- Development of the Convergent, Kilogram-Scale Synthesis of an Antibacterial Clinical Candidate Using Enantioselective Hydrogenation
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Early chemical development studies into the best way of assembling AZD9742, an antibacterial drug candidate, have involved swapping the order of two reductive aminations. The orthogonally functionalized aminopiperidine partner for these couplings is now enantioselectively synthesized using ruthenium-catalyzed asymmetric hydrogenation. The challenge of controlling defluorination through an appropriate catalyst choice has hitherto prevented this revised sequence from reaching its full potential. However, it is still shown to allow access to the active pharmaceutical ingredient in a stereochemically pure form and has been demonstrated on a multikilogram scale. The reductive aminations in both the original and revised sequences provided different scale-up challenges, and the solutions implemented are described.
- Benson, Helen,Bones, Karen,Churchill, Gwydion,Ford, Gair,Frodsham, Lianne,Janbon, Sophie,Millington, Fiona,Powell, Lyn,Raw, Steven A.,Reid, Julie,Stark, Andrew,Steven, Alan
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p. 588 - 598
(2020/05/19)
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- Functionality study of chalcone-hydroxypyridinone hybrids as tyrosinase inhibitors and influence on anti-tyrosinase activity
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In an attempt to synthesise new tyrosinase inhibitors, we designed and synthesised a series of chalcone-hydroxypyridinone hybrids as potential tyrosinase inhibitors adopting strategic modifications of kojic acid. All the newly synthesised compounds were characterised by NMR and mass spectrometry. Initial screening of the target compounds demonstrated that compounds 1a, 1d, and 1n had relatively strong inhibitory activities against tyrosinase monophenolase, with IC50 values of 3.07 ± 0.85, 2.25 ± 0.8 and 2.75 ± 1.19 μM, respectively. The inhibitory activity against monophenolase was 6- to 8-fold higher than that of kojic acid. Compounds 1a, 1d, and 1n also showed inhibition of diphenolase, with IC50 values of 17.05 ± 0.07, 11.70 ± 0.03 and 19.3 ± 0.28 μM, respectively. The inhibition kinetics of diphenolase indicates that compounds 1a and 1d induce reversible inhibition on tyrosinase. Finally, we found that copper coordination should be one of the important inhibitory mechanism of these compounds in tyrosinase.
- Singh, L. Ravithej,Chen, Yu-Lin,Xie, Yuan-Yuan,Xia, Wei,Gong, Xing-Wen,Hider, Robert C.,Zhou, Tao
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p. 1562 - 1567
(2020/08/07)
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- Novel compounds that are inhibitors of YAP/TAZ-TEAD interaction and their use in the treatment of malignant mesothelioma
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These compounds are useful as inhibitors of the YAP/TAZ-TEAD interaction.
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- Hydroxypyridinone derivative of aza-chalcone structure, preparation method and application
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The invention discloses a hydroxypyridinone derivative of an aza-chalcone structure. According to a structural formula I, X is O and N-CnH2N+1(n=0-12); R2 is H, 4-F, 2-OH, 4-OCH3, 3,4-di-OCH3 and 3,4-di-OH. The invention further discloses a preparation me
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Paragraph 0031-0033
(2019/10/02)
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- Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections
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Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated monosulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure-activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.
- Tan, Liang,Tao, Yunliang,Wang, Ting,Zou, Feng,Zhang, Shuhua,Kou, Qunhuan,Niu, Ao,Chen, Qian,Chu, Wenjing,Chen, Xiaoyan,Wang, Haidong,Yang, Yushe
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p. 2669 - 2684
(2017/04/21)
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- NEW ANTIBACTERIAL COMPOUNDS
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The present invention relates to novel antibacterial compounds, pharmaceutical compositions containing them and their use as antimicrobials.
