- Reduction of sulfamethoxazole hydroxylamine (SMX-HA) by the mitochondrial amidoxime reducing component (mARC)
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Under high dose treatment with sulfamethoxazole (SMX)/trimethoprim (TMP), hypersensitivity reactions occur with a high incidence. The mechanism of this adverse drug reaction is not fully understood. Several steps in the toxification pathway of SMX were investigated. The aim of our study was to investigate the reduction of sulfamethoxazole hydroxylamine (SMX-HA) in this toxification pathway, which can possibly be catalyzed by the mARC-containing N-reductive enzyme system. Western blot analyses of subcellular fractions of porcine tissue were performed with antibodies against mARC-1, mARC-2, cytochrome b5 type B, and NADH cytochrome b5 reductase. Incubations of porcine and human subcellular tissue fractions and of the heterologously expressed human components of the N-reductive enzyme system were carried out with SMX-HA. mARC-1 and mARC-2 knockdown was performed in HEK-293 cells. Kinetic parameters of the heterologously expressed human protein variants V96L, A165T, M187 K, C246S, D247H, and M268I of mARC-1 and G244S and C245W of mARC-2 and N-reductive activity of 2SF, D14G, K16E, and T22A of cytochrome b5 type B were analyzed. Western blot analyses were consistent with the hypothesis that the mARC-containing N-reductive enzyme system might be involved in the reduction of SMX-HA. In agreement with these results, highest reduction rates were found in mitochondrial subcellular fractions of porcine tissue and in the outer membrane vesicle (OMV) of human liver tissue. Knockdown studies in HEK-293 cells demonstrated that mARC-1 and mARC-2 were capable of reducing SMX-HA in cell metabolism. Investigations with the heterologously expressed human mARC-2 protein showed a higher catalytic efficiency toward SMX-HA than mARC-1, but none of the investigated human protein variants showed statistically significant differences of its N-reductive activity and was therefore likely to participate in the pathogenesis of hypersensitivity reaction under treatment with SMX. (Chemical Equation Presented).
- Ott, Gudrun,Plitzko, Birte,Krischkowski, Carmen,Reichmann, Debora,Bittner, Florian,Mendel, Ralf R.,Kunze, Thomas,Clement, Bernd,Havemeyer, Antje
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- Synthesis of novel sulfamethaoxazole 4-thiazolidinone hybrids and their biological evaluation
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A search for potent antitubercular agents prompted us to design and synthesize sulfamethaoxazole incorporated 4-thiazolidinone hybrids (7a-l) by using a cyclocondensation reaction between 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide (4), aryl aldehyde (5a-l), and mercapto acetic acid (6) resulting in good to excellent yields. All the newly synthesized 4-thiazolidinone derivatives were screened for their in vitro antitubercular activity against M. Bovis BCG and M. tuberculosis H37Ra (MTB) strains. The compounds 7d, 7g, 7i, 7k, and 7l revealed promising antimycobacterial activity against M. Bovis and MTB strains with IC90 values in the range of 0.058-0.22 and 0.43-5.31 μg/mL, respectively. The most active compounds were also evaluated for their cytotoxicity against MCF-7, HCT 116, and A549 cell lines and were found to be non-cytotoxic. Moreover, the synthesized compounds were also analyzed for ADME (absorption, distribution, metabolism, and excretion) properties and showed potential as good oral drug candidates.
- Al-Omar, Mohamed A.,Bhat, Mashooq A.,Khan, Azmat Ali,Naglah, Ahmed M.
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- Synthesis of calix[4]azacrown substituted sulphonamides with antioxidant, acetylcholinesterase, butyrylcholinesterase, tyrosinase and carbonic anhydrase inhibitory action
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A series of novel calix[4]azacrown substituted sulphonamide Schiff bases was synthesised by the reaction of calix[4]azacrown aldehydes with different substituted primary and secondary sulphonamides. The obtained novel compounds were investigated as inhibitors of six human (h) isoforms of carbonic anhydrases (CA, EC 4.2.1.1). Their antioxidant profile was assayed by various bioanalytical methods. The calix[4]azacrown substituted sulphonamide Schiff bases were also investigated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase enzymes, associated with several diseases such as Alzheimer, Parkinson, and pigmentation disorders. The new sulphonamides showed low to moderate inhibition against hCAs, AChE, BChE, and tyrosinase enzymes. However, some of them possessed relevant antioxidant activity, comparable with standard antioxidants used in the study.
