- Arylsulfonyl]-1H-indoles: Synthesis, SAR and biological evaluation as a novel class of 5-HT6 Receptor Antagonists
-
In continuation to our efforts to develop better treatment options for cognitive decline, we have been focussing on 5-HT6 receptor (5-HT6R) antagonists, which are known to be involved in improving cognitive function in numerous animal models. In this paper, we report a novel series of [3-[(1-Methylpiperidin-4-yl) methyl] arylsulfonyl]-1H-indole derivatives as potent and selective 5-HT6R antagonists. The lead compound from this series shows potent in vitro binding affinity, functional antagonistic activity at 5-HT6R, good pharmacokinetic profile, excellent selectivity and no Cytochrome P450 liabilities. [Figure not available: see fulltext.]
- Nirogi, Ramakrishna V.S.,Badange, Rajesh Kumar,Kandukuri, Kiran Kumar,Khagga, Mukkanti
-
-
Read Online
- Molecular hybrid design, synthesis and biological evaluation of N-phenyl sulfonamide linked N-acyl hydrazone derivatives functioning as COX-2 inhibitors: New anti-inflammatory, anti-oxidant and anti-bacterial agents
-
Herein, we report the design, synthesis and biological evaluation of the anti-inflammatory activities of N-phenyl sulfonamide linked N-acylhydrazones (NPS-NAH), using the molecular hybridization approach. Hybrid compounds were further validated by theoretical studies. Compound 1f from series-1 and compound 2a from series-2 exhibited strong selective COX-2 enzyme inhibition at IC50 = 8.9 μM and 8.4 μM respectively. Effective in vivo anti-inflammatory profiling of potent and selective COX-2 inhibitors, including compound 1f and 2a was carried out and compared with known COX-2 inhibitors. Subsequently, these compounds were tested for antioxidant activity, and 1h (IC50 = 28.62 μM) from series-1 and compound 2d (IC50 = 25.34 μM) from series-2 were found to be potent anti-oxidants. Additionally, these compounds were screened for antibacterial activity, and compound 1l and 2b exhibited better Gram +ve and -ve anti-bacterial activity than the reference standards, Ciprofloxacin and Norfloxacin. These results validated the idea of exploiting the hybridization strategy for the identification of new N-phenyl sulfonamide-NAH derivatives for optimizing anti-inflammatory, antioxidant and anti-bacterial activities.
- Gorantla, Vasubabu,Gundla, Rambabu,Jadav, Surender Singh,Anugu, Sreenivasa Reddy,Chimakurthy, Jithendra,Nidasanametla, Satya Kameswararao,Korupolu, Raghubabu
-
-
Read Online
- Alternative Strategy to Obtain Artificial Imine Reductase by Exploiting Vancomycin/D-Ala-D-Ala Interactions with an Iridium Metal Complex
-
Based on the supramolecular interaction between vancomycin (Van), an antibiotic glycopeptide, and D-Ala-D-Ala (DADA) dipeptides, a novel class of artificial metalloenzymes was synthesized and characterized. The presence of an iridium(III) ligand at the N-terminus of DADA allowed the use of the metalloenzyme as a catalyst in the asymmetric transfer hydrogenation of cyclic imines. In particular, the type of link between DADA and the metal-chelating moiety was found to be fundamental for inducing asymmetry in the reaction outcome, as highlighted by both computational studies and catalytic results. Using the [IrCp*(m-I)Cl]Cl Van complex in 0.1 M CH3COONa buffer at pH 5, a significant 70% (S) e.e. was obtained in the reduction of quinaldine B.
- Facchetti, Giorgio,Bucci, Raffaella,Fusè, Marco,Erba, Emanuela,Gandolfi, Raffaella,Pellegrino, Sara,Rimoldi, Isabella
-
supporting information
p. 2976 - 2982
(2021/03/01)
-
- Catalyst-controlled site-selective N-H and C3-arylation of carbazoleviacarbene transfer reactions
-
A site-selective direct arylation reaction of carbazole and other N-heterocycles with diazo-naphthalen-2(1H)-ones has been developed. While Au(i)-NHC catalysts lead to selective C3-arylation, palladium acetate allows for selective N-H arylation, displaying complete site-selectivity each. To show the applicability of these arylation reactions, one-pot, two-fold diarylation reactions of carbazole were demonstrated.
