfides from α-Thiophosphorylated Ketones and Thiosulfonates
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We developed a simple and efficient method for the synthesis of functionalized unsymmetrical Z-alkenyl disulfides under mild conditions in moderate to good yields. The designed method is based on the reaction of α-thiophosphorylated carbonyl compounds with thiotosylates in the presence of a base. The developed method allows the preparation of unsymmetrical Z-alkenyl disulfides bearing additional hydroxy, carboxy, or ester functionalities. (Figure presented.).
- Musiejuk, Mateusz,Doroszuk, Justyna,J?drzejewski, Bartosz,Ortiz Nieto, Gregory,Marin Navarro, Marisol,Witt, Dariusz
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supporting information
p. 618 - 626
(2019/12/24)
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- Synthesis and preliminary evaluation of benzofuran-oxadiazole conjugates as potential antitubercular agents
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In the present study, a series of benzofuran-oxadiazole conjugates 7(a-o) was designed, synthesized and characterized through IR,1H NMR,13C NMR and mass spectral data. All the compounds were screened for preliminary antitubercular activity against Mycobacterium phlei and Mycobacterium tuberculosis H37RV. Among all the target compounds, the compound possessing chlorine (7k, MIC 1.56 μg/mL) and bromine (7m, MIC 1.56 μg/mL) on 6th position of benzofuran showed highest activity against Mycobacterium phlei. Whereas, bromine on either 5th position (7l, MIC 3.125 μg/mL) or 6th position (7m MIC 3.125 μg/mL) on benzofuran exhibited highest activity for Mycobacterium tuberculosis (H37 RV).
- Negalurmath, Veerabhadrayya S.,Kotresh, Obelannavar,Basanagouda, Mahantesha
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p. 965 - 970
(2019/03/07)
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- Click chemistry based regioselective one-pot synthesis of coumarin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones as newer potent antitubercular agents
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Coumarin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones (8k-z) were synthesized via copper(I)-catalyzed azide-alkyne cycloaddition click chemistry. The synthesized hybrid molecules were characterized by spectral studies. Compounds 8k-z were screened for their in vitro anti-TB activity by using the Microplate Alamar Blue assay and for cytotoxicity using the MTT assay. Some of the compounds were found to be most potent against the tested Mycobacterium tuberculosis H37Rv strain with a MIC of 1.60 μg/ml. Further, docking the compounds into the InhA binding pocket showed strong binding interactions and effective overall docking scores were recorded. The drug-likeness and toxicity studies were computed using Molinspiration and Protox, respectively.
- Somagond, Shilpa M.,Kamble, Ravindra R.,Bayannavar, Praveen K.,Shaikh, Saba Kauser J.,Joshi, Shrinivas D.,Kumbar, Vijay M.,Nesaragi, Aravind R.,Kariduraganavar, Mahadevappa Y.
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- Method for preparing cefcapene side chain acid
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The invention relates to a method for preparing cefcapene side chain acid, and belongs to the technical field of refined medical intermediates. The method comprises the following steps: adding ketene dimer into an alcohol organic solvent in the presence of nitrogen, dropwise adding bromine for reaction, adding a mixed liquid of dichloromethane and water for quenching reaction, separating an organic phase, adding acetic acid into the organic phase, dropwise adding propyl aldehyde and an organic alkali catalyst A for reaction, then adding thiourea for reaction, performing vacuum distillation for concentration, adding dichloromethane, di-tert-butyl dicarbonate ester and an organic alkali catalyst B into a concentrated solution for reaction, adding a caustic soda liquid for reaction, cooling, dropwise adding hydrochloric acid for crystallization, filtering, performing drip washing with an isopropanol solution, and drying, thereby obtaining (Z)-2-(2-t-butyloxycarboryl aminothiazole-4-yl)-2-pentenoic acid, that is, the cefcapene side chain acid. As the ketene dimer is adopted as an initial raw material, the method is small in side reaction, high in yield, high in purity of obtained products and gentle in reaction condition, and industrial production can be relatively easily achieved.
