636-76-0Relevant articles and documents
3-Functionalised benzenesulphonamide based 1,3,4-oxadiazoles as selective carbonic anhydrase XIII inhibitors: Design, synthesis and biological evaluation
Swain, Baijayantimala,Abhay,Singh, Priti,Angeli, Andrea,Aashritha, Kamtam,Nagesh, Narayana,Supuran, Claudiu T.,Arifuddin, Mohammed
, (2021/02/27)
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.
Design and synthesis of benzenesulfonamide-linked imidazo[2,1-b][1,3,4]thiadiazole derivatives as carbonic anhydrase I and II inhibitors
Swain, Baijayantimala,Aashritha, Kamtam,Singh, Priti,Angeli, Andrea,Kothari, Abhay,Sigalapalli, Dilep K.,Yaddanapudi, Venkata M.,Supuran, Claudiu T.,Arifuddin, Mohammed
, (2021/03/26)
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.
INHIBITORS OF α-AMINO-β-CARBOXYMUCONIC ACID SEMIALDEHYDE DECARBOXYLASE
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, (2020/06/10)
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.
Synthesis of a new series of 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides as carbonic anhydrase I, II, IV and IX inhibitors
Swain, Baijayantimala,Angeli, Andrea,Angapelly, Srinivas,Thacker, Pavitra S.,Singh, Priti,Supuran, Claudiu T.,Arifuddin, Mohammed
, p. 1199 - 1209 (2019/07/02)
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.
Development and evaluation of ST-1829 based on 5-benzylidene-2-phenylthiazolones as promising agent for anti-leukotriene therapy
Lill, Andreas P.,R?dl, Carmen B.,Steinhilber, Dieter,Stark, Holger,Hofmann, Bettina
, p. 503 - 523 (2014/12/11)
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.
Design, synthesis, and pharmacological evaluation of highly potent and selective dipeptidyl peptidase-4 inhibitors
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)
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.
N'-Alkylaminosulfonyl Analogues of 6-Fluorobenzylideneindolinones with Desirable Physicochemical Profiles and Potent Growth Inhibitory Activities on Hepatocellular Carcinoma
Chen, Xiao,Yang, Tianming,Deivasigamani, Amudha,Shanmugam, Muthu K.,Hui, Kam-Man,Sethi, Gautam,Go, Mei-Lin
supporting information, p. 1548 - 1558 (2015/09/07)
The benzylideneindolinone 6-chloro-3-(3′-trifluoromethylbenzylidene)-1,3-dihydroindol-2-one (4) was reported to exhibit potent and selective growth inhibitory effects on hepatocellular carcinoma (HCC). Corroborative evidence supported multi-receptor tyrosine kinase (RTK) inhibition as a possible mode of action. However, the poor physicochemical properties of 4 limited its furtherance as a lead compound. In this study, the modification of 4 was investigated with the aim of improving its potency and physicochemical profile. The 6-fluorobenzylideneindolinone 3-12 bearing a 3′-N-propylaminosulfonyl substituent was found to be a promising substitute. Compound 3-12 [6-fluoro-3-(3′-N-propylaminosulfonylbenzylidene)-1,3-dihydroindol-2-one] was found to be tenfold more soluble than 4 and to have sub-micromolar growth inhibitory activities on HCC cells. It is apoptogenic and inhibits the phosphorylation of several RTKs in HuH7, of which the inhibition of FGFR4 and HER3 are prominent. Compound 3-12 decreased the tumor load in a physiologically relevant orthotopic HCC xenograft murine model. Structure-activity relationships support pivotal roles for the fluoro and N′-propylaminosulfonyl moieties in enhancing cell-based activity and moderating the physicochemical profile (solubility, permeability) of 3-12.
BENZYLIDENE-INDOLINONE COMPOUNDS AND THEIR MEDICAL USE
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Paragraph 0233-0235, (2013/03/26)
Compounds of general formula I: wherein R1a, R1b, R2, R3a, R3b and X are as defined herein are tyrosine kinase inhibitors and are useful for the treatment of various diseases and conditions, for examp
Structure optimization of 2-benzamidobenzoic acids as PqsD inhibitors for Pseudomonas aeruginosa infections and elucidation of binding mode by SPR, STD NMR, and molecular docking
Weidel, Elisabeth,De Jong, Johannes C.,Brengel, Christian,Storz, Michael P.,Braunshausen, Andrea,Negri, Matthias,Plaza, Alberto,Steinbach, Anke,Müller, Rolf,Hartmann, Rolf W.
supporting information, p. 6146 - 6155 (2013/09/02)
Pseudomonas aeruginosa employs a characteristic pqs quorum sensing (QS) system that functions via the signal molecules PQS and its precursor HHQ. They control the production of a number of virulence factors and biofilm formation. Recently, we have shown that sulfonamide substituted 2-benzamidobenzoic acids, which are known FabH inhibitors, are also able to inhibit PqsD, the enzyme catalyzing the last and key step in the biosynthesis of HHQ. Here, we describe the further optimization and characterization of this class of compounds as PqsD inhibitors. Structural modifications showed that both the carboxylic acid ortho to the amide and 3′-sulfonamide are essential for binding. Introduction of substituents in the anthranilic part of the molecule resulted in compounds with IC50 values in the low micromolar range. Binding mode investigations by SPR with wild-type and mutated PqsD revealed that this compound class does not bind into the active center of PqsD but in the ACoA channel, preventing the substrate from accessing the active site. This binding mode was further confirmed by docking studies and STD NMR.
Semisynthesis of fluorescent metabolite sensors on cell surfaces
Brun, Matthias A.,Griss, Rudolf,Reymond, Luc,Tan, Kui-Thong,Piguet, Joachim,Peters, Ruud J.R.W.,Vogel, Horst,Johnsson, Kai
supporting information; experimental part, p. 16235 - 16242 (2011/12/01)
Progress in understanding signal transduction and metabolic pathways is hampered by a shortage of suitable sensors for tracking metabolites, second messengers, and neurotransmitters in living cells. Here we introduce a class of rationally designed semisyn