- Bahukhandi, Srishti Ballabh,Bera, Sourav Sekhar,Empel, Claire,Koenigs, Rene M.
-
supporting information
p. 6193 - 6196
(2021/06/30)
-
- Design and synthesis of newer N-benzimidazol-2yl benzamide analogues as allosteric activators of human glucokinase
-
Allosteric activators of human glucokinase (GK) had revealed significant hypoglycemic effects for therapy of type-2 diabetes (T2D) in animal as well as human models. Some newer N-benzimidazol-2yl substituted benzamide analogues were prepared and assessed for activation of GK accompanied by molecular docking investigations for predicting the bonding interactions of these derivatives with the residues in allosteric site of GK protein. Amongst the derivatives synthesized, compounds 2 and 7 strongly increased catalytic action of GK (GK activation fold >2.0 in comparison to control) in vitro. The results of in-vitro testing were supported by the molecular docking investigations of these analogues with GK protein’s allosteric site residues (showed appreciable H-bond interactions with Arg63 residue of GK). Derivatives investigated in present study afforded few lead compounds for the discovery of harmless and strong allosteric GK activating compounds for treating T2D.
- Singh, Sukhbir,Arora, Sandeep,Dhalio, Ervon,Sharma, Neelam,Arora, Kunal,Grewal, Ajmer Singh
-
p. 760 - 770
(2021/01/20)
-
- 3-Functionalised benzenesulphonamide based 1,3,4-oxadiazoles as selective carbonic anhydrase XIII inhibitors: Design, synthesis and biological evaluation
-
A new series of benzenesulphonamide linked-1,3,4-oxadiazole hybrids (6a–s) has been synthesized and tested for their carbonic anhydrase inhibition against human (h) carbonic anhydrase (CA) isoforms hCA I, II, IX, and XIII. Fluorescence properties of some of the synthesized molecules were studied. Most of the molecules exhibited significant inhibitory power, comparable or better than the standard drug acetazolamide (AAZ) on hCA XIII. Out of 19 tested molecules, compound 6e (75.8 nM) was 3 times more potent than AAZ (250.0 nM) against hCA I, whereas compound 6e (15.4 nM), 6g (16.2 nM), 6h (16.4 nM) and 6i (17.0 nM) were found to be more potent than AAZ (17.0 nM) against isoform hCA XIII. It is anticipated that these compounds could be taken as the potential leads for the development of selective hCA XIII isoform inhibitors with improved potency.
- Swain, Baijayantimala,Abhay,Singh, Priti,Angeli, Andrea,Aashritha, Kamtam,Nagesh, Narayana,Supuran, Claudiu T.,Arifuddin, Mohammed
-
-
- Design and synthesis of benzenesulfonamide-linked imidazo[2,1-b][1,3,4]thiadiazole derivatives as carbonic anhydrase I and II inhibitors
-
A novel series of imidazothiadiazole-linked benzenesulfonamide derivatives (5a–t) was synthesized and subjected for screening against the four physiologically and pharmacologically relevant human carbonic anhydrase (hCA) isoforms: hCA I, II, VA, and IX. The compounds selectively inhibited hCA I and II over hCA VA and IX. Furthermore, among the two cytosolic isoforms, hCA II was more effectively inhibited as compared with hCA I. The most active compounds were 5o with Ki = 0.246 μM and 5p with Ki = 0.376 μM against hCA II, whereas compound 5f showed good inhibition against both hCA I and II with Ki = 0.493 and 0.4 μM, respectively. This class of underexplored sulfonamides may be used to design isoform-selective CA inhibitors targeting enzymes of medicinal chemistry interest.
- Swain, Baijayantimala,Aashritha, Kamtam,Singh, Priti,Angeli, Andrea,Kothari, Abhay,Sigalapalli, Dilep K.,Yaddanapudi, Venkata M.,Supuran, Claudiu T.,Arifuddin, Mohammed
-
-
- INHIBITORS OF α-AMINO-β-CARBOXYMUCONIC ACID SEMIALDEHYDE DECARBOXYLASE
-
The present disclosure discloses compounds capable of modulating the activity of α-amino-β-carboxymuconic acid semialdehyde decarboxylase (ACMSD), which are useful for the prevention and/or the treatment of diseases and disorders associated with defects in NAD+ biosynthesis, e.g., metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and diseases associated with ageing. The present application also discloses pharmaceutical compositions comprising said compounds and the use of such compounds as a medicament.