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Paragraph 0036; 0037
(2017/07/20)
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- Design, Synthesis, and Anticancer Activity of 3H–benzo[f]chromen-3-one Derivatives
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A series of substituted aminomethylbenzocoumarin derivatives 8a–i have been synthesized, characterized, and structure of compound 8g was confirmed by X-ray single crystal analysis. All the synthesized compounds were tested for their anticancer activity against cancer cell lines A549 (lung carcinoma cell line), MCF7 (breast cancer cell line), and A375 (melanoma cell line). Compounds 8a, 8f, and 8h showed excellent growth inhibitory activity against all three cell lines, respectively. Compounds 8a and 8f were also found to be quite promising at very low concentration as an anticancer agent against MCF7 and A549 cell lines. Compounds 8g and 8i showed excellent antimitotic activity with IC50 0.32 and19.98?nM for A549 cell line.
- Soni, Rina,Umar, Shweta,Shah, Nirav N.,Balkrishnan, Suresh,Soman, Shubhangi S.
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p. 2501 - 2510
(2017/07/25)
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- Oxiracetam synthesis technology
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The invention belongs to the field of pharmaceutical chemicals and particularly relates to an oxiracetam synthesis technology, ethyl acetoacetate and glycine are taken as the raw materials, the ethyl acetoacetate is changed into 4-halogeneated ethyl acetoacetate by halogenation reaction, the 4-halogeneated ethyl acetoacetate and glycine ester formed by the glycine are cyclized to form 2,4-dioxo-1-pyrrolidine acetate, and 4-hydroxy-2-oxo-1-pyrrolidineacetamide is obtained after hydrolysis and aminolysis. According to the oxiracetam synthesis technology, the related raw materials are easy to obtain, and the synthesis technology is simple and has good industrial values.
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Paragraph 0029-0031
(2017/02/28)
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- HETEROCYCLICALLY SUBSTITUTED TRIFLUOROMETHYLPYRIMIDINONES AND THEIR USE
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The present application relates to novel heterocyclically substituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
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Paragraph 0211
(2017/02/24)
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- Diphosphoric acid compounds, and preparation method and application thereof
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The invention discloses compounds disclosed as Formula II. In the Formula II, R is disclosed in the specification, wherein R1 is H, OH or halogen; R2 is disclosed in the specification, n1=0-10, n2=0-10, and n3=0-10; Ar is aryl, arylidene, R99-substituted aryl or R99-substituted arylidene; at least one of R3, R4, R5 and R6 is selenium or sulfur atom, and the rest is carbon or nitrogen atom; and R3, R4, R5 and R6 are connected through a single bond or double bond. As for old patients with osteoporosis, the compounds can keep the osteocyte bone formation and bone destroy at an ideal dynamic balance.
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Paragraph 0169
(2016/10/31)
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- HETEROCYCLIC SUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
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The present application relates to novel heterocyclically substituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
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Paragraph 0499
(2016/10/04)
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- Efficient and Convenient Method for Synthesis of Benzofuran-3-acetic Acids and Naphthafuran-acetic Acids
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Herein, we report an efficient and convenient method for synthesis of benzofuran-3-acetic acids and naphthafuran-acetic acids 5a-p by the reaction of substituted-4-bromomethylcoumarins with aqueous sodium hydroxide at refluxing temperature. The obtained products are characterized by infrared, 1H NMR, 13C NMR, and mass spectral data. Structures 5a and 5e are confirmed by their single x-ray diffraction studies. The advantages of this method are good yields, easy workup, and no chromatographic purifications.
- Basanagouda, Mahantesha,Narayanachar,Majati, Iranna B.,Mulimani, Shiddappa S.,Sunnal, Satish B.,Nadiger, Rohit V.,Ghanti, Ashok S.,Gudageri, Siddeshwar F.,Naik, Ravi,Nayak, Akshata
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p. 2195 - 2202
(2015/09/22)
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- Synthesis, structure-activity relationship of iodinated-4-aryloxymethyl- coumarins as potential anti-cancer and anti-mycobacterial agents
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A series of new iodinated-4-aryloxymethylcoumarins 6, 8 and 10 have been obtained from the reaction of various 4-bromomethylcoumarins 4 with 2-iodophenol 5, 3-iodophenol 7 and 4-iodophenol 9 respectively. All the title compounds were screened for anticancer activity against two cancer cell lines (MDA-MB human adenocarcinoma mammary gland and A-549 human lung carcinoma) and two mycobacterial strains (Mycobacterium tuberculosis H37 RV and Mycobacterium phlei). The SAR results indicate that nine compounds are potent, among these 10h and 10i having chlorine are most effective. This is the first report assigning in vitro anti-mycobacterial, anticancer and structure-activity relationship for this new class of iodinated-4-aryloxymethyl-coumarins.