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Page/Page column 150
(2018/01/19)
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- Tyrosinase inhibitor, preparation method and uses thereof
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The present invention discloses an oxime ether group-containing hydroxypyridone derivative having tyrosinase inhibition activity. The preparation method comprises that the site 5 hydroxy of kojic acid is benzylated, the benzylated kojic acid reacts with a
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Paragraph 0024-0026; 0028-0030
(2017/09/01)
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- Preparation method and uses of multifunctional hydroxypyridone derivative and hydrate thereof
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The invention discloses a multifunctional hydroxypyridone derivative and a hydrate thereof. The preparation method comprises that the site 5 hydroxy of kojic acid is benzylated, the benzylated kojic acid reacts with ammonia water, the site 2 hydroxymethyl
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Paragraph 0031-0032
(2017/09/01)
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- Hydroxypyridinones with enhanced iron chelating properties. Synthesis, characterization and in vivo tests of 5-hydroxy-2-(hydroxymethyl)pyridine- 4(1H)-one
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The synthesis of 5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one (P1) is presented, together with the evaluation of its coordination ability towards Fe3+, studied by a combination of chemical, computational, and animal approaches. The use of complementary analytical techniques has allowed us to give evidence of the tautomeric changes of P1 as a function of pH, and to determine their influence on the coordinating ability of P1 towards Fe3+. The pFe3+ value 22.0 of P1-iron complexes is noticeably higher than that of deferiprone (20.6), one of the three clinical chelating agents in therapeutic use for iron overload diseases. This is due on one side to the tautomeric change to the catechol form, and on the other to the lower protonation constant of the OH group. Bio-distribution studies on mice allowed us to confirm in vivo the efficacy of P1. Furthermore the coordinating ability toward Al3+, Cu2+ and Zn2+ has been studied to evaluate the possible use of P1 against a second toxic metal ion (Al3+), and to envisage its potential influence on the homeostatic equilibria of essential metal ions. The chelating ability of P1 toward these ions, not higher than that of the corresponding deferiprone, contributes to render P1 a more selective iron chelator.
- Lachowicz,Nurchi,Crisponi,Jaraquemada-Pelaez,Arca,Pintus,Santos,Quintanova,Gano,Szewczuk,Zoroddu,Peana,Domínguez-Martín,Choquesillo-Lazarte
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p. 6517 - 6528
(2016/05/09)
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- Design and synthesis of novel hydroxypyridinone derivatives as potential tyrosinase inhibitors
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Two groups of novel hydroxypyridinone derivatives 6(a-e) and 12(a-c), were designed as potential tyrosinase inhibitors, and synthesized using kojic acid as a starting material. The tyrosinase inhibitory activity of these two groups was demonstrated to be potent, especially compounds 6e and 12a, whose IC50 values for monophenolase activity were 1.95 μM and 2.79 μM, respectively. Both of these values are lower than that of kojic acid (IC50 = 12.50 μM). Compounds 6e and 12a were investigated for the inhibitory effect on diphenolase activity. The results showed that the inhibitory mechanism of these two compounds was reversible and that the inhibitory type was a competitive-uncompetitive mixed-type. The values of IC50 of 6e and 12a on the diphenolase activity of tyrosinase were determined to be 8.97 μM and 26.20 μM, respectively. The inhibitory constants (KI and KIS) of 6e were determined as 17.17 μM and 22.09 μM, respectively; and the KI and KIS values of 12a were 34.41 μM and 79.02 μM, respectively. Compound 6e showed a greater ability to reduce copper and a stronger copper chelating ability than kojic acid.
- Zhao, De-Yin,Zhang, Ming-Xia,Dong, Xiao-Wu,Hu, Yong-Zhou,Dai, Xiao-Yan,Wei, Xiaoyi,Hider, Robert C.,Zhang, Jin-Chao,Zhou, Tao
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p. 3103 - 3108
(2016/06/13)
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- Design, synthesis and anti-HIV-1 evaluation of a series of 5-hydroxypyridine-4-one derivatives as possible integrase inhibitors
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A series of 5-hydroxypyridine-4-one derivatives were synthesized and subjected to HIV-1 replication inhibition assay. Docking studies provide a detailed molecular binding model for this class of compounds interacting with integrase enzyme. All of the deri
- Rostami, Mahboubeh,Sirous, Hajar,Zabihollahi, Rezvan,Aghasadeghi, Mohammad R.,Sadat, Seyed Mehdi,Namazi, Rahele,Saghaie, Lotfollah,Memarian, Hamid R.,Fassihi, Afshin
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p. 4113 - 4127
(2015/11/02)
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- INHIBITORS OF DNA GYRASE FOR THE TREATMENT OF BACTERIAL INFECTIONS
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The present invention relates to compounds which specifically inhibit bacterial DNA Gyrase and can be used for the treatment of respiratory tract infections.
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- The design of efficient and selective routes to pyridyl analogues of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde
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This Letter describes the synthetic routes to challenging pyridyl analogues of 2,3-dihydro-1,4-benzodioxin- 6-carbaldehyde which were key intermediates for our antibacterial medicinal chemistry programme. All routes described started from kojic acid (8) and have been used to give multigram quantities of each aldehyde.
- Barfoot, Christopher W.,Brown, Pamela,Dabbs, Steven,Davies, David T.,Hennessy, Alan J.,Miles, Timothy J.,Pearson, Neil D.