- -
-
Paragraph 00495
(2020/06/10)
-
- Preparation method of prednisolone sodium benzoylsulfonate
-
The invention provides a preparation method of prednisolone sodium benzoylsulfonate. The preparation method comprises the following steps: 1) carrying out a reaction on 3-sodium carboxybenzenesulfonate with a nitrogen heterocyclic ring-containing carbonylation reagent to generate an azaamide intermediate (formula II); and 2) in the presence of an organic sodium salt and an N-halogenated amide reagent, carrying out a reaction on the azaamide intermediate (formula II) with prednisolone to obtain prednisolone sodium benzoylsulfonate. The method has the advantages of mild reaction conditions, simple post-treatment, suitability for industrial production, good product quality and few impurities.
- -
-
Paragraph 0064-0066
(2020/07/24)
-
- A 'sulfonyl-azide-free' (SAFE) aqueous-phase diazo transfer reaction for parallel and diversity-oriented synthesis
-
Diazo transfer reactions are notoriously associated with the use of potentially explosive sulfonyl azides. The first 'sulfonyl-azide-free' (SAFE) protocol for producing diazo compounds from their active-methylene precursors via the Regitz diazo transfer reaction was developed and has displayed a remarkable substrate scope. It can be applied to generating arrays of diazo compounds for further evolution via combinatorial chemistry and a range of scaffold-generating transformations.
- Dar'In, Dmitry,Kantin, Grigory,Krasavin, Mikhail
-
supporting information
p. 5239 - 5242
(2019/05/08)
-
- Synthesis of a new series of 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides as carbonic anhydrase I, II, IV and IX inhibitors
-
The synthesis of a novel series of 3-functionalised benzenesulfonamides incorporating phenyl-1,2,3-triazole with an amide linker was achieved by using the “click-tail” approach. The new compounds, including the intermediates, were assayed as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isoforms) and also for hCA IV and IX (transmembrane isoforms) taking acetazolamide as standard drug. Most of these compounds exhibited excellent activity against all these isoforms. hCA I was inhibited with Kis in the range of 50.8–966.8 nM, while the glaucoma associated hCA II was inhibited with Kis in the range of 6.5–760.0 nM. Isoform hCA IV was inhibited with Kis in the range of 65.3–957.5 nM, whereas the tumor associated hypoxia induced hCA IX was inhibited with Kis in the range of 30.8–815.9 nM. The structure activity relationship study for the 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides against these isoforms was also inferred from the results.
- Swain, Baijayantimala,Angeli, Andrea,Angapelly, Srinivas,Thacker, Pavitra S.,Singh, Priti,Supuran, Claudiu T.,Arifuddin, Mohammed
-
p. 1199 - 1209
(2019/07/02)
-
- Potent hydrazone derivatives targeting esophageal cancer cells
-
Hydrazone and their derivatives are a series of highly active molecules, which are widely used as lead compounds for the research and development of new anti-cancer drugs. In this study, 20 compounds were synthesized, based on this scaffold and their in vitro cytotoxicity against 6 cancer cell lines, including EC9706, SMMC-7721, MCF7, PC3, MGC-803 and EC109 was tested. Among them, compound 6p, showed strong anti-proliferative activities on esophageal carcinoma cells: EC9706 and EC109 with IC50 values of 1.09 ± 0.03 and 2.79 ± 0.45 μM, respectively. 6p also significantly induces both EC9706 and EC109 cell cycle arrest at G0/G1 phase and cell apoptosis, as well as intracellular ROS accumulation, which could be markedly reversed caspase or ROS inhibitor: NAC. Meanwhile, treatment of compound 6p results in significant declined mitochondria membrane potential, increases in the expression of P53 and bax, as well as decrease in Bcl-2. 6p also activates caspase-8/9/3, PARP and Bid, indicating that 6p induces cancer cell apoptosis via the death receptor-mediated extrinsic pathway and the mitochondria-mediated intrinsic pathway. Further studies also proved that 6p does not show obvious side effects at cellular and in vivo levels. Our findings suggested that hydrazone derivative: compound 6p may serve as a lead compound for further optimization against esophageal cancer cells.