- Basanagouda, Mahantesha,Jambagi, Vishwanath B.,Barigidad, Nivedita N.,Laxmeshwar, Sandeep S.,Devaru, Venkatesh,Narayanachar
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p. 225 - 233
(2014/02/14)
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- Discovery of PF-5190457, a potent, selective, and orally bioavailable ghrelin receptor inverse agonist clinical candidate
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The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.
- Bhattacharya, Samit K.,Andrews, Kim,Beveridge, Ramsay,Cameron, Kimberly O.,Chen, Chiliu,Dunn, Matthew,Fernando, Dilinie,Gao, Hua,Hepworth, David,Jackson, V. Margaret,Khot, Vishal,Kong, Jimmy,Kosa, Rachel E.,Lapham, Kimberly,Loria, Paula M.,Londregan, Allyn T.,McClure, Kim F.,Orr, Suvi T. M.,Patel, Jigna,Rose, Colin,Saenz, James,Stock, Ingrid A.,Storer, Gregory,Vanvolkenburg, Maria,Vrieze, Derek,Wang, Guoqiang,Xiao, Jun,Zhang, Yingxin
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supporting information
p. 474 - 479
(2014/06/09)
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- DRUG DERIVATIVES
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The present invention relates to derivatives of known active pharmaceutical compounds. These derivatives are differentiated from the parent active compound by virtue of being redox derivatives of the active compound. This means that one or more of the functional groups in the active compound has been converted to another group in one or more reactions which may be considered to represent a change of oxidation state. We refer to these compounds generally as redox derivatives. The derivatives of the invention may be related to the original parent active pharmaceutical compound by only a single step transformation, or may be related via several synthetic steps including one or more changes of oxidation state. In certain cases, the functional group obtained after two or more transformations may be in the same oxidation state as the parent active compound (and we include these compounds in our definition of redox derivatives). In other cases, the oxidation state of the derivative of the invention may be regarded as being different from that of the parent compound. In many cases, the compounds of the invention have inherent therapeutic activity on their own account. In some cases, this activity relative to the same target or targets of the parent compound is as good as or better than the activity which the parent compound has against the target or targets.
- -
-
Paragraph 0252; 0253
(2013/09/12)
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- USE OF GHRELIN RECEPTOR INVERSE AGONISTS OR ANTAGONISTS FOR TREATING SLEEP DISORDERS
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The present invention relates to methods of treating sleep disorders in patients comprising administration of a ghrelin receptor inverse agonist or antagonist. The invention also includes methods of treating sleep disorders comprising the administration of a pharmaceutical composition comprising a ghrelin receptor inverse agonist or antagonist and at least one pharmaceutically acceptable carrier, diluent, or excipient.
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Page/Page column 15
(2014/01/08)
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- DRUG DERIVATIVES
-
The present invention relates to derivatives of known active pharmaceutical compounds. These derivatives are differentiated from the parent active compound by virtue of being redox derivatives of the active compound. This means that one or more of the functional groups in the active compound has been converted to another group in one or more reactions which may be considered to represent a change of oxidation state. We refer to these compounds generally as redox derivatives. The derivatives of the invention may be related to the original parent active pharmaceutical compound by only a single step transformation, or may be related via several synthetic steps including one or more changes of oxidation state. In certain cases, the functional group obtained after two or more transformations may be in the same oxidation state as the parent active compound (and we include these compounds in our definition of redox derivatives). In other cases, the oxidation state of the derivative of the invention may be regarded as being different from that of the parent compound. In many cases, the compounds of the invention have inherent therapeutic activity on their own account. In some cases, this activity relative to the same target or targets of the parent compound is as good as or better than the activity which the parent compound has against the target or targets.