- Akocak, Suleyman,Boga, Mehmet,Kalay, Erbay,Lolak, Nebih,Nocentini, Alessio,Oguz, Mehmet,Supuran, Claudiu T.,Yilmaz, Mustafa
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p. 1215 - 1223
(2020/05/27)
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- Divergent Late-Stage (Hetero)aryl C?H Amination by the Pyridinium Radical Cation
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(Hetero)arylamines constitute some of the most prevalent functional molecules, especially as pharmaceuticals. However, structurally complex aromatics currently cannot be converted into arylamines, so instead, each product isomer must be assembled through a multistep synthesis from simpler building blocks. Herein, we describe a late-stage aryl C?H amination reaction for the synthesis of complex primary arylamines that other reactions cannot access directly. We show and rationalize through a mechanistic analysis the reasons for the wide substrate scope and the constitutional diversity of the reaction, which gives access to molecules that would not have been readily available otherwise.
- Ham, Won Seok,Hillenbrand, Julius,Jacq, Jér?me,Genicot, Christophe,Ritter, Tobias
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supporting information
p. 532 - 536
(2019/01/04)
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- Industrial preparation method of Sinomin
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The invention discloses an industrial preparation method of Sinomin. According to the industrial preparation method, 3-amino-5-methylisoxazole and diphenyl urea sulfonyl chloride are used as raw materials, under the condition of basicity, condensation reaction is performed at first, then hydrolysis, acidification, concentration under reduced pressure, centrifugation and drying are performed so asto prepare the Sinomin. The used raw materials are easy to obtain, the preparation method is low-cost, post-treatment is simple, the finished product does not need to be recrystallized, the reaction operation is highly safe, product purity is greater than or equal to 99.5%, the yield of the product is 92-95%, the preparation method does not contaminate environment heavily, so that the industrial preparation method is based on the principle of green chemistry, and is easy to industrialize.
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Paragraph 0015-0018
(2019/01/13)
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- Structure-based virtual screening and optimization of modulators targeting Hsp90-Cdc37 interaction
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Identification of novel Hsp90 inhibitors to disrupt Hsp90-Cdc37 protein-protein interaction (PPI) could be an alternative strategy to achieve Hsp90 inhibition. In this paper, a series of small molecules targeting Hsp90-Cdc37 complex are addressed and characterized. The molecules' key characters are determined by utilizing a structure-based virtual screening workflow, derivatives synthesis, and biological evaluation. Structural optimization and structure–activity relationship (SAR) analysis were then carried out on the virtual hit of VS-8 with potent activity, which resulted in the discovery of compound 10 as a more potent regulator of Hsp90-Cdc37 interaction with a promising inhibitory effect (IC50?=?27?μM), a moderate binding capacity (KD?=?40?μM) and a preferable antiproliferative activity against several cancer lines including MCF-7, SKBR3 and A549?cell lines (IC50?=?26?μM, 15?μM and 38?μM respectively). All the data suggest that compound 10 exhibits moderate inhibitory effect on Hsp90-Cdc37 and could be regard as a first evidence of a non-natural compound targeting Hsp90-Cdc37 PPI.
- Wang, Lei,Li, Li,Zhou, Zi-Han,Jiang, Zheng-Yu,You, Qi-Dong,Xu, Xiao-Li
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- Catalyzed preparation method of sulfamethoxazole
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The invention provides a catalyzed preparation method of sulfamethoxazole. The preparation method comprises the following steps: synthesis of p-acetamidobenzene sulfonyl chloride, synthesis of 3-(p-acetamidobenzene sulfonamide)-5-methylisoxazole, and synthesis of sulfamethoxazole; and the method has a high yield, and accords with needs of industrial large-scale production.
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Paragraph 0013; 0017; 0022; 0027; 0037
(2018/02/04)
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- Design, synthesis and evaluation of novel polypharmacological antichlamydial agents
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Abstract Discovery of new polypharmacological antibacterial agents with multiple modes of actions can be an alternative to combination therapy and also a possibility to slow development of antibiotic resistance. In support to this hypothesis, we synthesized 16 compounds by combining the pharmacophores of Chlamydia trachomatis inhibitors and inhibitors of type III secretion (T3S) in gram-negative bacteria. In this study we have developed salicylidene acylhydrazide sulfonamides (11c & 11d) as new antichlamydial agents that also inhibit T3S in Yersinia pseudotuberculosis.
