59649-56-8Relevant academic research and scientific papers
Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria
Moreau, Robert J.,Skepper, Colin K.,Appleton, Brent A.,Blechschmidt, Anke,Balibar, Carl J.,Benton, Bret M.,Drumm, Joseph E.,Feng, Brian Y.,Geng, Mei,Li, Cindy,Lindvall, Mika K.,Lingel, Andreas,Lu, Yipin,Mamo, Mulugeta,Mergo, Wosenu,Polyakov, Valery,Smith, Thomas M.,Takeoka, Kenneth,Uehara, Kyoko,Wang, Lisha,Wei, Jun-Rong,Weiss, Andrew H.,Xie, Lili,Xu, Wenjian,Zhang, Qiong,De Vicente, Javier
supporting information, p. 3309 - 3324 (2018/05/01)
The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli ΔtolC mutant strain.
Design, synthesis and characterization of potent microtubule inhibitors with dual anti-proliferative and anti-angiogenic activities
Zhang, Huijun,Fang, Xiong,Meng, Qian,Mao, Yujia,Xu, Yan,Fan, Tingting,An, Jing,Huang, Ziwei
supporting information, p. 380 - 396 (2018/08/17)
Microtubule has been an important target for anticancer drug development. Here we report the discovery and characterization of a series of fused 4-aryl-4H-chromene-based derivatives as highly potent microtubule inhibitors. Among a total of 37 derivatives synthesized, 23 exhibited strong in vitro anti-proliferative activities against A375 human melanoma cells. The relationship between the biological activities of these microtubule inhibitors and their chemical structure variations was analyzed. Studies of compounds 27a, 19a and 9a in parallel with colchicine as the positive control compound in a panel of biological assays revealed that these compounds blocked cell cycle progression, increased apoptosis, and inhibited HUVEC capillary tube formation at low nanomolar concentrations. The most potent compound 27a was also tested in eight additional cancer cell lines besides A375 cells and two non-cancer cells and showed potent and selective activity on these cancer cells. To understand the molecular and structure mechanism of action of these compounds, tubulin polymerization and molecular docking studies were carried out for 27a as the representative. The results were consistent with the mechanism by which 27a interacts with the colchicine binding site on tubulin and disrupts tubulin polymerization. With potent dual actions of microtubule destabilization and vascular disruption described above, this small molecule can serve as a valuable research probe of the function and role of microtubules in human diseases and promising lead for developing new therapeutic agents.
Exploration of SAR for novel 2-benzylbenzimidazole analogs as inhibitor of transcription factor NF-κB
Boggu, Pulla Reddy,Venkateswararao, Eeda,Manickam, Manoj,Kim, Youngsoo,Jung, Sang-Hun
, p. 469 - 479 (2017/04/13)
A novel series of 2-benzylbenzimidazole analogs was designed, synthesized and investigated for their in vitro activities against LPS induced NF-κB inhibition in RAW 264.7 cells using the SEAP assay. Among them, 4-((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6e, >100% inhibition at 30?μM, IC50?=?3.0?μM), 4-((5-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6j, 96% inhibition at 30?μM, IC50?=?4.0?μM) and 2-((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6k, 95% inhibition at 30?μM, IC50?=?5.0?μM) showed strong inhibitory activity. The structure activity relationship confirmed that the substitution on benzimidazole ring A with hydrophobic cyclohexylmethoxy group at position 4 or 5 markedly enhances the activity. In addition, the hydrophilic hydrogen bonding donor group (OH) at position 2 or 4 on phenyl ring B connected with one methylene spacer to the benzimidazole ring is favorable for the inhibitory activity. However, hydrophobic (–OCH3 and –Cl) groups on phenyl ring B decrease the activity.
Synthesis and biological evaluation of novel analogues of the pan class i phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(Difluoromethyl)-1-[4,6-di(4- morpholinyl)-1,3,5-triazin-2-yl]-1 H -benzimidazole (ZSTK474)
Rewcastle, Gordon W.,Gamage, Swarna A.,Flanagan, Jack U.,Frederick, Raphael,Denny, William A.,Baguley, Bruce C.,Kestell, Philip,Singh, Ripudaman,Kendall, Jackie D.,Marshall, Elaine S.,Lill, Claire L.,Lee, Woo-Jeong,Kolekar, Sharada,Buchanan, Christina M.,Jamieson, Stephen M. F.,Shepherd, Peter R.
experimental part, p. 7105 - 7126 (2011/12/04)
A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2- yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1 -/- mice, and at a dose of 50 mg/kg given by ip injection at a qd ?- 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
NOVEL FLUORINE-CONTAINING DICARBOXYLIC ACIDS AND THEIR NOVEL POLYMER COMPOUNDS
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, (2009/02/11)
Disclosed is a fluorine-containing dicarboxylic acid represented by formula (1), wherein n represents an integer of 1-4, and the two carboxylic groups are not adjacent to each other on the aromatic ring. It is possible to obtain a linear polymer compound by reacting the fluorine-containing dicarboxylic acid with a comonomer (e.g., diaminodiol). By thermal cyclization, this linear polymer compound can be converted into another polymer compound having superior characteristics.
6-HYDROXY-DIBENZODIAZEPINONES USEFUL AS HEPATITIS C VIRUS INHIBITORS
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Page/Page column 49, (2008/12/08)
Inhibitors of HCV replication of formula (I) the stereoisomers, prodrugs, tautomers, racemics, salts, hydrates or solvates thereof wherein R1, R2; R3; R4a and R4b have the meaning defined in the claims.The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use in HCV therapy.
10-SULFONYL-DIBENZODIAZEPINONES USEFUL AS HEPATITIS C VIRUS INHIBITORS
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Page/Page column 37-38, (2008/12/08)
Inhibitors of HCV replication of formula (I) and the stereoisomers, prodrugs, tautomers, racemics, salts, hydrates or solvates thereof, wherein X, Y, R1; R2; R3; R4a and R4b have the meaning defined in the claims. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use in HCV therapy.
Computational design, synthesis and biological evaluation of para-quinone-based inhibitors for redox regulation of the dual-specificity phosphatase Cdc25B
Keinan, Shahar,Paquette, William D.,Skoko, John J.,Beratan, David N.,Yang, Weitao,Shinde, Sunita,Johnston, Paul A.,Lazo, John S.,Wipf, Peter
experimental part, p. 3256 - 3263 (2009/02/05)
Quinoid inhibitors of Cdc25B were designed based on the Linear Combination of Atomic Potentials (LCAP) methodology. In contrast to a published hypothesis, the biological activities and hydrogen peroxide generation in reducing media of three synthetic models did not correlate with the quinone half-wave potential, E1/2.
STUDY OF ELECTROPHILIC SUBSTITUTION AND OXIDATION REACTIONS OF 4- AND 5-HYDROXYBENZO-2,1,3-SELENADIAZOLES
Belen'kaya, I. A.,Sirik, S. A.,Shapiro, Yu. E.,D'yachenko, E. K.
, p. 956 - 961 (2007/10/02)
The halogenation, nitrosation, and oxidation of 4- and 5-hydroxybenzo-2,1,3-selenadiazoles have been studied, as has the acetylation of these hydroxy compounds and their halogen and nitroso derivatives.The structure of the resulting compounds has been demonstrated, and it has been found that the nitroso-substituted derivatives exist primarily in the tautomeric oxime form.
Derivatives of benzimidazoles active as anti-ulcer agents
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, (2008/06/13)
Novel compounds of the general formula I STR1 processes for its preparation, pharmaceutical compositions containing such compounds as the active ingredient and the use of the compounds in medicine.