- Li, Ling-Yu,Peng, Jia-Di,Zhou, Wenjuan,Qiao, Hui,Deng, Xin,Li, Zhou-Hua,Li, Ji-Deng,Fu, Yun-Dong,Li, Song,Sun, Kai,Liu, Hong-Min,Zhao, Wen
-
p. 359 - 371
(2018/02/27)
-
- Synthesis and Biological Evaluation of 4-Sulfamoylphenyl/Sulfocoumarin Carboxamides as Selective Inhibitors of Carbonic Anhydrase Isoforms hCA II, IX, and XII
-
With the aim to develop potent and selective human carbonic anhydrase inhibitors (hCAIs), we synthesized 4-sulfamoylphenyl/sulfocoumarin benzamides (series 5 a–r and series 7 a–q) and evaluated their inhibition profiles against five isoforms of the zinc-containing human carbonic anhydrase (hCA, EC 4.2.1.1): cytosolic hCA I and II, and the transmembrane isozymes hCA IV, IX, and XII. Compounds 5 a–r were found to selectively inhibit hCA II in the nanomolar range, while being less effective against the other hCA isoforms. As noted from the literature, sulfocoumarin (1,2-benzoxathiine 2,2-dioxide) acts as a “prodrug” inhibitor and is hydrolyzed by the esterase activity of hCA to form 2-hydroxyphenylvinylsulfonic acid, which thereafter binds to the enzyme in a manner similar to that of coumarins and sulfoxocoumarins. All these sulfocoumarins (compounds 7 a–q) were found to be very weak or ineffective as inhibitors of the housekeeping off-target hCA isoforms I and II, and effectively inhibited the transmembrane tumor-associated isoforms IX and XII in the high nanomolar to micromolar ranges. Further structural modifications of these molecules could be useful for the development of effective hCA inhibitors used for the treatment of glaucoma, epilepsy, and cancer.
- Angapelly, Srinivas,Angeli, Andrea,Khan, Arbaj Jabbar,Sri Ramya,Supuran, Claudiu T.,Arifuddin, Mohammed
-
p. 1165 - 1171
(2018/05/30)
-
- Method for preparing 3-chlorosulfonylbenzoyl chloride
-
The invention discloses a method for preparing 3-chlorosulfonylbenzoyl chloride. The method comprises the following steps: (1) benzoic acid and excess chlorosulfonic acid are subjected to a sulfonylation reaction with 20 wt% fuming sulfuric acid as a catalyst to prepare a sulfonating liquid; and (2) the sulfonating liquid prepared in the step (1) and oxalyl chloride are subjected to an acylation reaction with DMF as a catalyst to prepare the target product 3-chlorosulfonylbenzoyl chloride. The method has mild reaction conditions, short reaction time, simple operation, high yield, good productquality, and almost no pollution to environment, is suitable for industrial production, and has a very good application prospect.
- -
-
Paragraph 0032; 0034; 0035
(2018/09/08)
-
- USE OF DDX3 INHIBITORS AS ANTIPROLIFERATIVE AGENTS
-
The present invention refers to compounds of formula I or II endowed with DDX3 inhibitory activity, relative pharmaceutical compositions and their use as antihyperproliferative agents. (I) or (II)
- -
-
Page/Page column 96; 97
(2017/10/30)
-
- Small Molecule Microarray Based Discovery of PARP14 Inhibitors
-
Poly(ADP-ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray-based strategy for high-throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with >20-fold selectivity over PARP1. Co-crystallization of the PARP14/H10 complex indicated H10 bound to both the nicotinamide and the adenine subsites. Further structure–activity relationship studies identified important binding elements in the adenine subsite. In tumor cells, H10 was able to chemically knockdown endogenous PARP14 activities.
- Peng, Bo,Thorsell, Ann-Gerd,Karlberg, Tobias,Schüler, Herwig,Yao, Shao Q.