- Sunduru, Naresh,Salin, Olli,Gylfe, ?sa,Elofsson, Mikael
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p. 595 - 603
(2015/08/03)
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- Identification of ML251, a potent inhibitor of T. brucei and T. cruzi phosphofructokinase
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Human African Trypanosomiasis (HAT) is a severe, often fatal disease caused by the parasitic protist Trypanosoma brucei. The glycolytic pathway has been identified as the sole mechanism for ATP generation in the infective stage of these organisms, and several glycolytic enzymes, phosphofructokinase (PFK) in particular, have shown promise as potential drug targets. Herein, we describe the discovery of ML251, a novel nanomolar inhibitor of T. brucei PFK, and the structure-activity relationships within the series.
- Brimacombe, Kyle R.,Walsh, Martin J.,Liu, Li,Vasquez-Valdivieso, Montserrat G.,Morgan, Hugh P.,McNae, Iain,Fothergill-Gilmore, Linda A.,Michels, Paul A. M.,Auld, Douglas S.,Simeonov, Anton,Walkinshaw, Malcolm D.,Shen, Min,Boxer, Matthew B.
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supporting information
p. 12 - 17
(2014/02/14)
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- Sulfonamide molecular crystals: Structure, sublimation thermodynamic characteristics, molecular packing, hydrogen bonds networks
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The crystal structures of ten sulfonamides have been determined by X-ray diffraction. On the basis of our previous data, the obtained results and literature data crystal properties including molecular conformational states, packing architecture, and hydrogen bond networks were comparatively analyzed using graph set notations. Conformational flexibility of the bridge connecting two phenyl rings was studied. It was found out that the most frequently occurring graphs for compounds with a single hydrogen bond are infinite chains with four atoms included. The molecular packing architecture of the selected crystals may be conditionally divided into three different groups. The idea underlying such classification is the difference in structure and composition of molecular layers that can be singled out for most packings. The influence of various molecular fragments on crystal lattice energy was analyzed. A correlation between melting points and fragmental molecular interactions in the crystal lattices was obtained. The thermodynamic aspects of the sulfonamide sublimation were studied by determining the temperature dependence of vapor pressure using the transpiration method. A correlation between the Gibbs energy of the sublimation process and the melting points was found. Besides, a regression equation was derived to describe the correlation between the sublimation entropy terms and crystal density data calculated from X-ray diffraction results.
- Perlovich, German L.,Ryzhakov, Alex M.,Tkachev, Valery V.,Hansen, Lars Kr.,Raevsky, Oleg A.
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p. 4002 - 4016
(2013/09/24)
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- PHENYL CARBOXAMIDE AND SULFONAMIDE DERIVATIVES FOR USE AS 11-BETA-HYDROXYSTEROID DEHYDROGENASE
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There is provided a compound having Formula (I) R1-Z-R2 Formula (I) wherein R1 is an optionally substituted phenyl ring; R2 is or comprises an optionally substituted aromatic ring; and Z is -X-Y-L- or -Y-X-L- wherein either X is selected from -S(=O)(=O)- and -C(=O)-, and Y is -NR3-; or X is selected from -S(=O)(=O)- and -S-, and Y is -C(R4)(R5)-; L is an optional linker; and R3, R4 and R5 are each independently selected from H and hydrocarbyl; and wherein when R2 comprises the following structural moiety, Formula (II) wherein Q is an atom selected from the group consisting of S, O, N and C; the compound is selected from compounds of the formulae R1-C(=O)-NR3-L-R2; R1-S(=O)(=O)-C(R4)(R5)-L-R2; R1-S-C(R4)(R5)-L-R2; R1-NR3-S(=O)(=O)-L-R2; R1-NR3-C(=O)-L-R2; R1-C(R4)(R5)-S(=O)(=O)-L-R2; and R1-C(R4)(R5)-S-L-R2. These compounds are useful as 11β-hydroxysteriod dehydrogenase inhibitors in the treatment of i.a. diabetes.
