- 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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- 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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- Enzyme-mediated protein haptenation of dapsone and sulfamethoxazole in human keratinocytes: I. Expression and role of cytochromes P450
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Cutaneous drug reactions (CDRs) are among the most common adverse drug reactions and are responsible for numerous minor to life-threatening complications. Several arylamine drugs, such as sulfamethoxazole (SMX) and dapsone (DDS), undergo bioactivation, resulting in adduction to cellular proteins. These adducted proteins may initiate the immune response that ultimately results in a CDR. Recent studies have demonstrated that normal human epidermal keratinocytes (NHEKs) can bioactivate these drugs, resulting in protein haptenation. We sought to identify the enzyme(s) responsible for this bioactivation in NHEKs. Using immunofluorescence confocal microscopy and an adduct-specific enzyme-linked immunosorbent assay (ELISA), we found that N-acetylation of the primary amine of SMX and DDS markedly reduced the level of protein haptenation in NHEKs. Detection of mRNA and/or protein confirmed the presence of CYP3A4, CYP3A5, and CYP2E1 in NHEKs. In contrast, although a faint band suggestive of CYP2C9 protein was detected in one NHEK sample, a CYP2C9 message was not detectable. We also examined the ability of chemical inhibitors of cytochromes P450 (aminobenzotriazole and 1-dichloroethylene) and cyclooxygenase (indomethacin) to reduce protein haptenation when NHEKs were incubated with SMX or DDS by either confocal microscopy or ELISA. These inhibitors did not significantly attenuate protein adduction with either SMX or DDS, indicating that cytochromes P450 and cyclooxygenase do not play important roles in the bioactivation of these xenobiotics in NHEKs and thus suggesting the importance of other enzymes in these cells.
- Vyas, Piyush M.,Roychowdhury, Sanjoy,Khan, Farah D.,Prisinzano, Thomas E.,Lamba, Jatinder,Schuetz, Erin G.,Blaisdell, Joyce,Goldstein, Joyce A.,Munson, Kimber L.,Hines, Ronald N.,Svensson, Craig K.
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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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- 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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- 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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- A facile and efficient method for the selective deacylation of N-arylacetamides and 2-chloro-Narylacetamides catalyzed by SOCl2
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Thionyl chloride efficiently and selectively promoted the deacylation of N-arylacetamides and 2-chloro-N-arylacetamides, under anhydrous conditions, without effecting the ester group, aminosulfonyl group, or benzyloxyamide group. This method, which has been successfully applied to a variety of substrates including different N-arylacetamides and 2-chloro-N-arylacetamides, has the attractive advantages of inexpensive reagents, satisfactory selectivity, excellent yields, short reaction time, and convenient workup. This new method can probably be used to selectively deacylate between aromatic amides and alkyl amides. Springer Science+Business Media B.V. 2011.
- Wang, Gong-Bao,Wang, Lin-Fa,Li, Chao-Zhang,Sun, Jing,Zhou, Guang-Ming,Yang, Da-Cheng
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experimental part
p. 77 - 89
(2012/05/20)
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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
(2010/02/11)
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- Evaluation of antimicrobial agents for veterinary use in the ecotoxicity test using microalgae
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The influence of antimicrobial agents approved as veterinary drugs in Japan on the growth of green algae, Selenastrum capricornutum and Chlorella vulgaris, was studied in accordance with the OECD guidelines for testing chemicals. Among the agents tested, growth inhibitory activity was very varied, i.e. erythromycin showed the strongest activity (EC50, 50% effective concentration, =0.037 mg/l), sulfa drugs had activity to some extent (EC 50s of sulfamethoxazole, sulfadiazine, and sulfadimethoxine were 1.5, 2.2, and 2.3 mg/l, respectively), but ampicillin and cefazolin did not inhibit growth (EC50s > 1000 mg/l). We also investigated synergistic effect of combining sulfa drugs with trimethoprim or pyrimethamine, which are commonly used as a combined drug. By adding trimethoprim, the growth inhibitory activity of sulfamethoxazole and sulfadiazine was significantly enhanced. Growth inhibition by sulfa drugs was reduced by the addition of folic acid, indicating that they inhibit folate synthesis in green algae.
- Eguchi, Kaoru,Nagase, Hiroyasu,Ozawa, Manao,Endoh, Yuuko S.,Goto, Kisako,Hirata, Kazumasa,Miyamoto, Kazuhisa,Yoshimura, Haruo
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p. 1733 - 1738
(2007/10/03)
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- In vitro formation, disposition and toxicity of N-acetoxy- sulfamethoxazole, a potential mediator of sulfamethoxazole toxicity
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Variation in the formation and disposition of the hydroxylamine of (SMX- HA) is thought to play an important role in the pathogenesis of sulfamethoxazole (SMX)-induced idiosyncratic adverse drug reactions. We hypothesized that, in analogy to carcinogenic arylamines, SMX-HA might be further converted to an electrophilic N-acetoxy metabolite which could play a role in mediating SMX toxicity. Accordingly, we chemically synthesized N- acetoxy-SMX, and examined the characteristics of its formation, metabolism, cytotoxicity and mutagenicity in human and bacterial test systems. The human arylamine N-acetyl-transferases, (NAT)1 and NAT2, were capable of converting SMX-HA to N-acetoxy-SMX. NAT1 and NAT2 possessed similar affinities for SMX- HA (apparent K(m) values of 650 and 520 μM, respectively), but the apparent maximal velocity of the NAT1-mediated acetylation was higher than that of NAT2. (1332 vs. 37 nmol/min/U of immunoreactive NAT protein). Human peripheral blood mononuclear cells 12,000 x g supernatant fractions converted N-acetoxy-SMX mainly back to SMX-HA, and also to a lesser extent to SMX, at clinically relevant concentrations. Similar pathways were observed in human hepatic cytosolic fractions. In a cytotoxicity assay, N-acetoxy-SMX was significantly more toxic to human peripheral blood mononuclear cells than SMX-HA (16.6 vs. 11.5% dead cells at a concentration of 300 μM). N-acetoxy- SMX was weakly mutagenic to the Salmonella typhimurium TA100 strain in the Ames test. These data suggest that the N-acetoxy metabolites of sulfonamides could potentially play a role in mediating sulfonamide idiosyncratic adverse drug reactions.
- Nakamura,Uetrecht,Cribb,Miller,Zahid,Hill,Josephy,Grant,Spielberg
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p. 1099 - 1104
(2007/10/03)
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- The metabolism of four sulphonamides in cows
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The metabolism of sulphanilamide, sulphadimidine (4,6 dimethyl 2 sulphanilamido pyrimidine), sulphamethoxazole (5 methyl 3 sulphanilamidoisoxazole) and sulphadoxine (5,6 dimethoxy 4 sulphanilamidopyrimidine) given by intravenous injection has been examined in cows. The sulphonamides were present mainly as unchanged drugs in blood samples collected 2 hr after administration. The sulphonamides were excreted in the milk partly as unchanged drugs and partly as conjugated metabolites whereas only small amounts were excreted as the N4 acetyl derivatives. The unchanged drug and the N4 acetyl derivative were the major constituents in urine samples after administration of sulphanilamide, sulphamethoxazole and sulphadoxine. Besides the unchanged drug, the N4 acetyl derivative and the conjugated metabolites, three further metabolites of sulphadimidine were isolated from urine samples and identified. They were 5 hydroxy 4,6 dimethyl 2 sulphanilamidopyrimidine, 4 hydroxymethyl 6 methyl 2 sulphanilamido pyrimidine and sulphaguanidine.
- Nielsen
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p. 1039 - 1045
(2007/10/04)
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