-
supporting information
p. 248 - 253
(2016/12/30)
-
- Synthesis,docking and evaluation of phenylacetic acid and trifluoro-methylphenyl substituted benzamide derivatives as potential ppar? agonists
-
Background: Peroxisome proliferator-activated receptor (PPAR) ? is a type of PPARs belonging to the steroid or nuclear hormone receptor super family. Activation of PPAR? leads to metabolism of fat instead of glucose by body for energy requirements. PPAR? represent an emerging pharmacological target for the treatment of metabolic syndrome (MS). Many selective and potent PPAR? agonists had been synthesized with a potential role in the treatment of various disorders associated with MS including type 2 diabetes and inflammation. Objective: The present work was designed to synthesize and evaluate the antidiabetic and anti-inflammatory activity of some newer phenylacetic acid and trifluoromethylphenyl substituted benzamide derivatives as potential PPAR? agonists. Methods: This work involved the synthesis of newer sulfamoyl benzamide derivatives and their evaluation by molecular docking studies to determine the binding interactions for the best fit conformations in the binding site of the PPAR? protein. Based on the results of the in silico studies, the selected compounds were tested for their antidiabetic and anti-inflammatory activity in the animal models. Results: Amongst the synthesized molecules, compound 7 showed higher anti-diabetic activity and compound 19 showed higher anti-inflammatory activity. The experimental results were found to be in concordance with that of the in silico results. Most of the synthesized molecules were found to have drug like properties as devised by Lipinski's rule of five. Conclusion: These molecules can act as the starting hits for the design of safe, effective and bioavailable PPAR? agonists for the potential treatment of MS and related diseases.
- Grewal, Ajmer Singh,Lather, Viney,Pandita, Deepti,Bhayana, Garima
-
p. 1239 - 1251
(2017/11/14)
-
- Synthesis method of belinostat
-
The invention discloses a synthesis method of belinostat. The method comprises the following steps: by using benzoic acid as an initial material, performing six reaction steps of chlorosulfonation, aniline condensation, reduction, oxidation, Witting-Horner condensation and hydrolysis, acylating chlorination and hydroxylamine condensation to prepare a target compound. The initial material benzoic acid of the method is cheap and easy to obtain, the sulfonylation and acylating chlorination reaction are realized through one step, the preparation time is shortened, and the yield is improved. In the oxidation process, an oxidizing reagent which is cheap and does not contains metal ion is adopted so that the active ingredients easily achieve the requirement of heavy metal ion limitation, and the pollution to the environment is reduced. All reaction intermediates of the method are solid and can be purified through a salt formation or recrystallization method, the time-consuming and labor-consuming column chromatography purification is avoided, and the method is suitable for industrial production.
- -
-
Paragraph 0031; 0032; 0036; 0037; 0038
(2016/11/14)
-
- HUMAN HELICASE DDX3 INHIBITORS AS THERAPEUTIC AGENTS
-
The present invention refers to compounds endowed with RNA helicase DDX3 inhibitory activity of formula I and II and their therapeutic use, in particular for the treatment of viral diseases.
- -
-
Page/Page column 105
(2016/09/22)
-
- Synthesis, docking and antidiabetic activity of some newer benzamide derivatives as potential glucokinase activators
-
Background: Glucokinase activators (GKAs) are the new class of candidate drugs which act on glucokinase (GK) enzyme and show their hypoglycaemic activity. Objective: The present work was planned to synthesize and evaluate the antidiabetic activity of a series of newer benzamide derivatives as potential GKAs. Method: This work involved synthesis of newer benzamide derivatives from benzoic acid and their evaluation by docking studies to determine the binding interactions for the best fit conformations in the binding site of GK enzyme. Based on the results of docking studies, the selected molecules were tested for their antidiabetic activity in the animal model. Results: Amongst the synthesized molecules, compounds 14 and 20 with phenyl-substituted thiazole moiety on amide nitrogen, exhibited highest activity in vivo. The results of the in vivo antidiabetic studies were found to be consistent with those of docking studies. Conclusion: These newly synthesized molecules thus can be treated as the initial hits for the development of new, safe, effective and orally bioavailable GKAs as therapeutic agents for the treatment of diabetic disorders.
- Singh, Rohit,Lather, Viney,Pandita, Deepti,Judge, Vikramjeet,Arumugam, Karthikeyan N.,Grewal, Ajmer Singh
-
-
- Development and evaluation of ST-1829 based on 5-benzylidene-2-phenylthiazolones as promising agent for anti-leukotriene therapy
-
Different inflammatory diseases and allergic reactions are mediated by leukotrienes, which arise from the oxygenation of arachidonic acid catalyzed by 5-lipoxygenase (5-LO). One promising approach for an effective anti-leukotriene therapy is the inhibition of this key enzyme. This study presents the synthesis and development of a potent and direct 5-LO inhibitor based on the well characterized 5-benzylidene-2-phenylthiazolone C06, whose further pharmacological investigation was precluded due to its low solubility. Through optimization of C06, evaluation of structure-activity relationships including profound assessment of the thiazolone core and consideration of the solubility, the 5-benzyl-2-phenyl-4-hydroxythiazoles represented by 46 (ST-1829, 5-(4-chlorobenzyl)-2-p-tolylthiazol-4-ol) were developed. Compound 46 showed an improved 5-LO inhibitory activity in cell-based (ICinf50/inf values 0.141/4M) and cell-free assays (ICinf50/inf values 0.03 1/4M) as well as a prominent enhanced solubility. Furthermore, it kept its promising inhibitory potency in the presence of blood serum, excluding excessive binding to serum proteins. These facts combined with the non-cytotoxic profile mark a major step towards an effective anti-inflammatory therapy.