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Page/Page column 81
(2012/05/31)
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- Photochromic fused-naphthopyrans without residual color
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A series of new photochromic fused-naphthopyrans with an alkyl bridge between the pyran ring and the naphthalenic core was synthesized in several steps from 4-(bromomethyl)benzocoumarin. The presence of the alkyl bridge in these new fused-naphthopyrans prevents the formation of one long-lived photoisomer and therefore has a dramatic effect on their photochromic properties: UV irradiation of common naphthopyrans gives rise to two isomeric colored photoisomers, one of which fades very slowly and is responsible for a persistent residual color. UV excitation of these new uncolored fused-naphthopyrans leads to the formation of only one colored photoisomer that fades completely to the uncolored state in few seconds/minutes following a monoexponential decay law, thus avoiding the problem of the residual coloration typically observed with naphthopyrans.
- Sousa, Ceu M.,Berthet, Jerome,Delbaere, Stephanie,Coelho, Paulo J.
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experimental part
p. 3959 - 3968
(2012/06/18)
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- Design, synthesis and characterization of some novel 3-coumarinyl- 5-aryliden-1,3-thiazolidine-2,4-diones and their antioxidant activity
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In our effort to obtain biologically active compounds, new 3,5-disubstituted 1,3-thiazolidine-2,4- diones (5a - r) were synthesized. A series of 5-arylmethylidene-1,3-thiazolidine-2,4-diones (3a - r) were prepared by Knoevenagel reaction from 1,3-thiazolidine-2,4-dione (2) and appropriate aromatic aldehydes. Condensation of 3a - r with 7-hydroxy-4-bromomethyl-2-oxo- 2H-chromene (1) afforded novel 3-(7-hydroxy-2-oxo-2H-chromen-4-ylmethyl)-5- arylidene-1,3-thiazolidine-2,4-diones 5a - r. Compounds 3a - r and 5a - r were evaluated for their antioxidant activity (DPPH free radical scavenging activity).
- Cacic, Milan,Molnar, Maja
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scheme or table
p. 177 - 183
(2011/05/06)
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- 2,3-DIHYDRO-1H-INDEN-1-YL-2,7-DIAZASPIRO[3.5] NONANE DERIVATIVES
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The present invention provides a compound of Formula (I) or a pharmaceutically salt thereof wherein R1, R2, Ra, L, Z, Z1 and Z2 are as defined herein, that act as Ghrelin antagonists or inverse agonists; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by the antagonism of the Ghrelin receptor.
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Page/Page column 29
(2011/10/10)
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- Development of new thiazole-based iridium catalysts and their applications in the asymmetric hydrogenation of trisubstituted olefins
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New thiazole-based chiral N,P-ligands that are open-chain analogues of known cyclic thiazole ligands have been synthesized and evaluated in the iridium-catalyzed asymmetric hydrogenation of trisubstituted olefins. Chirality was introduced into the ligands through a highly diastereoselective alkylation using Oppolzer's camphorsultam as chiral auxiliary. In general, the new catalysts are as reactive and selective as their cyclic counterparts for the asymmetric hydrogenation of various trisubstituted olefins. This journal is The Royal Society of Chemistry.
- Cheruku, Pradeep,Paptchikhine, Alexander,Ali, Muhammad,Neudoerfl, Joerg-M.,Andersson, Pher G.
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p. 366 - 373
(2008/10/09)
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- Synthesis and biological activities of some new fluorinated coumarins and 1-aza coumarins
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A series of new fluorinated coumarins and 1-aza coumarins have been synthesized and the presence of fluorine in these molecules and its effect on their anti-microbial, anti-inflammatory and analgesic activities are discussed. The results of bioassay showed that these newly synthesized compounds containing fluorine exhibit moderate analgesic and excellent anti-inflammatory and potential anti-bacterial and anti-fungal activities, compared to the other halogenated compounds. All the newly synthesized compounds were characterized by elemental analysis, IR, 1H NMR, 13C NMR, 19F NMR, EI-MS, and FAB-MS. The ORTEP diagram of one of the compounds is reported herein.