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scheme or table
p. 5038 - 5040
(2011/01/04)
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- 5-Quinoline derivatives having an anti-bacterial activity
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The present invention describes novel anti-bacterial compounds of the formula (I). These compounds are, amongst others, of interest as inhibitors of DNA gyrase and topoisomerases, for example of topoisomerase II and IV.
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Page/Page column 12
(2010/12/31)
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- ANTIBACTERIAL AGENTS
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2H-chromen-2-one derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
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Page/Page column 32-33
(2008/06/13)
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- ANTIBACTERIAL AGENTS
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Naphthalene, quinoline, quinoxaline and naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
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Page/Page column 37
(2010/11/25)
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- ANTIBACTERIAL AGENTS
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Naphthyridine and quinoline derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
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Page/Page column 24
(2008/06/13)
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- ANTIBACTERIAL AGENTS
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Naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
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Page/Page column 26
(2008/06/13)
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- ANTIBACTERIAL AGENTS
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Naphthyridine and related derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
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Page/Page column 24
(2008/06/13)
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- ANTIBACTERIAL AGENTS
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Naphthalene, quinoline, quinoxaline and naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
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Page/Page column 94
(2010/02/15)
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- ANTIBACTERIAL AGENTS
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Naphthalene, quinoline, quinoxaline and naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
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Page/Page column 26
(2010/10/20)
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- NOVEL COMPOUNDS HAVING AN ANTI-BACTERIAL ACTIVITY
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The present invention describes novel anti-bacterial compounds of formula (I). These compounds are, amongst others, of interest as inhibitors of DNA gyrase.
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Page/Page column 69-70
(2010/10/20)
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- ANTIBACTERIAL AGENTS
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Naphthalene, quinoline, quinoxaline and naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
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Page/Page column 35
(2010/10/20)
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- COMPOUNDS
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Piperidine derivatives and pharmaceutically acceptable derivatives thereof useful in methods of treatment of bacterial infections in mammals, particularly in man.
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Page/Page column 54
(2008/06/13)
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- ANTIBACTERIAL COMPOUNDS
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Cyclohexane and cyclohexene derivatives and pharmaceutically acceptable derivatives thereof useful in methods of treatment of bacterial infections in mammals, particularly man
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- Compound with platelet aggregation inhibitor activity
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A compound represented by the general formula (I) and a pharmaceutically acceptable salt and solvate thereof having an effect for inhibiting the agglutination of platelets is disclosed: STR1 wherein R1 represents a group --W--(CH2)i --COOR3, R2 represents a hydrogen atom or a group --W--(CH2)i --COOR3 or --OR4, X represents --CH= or --N=, Y represents (i) a group --(CO)k --N(R5)--Z--, wherein Z represents a bond or a group --(CH2)m --CO-- or a group --(CH2)m --CHR6 --, (ii) a group --(CH2)m --N(R5)--(CO)k --, or (iii) a group --(CO)k -Het, wherein Het represents a five- or six-membered heterocyclic ring comprising a nitrogen atom, A represents (i) the following groups (III) or (IV) STR2 B represents a bond, C1-6 alkylene or C2-6 alkenylen.
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- Tetrahydrothienopyridine derivatives as novel GPIIB/IIIA antagonists
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The tetrahydrothienopyridine derivatives were derived from aminomethylcyclohexylcarboxylic acid as a lead moiety. Evaluation of the antiplatelet activity and receptor binding assay revealed that compound 1 (Me3277) was a novel and potent non-peptide and n
- Katano, Kiyoaki,Shitara, Eiki,Shimizu, Masaro,Sasaki, Kazue,Miura, Tomoaki,Isomura, Yasuko,Kawaguchi, Mami,Ohuchi, Shokichi,Tsuruoka, Takashi
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p. 2601 - 2606
(2007/10/03)
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- 2-oxo-1-[[(substituted sulfonyl)amino]carbonyl]azetidines
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Antibacterial activity is exhibited by 2-azetidinones having a 3-acylamino substituent and having an activating group in the 1-position of the formula STR1
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- 3-acylamino-2-oxo-1-azetidinesulfonic acids
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Antibacterial activity is exhibited by 2-azetidinones activated in the 1-position with an --SO3 H group and having in the 3-position an acylamino group of the formula STR1
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- Chemistry of Kojic Acid: One-Step Syntheses of Benzothiazoles and Other Fused Heterocycles from Kojic Acid Derivatives
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The reactions of the benzyl ether (1b) of kojic acid (1a) and its chloromethyl derivative (1c) were investigated as new routes to fused heterocyclic systems.The chloromethyl compound proved the more versatile intermediate yielding benzothiazoles with thio
- Teitei, Tsutomu
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p. 2307 - 2316
(2007/10/02)
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