- Lill, Andreas P.,R?dl, Carmen B.,Steinhilber, Dieter,Stark, Holger,Hofmann, Bettina
-
supporting information
p. 503 - 523
(2014/12/11)
-
- Design, synthesis, and pharmacological evaluation of highly potent and selective dipeptidyl peptidase-4 inhibitors
-
The optimization of a series of fused β-homophenylalanine inhibitors of dipeptidyl peptidase-4 (DPP-4) is described. Modification on the P2-binding moiety of 6 (IC50 = 10 nM) led to the discovery of β-homophenylalanine derivatives containing pyrrolidin-2-ylmethyl amides. The introduction of a sulfamine in the meta position of the phenyl ring improved the potency against DPP-4 (6-12-fold increase). Compound 14k showed DPP-4 inhibitory activity with an IC50 value of 0.87 nM. Meanwhile, in vivo experiments exhibited that 14h had an efficiency comparable to sitagliptin at the dose of 10 mg/kg.
- Jiang, Tao,Zhou, Yuren,Zhu, Jianming,Chen, Zhuxi,Sun, Peng,Zhang, Qiang,Wang, Zhen,Shao, Qiang,Jiang, Xiangrui,Li, Bo,Wang, Heyao,Zhu, Weiliang,Shen, Jingshan
-
p. 399 - 407
(2015/06/08)
-
- BENZAMIDE COMPOUNDS AND RELATED METHODS OF USE
-
Benzamide compounds and derivatives thereof, as can be used for selective inhibition of the SIRT2 enzyme and/or therapeutic use in the treatment of Huntington's disease.
- -
-
Paragraph 0076
(2014/07/08)
-
- Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors
-
Inhibitors of sirtuin-2 deacetylase (SIRT2) have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the neuroprotective sulfobenzoic acid scaffold and improving their pharmacology. To achieve that goal, 176 analogues were designed, synthesized, and tested in deacetylation assays against the activities of major human sirtuins SIRT1-3. This screen yielded 15 compounds with enhanced potency for SIRT2 inhibition and 11 compounds having SIRT2 inhibition equal to reference compound AK-1. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. These candidates were subjected to a dose-response bioactivity assay, measuring an increase in α-tubulin K40 acetylation in two neuronal cell lines, which yielded five compounds bioactive in both cell lines and eight compounds bioactive in at least one of the cell lines tested. These bioactive compounds were subsequently tested in a tertiary polyglutamine aggregation assay, which identified five inhibitors. ADME properties of the bioactive SIRT2 inhibitors were assessed, which revealed a significant improvement of the pharmacological properties of the new entities, reaching closer to the goal of a clinically-viable candidate.
- Khanfar, Mohammad A.,Quinti, Luisa,Wang, Hua,Choi, Soo Hyuk,Kazantsev, Aleksey G.,Silverman, Richard B.
-
p. 414 - 426
(2014/03/21)
-
- Aromatic sulfonyl fluorides covalently kinetically stabilize transthyretin to prevent amyloidogenesis while affording a fluorescent conjugate
-
Molecules that bind selectively to a given protein and then undergo a rapid chemoselective reaction to form a covalent conjugate have utility in drug development. Herein a library of 1,3,4-oxadiazoles substituted at the 2 position with an aryl sulfonyl fluoride and at the 5 position with a substituted aryl known to have high affinity for the inner thyroxine binding subsite of transthyretin (TTR) was conceived of by structure-based design principles and was chemically synthesized. When bound in the thyroxine binding site, most of the aryl sulfonyl fluorides react rapidly and chemoselectively with the pK a-perturbed K15 residue, kinetically stabilizing TTR and thus preventing amyloid fibril formation, known to cause polyneuropathy. Conjugation t50s range from 1 to 4 min, ～1400 times faster than the hydrolysis reaction outside the thyroxine binding site. X-ray crystallography confirms the anticipated binding orientation and sheds light on the sulfonyl fluoride activation leading to the sulfonamide linkage to TTR. A few of the aryl sulfonyl fluorides efficiently form conjugates with TTR in plasma. Eleven of the TTR covalent kinetic stabilizers synthesized exhibit fluorescence upon conjugation and therefore could have imaging applications as a consequence of the environment sensitive fluorescence of the chromophore.