- Kalkhambkar, Rajesh G.,Kulkarni, Geeta M.,Kamanavalli, Chandrappa M.,Premkumar,Asdaq,Sun, Chung Ming
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experimental part
p. 2178 - 2188
(2009/04/07)
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- Halogenated 4-aryloxymethylcoumarins as potent antimicrobial agents
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Halogenated phenols reacted with various 4-bromomethylcoumarins to furnish the corresponding 4-aryloxymethylcoumarins. Introduction of chloro and methoxy groups in the coumarin ring elicited considerable antimicrobial activity against B. subtilis, E. coli, A. niger and C. albicans. In the aryloxy moiety, the chloro group as a substituent were found to be more active than the corresponding bromo compounds. The growth inhibition was observed even at concentrations of less than 10 μg ml-1 in some cases.
- Shivashankar,Shastri, Lokesh A.,Kulkarni, Manohar V.,Rasal, Vijaykumar P.,Saindane, Deepak M.
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scheme or table
p. 1163 - 1168
(2009/12/25)
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- Photochemical α-bromination of ketones using N-bromosuccinimide: a simple, mild and efficient method
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Aromatic and aliphatic carbonyl compounds undergo facile bromination with N-bromosuccinimide under UV-vis irradiation to give the corresponding α-brominated ketones in good yields, at low temperatures (30 °C), without any catalyst, catalyst support or radical initiator and within a short time.
- Arbuj, Sudhir S.,Waghmode, Suresh B.,Ramaswamy
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p. 1411 - 1415
(2007/10/03)
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- NOVEL THIENOPYRIMIDINE DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to a novel thienopyrimidine derivative having an excellent anti? inflammatory and anti-cancer activity, or a pharmaceutically acceptable salt thereof, a process for the preparation thereof and a pharmaceutical composition comprising the same. The compound according to the present invention strongly inhibits IKB kinase-β (IKK-β) involved in the activation of a transcriptional factor, NF-κB, which is associated with inducing various immune and inflammatory diseases, whereby a composition comprising the compound is a useful therapeutic agent against inflammatory diseases, in particular, arthritis and cancer.
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Page/Page column 63
(2010/11/28)
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- Neurotrophic pyrrolidines and piperidines, and related compositions and methods
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This invention provides compounds having the following general structures: This invention also provides pharmaceutical compositions comprising same and methods of using these compositions to treat and prevent disorders characterized by neuronal damage.
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Page/Page column 66-67
(2010/02/08)
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- Nonselective bromination-selective debromination strategy: Selective bromination of unsymmetrical ketones on singly activated carbon against doubly activated carbon
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(Matrix presented) We have found a new synthetic method for the preparation of the α-bromoketones that are brominated in the less activated terminal position of unsymmetrical ketones. Brominations in short reaction times (kinetically controlled) provided internally brominated compounds as a major product. However, brominations in longer reaction times (thermodynamically controlled) gave more of the terminally brominated compound through the reversible reaction by Br2 and produced hydrogen bromide. Several brominated compounds at the terminal position were successfully prepared through the new synthetic route.
- Choi, Han Young,Chi, Dae Yoon
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p. 411 - 414
(2007/10/03)
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- Generation, electrocyclic ring opening, and unprecedented conversion of a 3-acylaminoazetinone into cis-3,4-disubstituted azetidinones
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An attempt to synthesize the nucleus of cefaclor by insertion of an appropriately functionalized rhodium carbene into a β-lactam N-H bond leads instead to attack at sulfur, followed by fragmentation into a four-membered thietanone and a four-membered 3-acylaminoazetinone. The azetinone undergoes electrocyclic ring opening, with a calculated half-life of 11 s at 40°C, to a trans-disubstituted vinyl isocyanate, but can be trapped by saturated, unsaturated allylic and benzylic alcohols to form 3,4-disubstituted azetidinones in which the cis- isomer predominates.
- Wolfe,Ro,Shi
-
p. 1259 - 1271
(2007/10/03)
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- Stereoselective reduction of alkyl 3-oxobutanoate by carbonyl reductase from Candida magnoliae
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The enantioselective reduction of alkyl 3-oxobutanoates by carbonyl reductase (S1) from Candida magnoliae was investigated. S1 reduced alkyl 4-halo-3-oxobutanoates to the corresponding enantiomerically pure (S)-3-hydroxy esters. Escherichia coli HB101 transformant co-overproducing the S1 and glucose dehydrogenase from Bacillus megaterium, produced optically pure alkyl 4-substituted-3-hydroxybutanoates in a two-phase water/organic solvent system.