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Page/Page column 89-90
(2010/02/11)
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- NADH cytochrome b5 reductase and cytochrome b5 catalyze the microsomal reduction of xenobiotic hydroxylamines and amidoximes in humans
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Hydroxylamine metabolites, implicated in dose-dependent and idiosyncratic toxicity from arylamine drugs, and amidoximes, used as pro-drugs, are metabolized by an as yet incompletely characterized NADH-dependent microsomal reductase system. We hypothesized that NADH cytochrome b5 reductase and cytochrome b5 were responsible for this enzymatic activity in humans. Purified human soluble NADH cytochrome b5 reductase and cytochrome b5 expressed in Escherichia coli, efficiently catalyzed the reduction of sulfamethoxazole hydroxylamine, dapsone hydroxylamine, and benzamidoxime, with apparent Km values similar to those found in human liver microsomes and specific activities (Vmax) 74 to 235 times higher than in microsomes. Minimal activity was seen with either protein alone, and microsomal protein did not enhance activity other than additively. All three reduction activities were significantly correlated with immunoreactivity for cytochrome b5 in individual human liver microsomes. In addition, polyclonal antibodies to both NADH cytochrome b5 reductase and cytochrome b5 significantly inhibited reduction activity for sulfamethoxazole hydroxylamine. Finally, fibroblasts from a patient with type II hereditary methemoglobinemia (deficient in NADH cytochrome b5 reductase) showed virtually no activity for hydroxylamine reduction, compared with normal fibroblasts. These results indicate a novel direct role for NADH cytochrome b5 reductase and cytochrome b5 in xenobiotic metabolism and suggest that pharmacogenetic variability in either of these proteins may effect drug reduction capacity.
- Kurian, Joseph R.,Bajad, Sunil U.,Miller, Jackie L.,Chin, Nathaniel A.,Trepanier, Lauren A.
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p. 1171 - 1178
(2007/10/03)
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- A base labile handle for solid phase organic chemistry
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Several arylsulfonamides have been synthesised on solid phase using a new base labile handle. Cleavage front the solid support is accomplished by oxidation of the sulfide to the sulfone, followed by β-elimination in base media.
- Garcia-Echeverria, Carlos
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p. 8933 - 8934
(2007/10/03)
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- Synthesis and reactions of nitroso sulphamethoxazole with biological nucleophiles: Implications for immune mediated toxicity
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Sulphamethoxazole hydroxylamine (SMX-NHOH) and nitroso sulphamethoxazole (SMX-NO) were prepared by a modified literature procedure. SMX-NO produced a complex set of unstable intermediates with sulphur nucleophiles, but did not react with amino containing compounds. No reactions were observed between sulphamethoxazole (SMX) / SMX-NHOH and the nucleophiles used in this study. Thus antigens formed from N-oxidation of SMX are likely to be unstable in vivo.
- Naisbitt, Dean J.,Neill, Paul M.,Pirmohamed, Munir,Park, B. Kevin
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p. 1511 - 1516
(2007/10/03)
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- Substituted sulfonamide derivatives which inhibit allergic reactions
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The present invention involves intradermal, percutaneous, parenteral, or enteral administration of a newly synthesized compound to detect, reduce, or eliminate the occurrence of allergic reactions to sulfonamides. The new compound is a substituted sulfonamide, the substituent being bound to the paraamino (4-position) group through an azo, amide, or other linkage. Because a purpose of the substituent is to make the new compound water soluble, it can take a variety of forms, but it must contain carbon and hydrogen, plus at least one of oxygen and nitrogen. Examples of usable substituents include imidazole, a carbohydrate, or an amino acid such as histidine, tyrosine, tryptophan, lysine, or tyrosine methyl ester; it may also be a synthetic polymer, polypeptde, polysaccharide, or an amino acid homopolymer.
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- Amidoxime derivatives
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Novel amidoxime derivatives having the following structural formula (IV) of (IV'): STR1 wherein R1 represents methyl or ethyl group and R2 represents hydrogen or methyl group, useful as a raw material for 3-amino-5-methyl isoxazole, are prepared from β-amino crotonitrile. Said isoxazole, useful as an intermediate for various medicines, may be prepared without producing any by-products of isomer.
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