- Grimster, Neil P.,Connelly, Stephen,Baranczak, Aleksandra,Dong, Jiajia,Krasnova, Larissa B.,Sharpless, K. Barry,Powers, Evan T.,Wilson, Ian A.,Kelly, Jeffery W.
-
supporting information
p. 5656 - 5668
(2013/06/04)
-
- Organic thiol metal-free stabilizers and plasticizers for halogen-containing polymers
-
Organic thiol compounds based on pentaerythritol and dipentaerythritol are described herein. More specifically, the compounds of the present invention are mixed esters of pentaerythritol and dipentaerythritol having at least one sulfhydryl group and preferably a plurality of sulfhydryl groups as well as at least one non-thiol-containing group. The organic thiol compounds are utilized to plasticize and/or heat stabilize halogen-containing polymer compositions especially poly(vinyl chloride) compositions. The compositions are substantially free or free of metal-based stabilizers, Lewis acids and terpenes. The compounds of the present invention are ideally utilized in polymers normally susceptible to deterioration and color change which can occur during processing of the polymer or exposure of the polymer to certain environments and surprisingly also serve as excellent plasticizers.
- -
-
Page/Page column 5
(2010/02/11)
-
- Phenylenediamine urotensin-II receptor antagonists and CCR-9 antagonists
-
The present invention relates to urotensin II receptor antagonists, CCR-9 antagonists, pharmaceutical compositions containing them and their use.
- -
-
-
- PRODRUGS OF PROTON PUMP INHIBITORS
-
Prodrugs of proton pump inhibitors of Formulas 1 through 4, (I-IV), where the symbols are as defined in the specification, and the R group includes at least one acidic group or its pharmaceutically acceptable salt, have improved aqueous solubility and bioavailability.
- -
-
Page 200-201
(2010/02/06)
-
- Urea-tetrahydrobenzoxanthene receptors for carboxylic acids
-
Hydrogen-bonding receptors for carboxylic acids have been prepared based on a cis tetrahydrobenzoxanthene skeleton. X-ray diffraction study of one of these compounds revealed that the cleft is suitable for establishing strong linear hydrogen bonds with the oxygen of a water molecule. Complexes that set only three H-bonds with the guests showed no chiral recognition with amino acid derivatives. However, suitable functionalization of the receptor provided a fourth H-bond with certain amino acid derivatives, leading to significant enantioselective complexation in this case.
- Oliva, Ana I.,Simón, Luis,Mu?iz, Francisco M.,Sanz, Francisca,Morán, Joaquín R.
-
p. 3755 - 3762
(2007/10/03)
-
- 2-arylalkylthio -imidazoles, 2-arylalkenyl -thio -imidazoles and 2-arylalkinyl -thio -imidazoles as anti -inflammatory substances and substances inhibiting the release of cytokine
-
The invention relates to 4-heteroaryl-5-phenylimidazole derivatives having 2-arylalkylthio, 2-arylalkenylthio and 2-arylalkynylthio substitution, of the general formula I: in which Ar is a phenyl radical, Het is a hetero aromatic radical, A is an alkylene chain, R1 is an alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamido or alkylcarbonyl group and R2 is an alkyl, hydroxyl, alkoxy, alkoxycarbonyl, sulfonamido, carboxyl, nitro or aminocarbonyl group or a halogen atom. n can be 1 or 2 and m is 0 to 2. The compounds according to the invention show antiinflammatory activity.
- -
-
-
- An Alternative Synthesis of Tiopinac
-
Tiopinac (1) thiepin-3-acetic acid, (1)> has been shown a high degree of antiinflammatory activity and a low incidence of side effects in animals (2).On the basis of results, Tiopinac was chosen for human evaluation in 1978 (2a).
- Thurber, T. Craig,Prince, Anthony,Halpern, Otto
-
p. 961 - 965
(2007/10/02)
-