- Yasohara, Yoshihiko,Kizaki, Noriyuki,Hasegawa, Junzo,Wada, Masaru,Kataoka, Michihiko,Shimizu, Sakayu
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p. 1713 - 1718
(2007/10/03)
-
- Inhibitors of protein isoprenyl transferases
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Compounds having the formula or a pharmaceutically acceptable salt thereof wherein R1is (a) hydrogen, (b) loweralkyl, (c) alkenyl, (d) alkoxy, (e) thioalkoxy, (f) halo, (g) haloalkyl, (h) aryl-L2—, and (i) heterocyclic-L2—; R2is selected from (a) (b) —C(O)NH—CH(R14)—C(O)OR15, (d) —C(O)NH—CH(R14)—C(O)NHSO2R16, (e) —C(O)NH—CH(R14)-tetrazolyl, (f) —C(O)NH-heterocyclic, and (g) —C(O)NH—CH(R14)—C(O)NR17R18; R3is substituted or unsubstituted heterocyclic or aryl, substituted or unsubstituted cycloalkyl or cycloalkenyl, and —P(W)RR3RR3′; R4is hydrogen, lower alkyl, haloalkyl, halogen, aryl, arylakyl, heterocyclic, or (heterocyclic)alkyl; L1is absent or is selected from (a) —L4—N(R5)—L5—, (b) —L4—O—L5—, (c) —L4—S(O)n—L5— (d) —L4—L6—C(W)—N(R5)—L5—, (e) —L4—L6—S(O)m—N(R5)—L5—, (f) —L4—N(R5)—C(W)—L7—L5—, (g) —L4—N(R5)—S(O)p—L7—L5—, (h) optionally substituted alkylene, (i) optionally substituted alkenylene, (j) optionally substituted alkynylene (k) a covalent bond, (l) and (m) are inhibitors of protein isoprenyl transferases. Also disclosed are protein isoprenyl transferase inhibiting compositions and a method of inhibiting protein isoprenyl transferases.
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- Silyl enol ethers as new protecting groups for alkyl 4-halo-3-oxobutanoates; the preparation of pure (3-alkoxycarbonyl-2-oxopropyl)triphenylphosphonium salts
-
A new method has been developed for the preparation of pure (3-alkoxycarbonyl-2-oxopropyl)triphenyl-phosphonium salts 8. Alkyl 4-bromo-3-oxobutanoates and alkyl 4-chloro-3-oxobutanoates 7 are protected as the trimethylsilyl enol ethers prior to treatment of the resulting bromo(trimethylsilyl enol ether) esters 20c and 21c with triphenylphosphine in toluene and then addition of a little water to give pure (3-isopropoxycarbonyl-2-oxopropyl)triphenylphosphonium bromide 8c. Bromo(silyl enol ether) esters react more efficiently with triphenylphosphine than the chloro(silyl enol ether) esters. tert-Butyldimethylsilyl enol ethers of alkyl 4-bromo-3-oxobutanoates and alkyl 4-chloro-3-oxobutanoates 7 also react with triphenylphosphine. Protection of isopropyl 4-bromo-3-oxobutanoate 7c as the enol acetate followed by subsequent reaction with triphenylphosphine gives (Z)-(2-acetoxy-3-isopropoxycarbonylbut-2-enyl)triphenylphosphonium bromide 17.
- Moorhoff, Cornelis M.
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p. 1987 - 1995
(2007/10/03)
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- Enzymatic Synthesis of Optically Active 2-Carbamoyloxymethyl-1,4-dihydropyridines, (R)-(+)- and (S)-(-)-NB 818
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Racemic dihydropyridines were resolved by enzyme-catalyzed hydrolysis in an organic solvent saturated with water.The chiral derivatives obtained were converted to (S)- and (R)-NB 818.
- Ebiike, Hirosato,Maruyama, Kaori,Achiwa, Kazuo
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p. 1153 - 1156
(2007/10/02)
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