Sulfanilamide Derivatives. I

Adams, Roger; Long, Peng-Wei; Johanson, A. J.

doi:10.1021/ja01878a022

Cited by 9 publications

(5 citation statements)

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“…A solution of 22 (9.2 g, 33.79 mmol) in CH 3 OH (250 mL) containing concentrated HCl (1.4 mL, 16.90 mmol) and with 5% Pd on activated carbon (1.0 g) in suspension, in a Parr apparatus, was shaken under 40 psi of hydrogen gas for 18 h. The reaction mixture was filtered through Celite, the catalyst washed with CH 3 OH (500 mL), and the solvent removed under reduced pressure. Extractive workup (EtOAc) gave the product as a pale yellow solid (7.5 g, 92%): mp 210−213 °C (lit …”

Section: Methodsmentioning

confidence: 99%

Structure-Based Design of Lipophilic Quinazoline Inhibitors of Thymidylate Synthase

et al. 1996

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To develop novel lipophilic thymidylate synthase (TS) inhibitors, the X-ray structure of Escherichia coli TS in ternary complex with FdUMP and the inhibitor 10-propargyl-5,8-dideazafolic acid (CB3717) was used as a basis for structure-based design. A total of 31 novel lipophilic TS inhibitors, lacking a glutamate residue, were synthesized; 26 of them had in common a N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylaniline+ ++ structure in which the aniline was appropriately substituted with simple lipophilic substituents either in position 3 or 4, or in both. Compounds were tested for their inhibition of E. coli TS and human TS and also for their inhibition of the growth in tissue culture of a murine leukemia, a human leukemia, and a thymidine kinase-deficient human adenocarcinoma. The crystal structures of five inhibitors complexed with E. coli TS were determined. Five main conclusions are drawn from this study. (i) A 3-substituent such as CF(3), iodo, or ethynyl enhances binding by up to 1 order of magnitude and in the case of CF(3) was proven to fill a nearby pocket in the enzyme. (ii) A simple strongly electron-withdrawing substituent such as NO(2) or CF(3)SO(2) in the 4-position enhances binding by 2 orders of magnitude; it is hypothesized that the transannular dipole so induced interacts favorably with the protein. (iii) Attempts to combine the enhancements of i and ii in the same molecule were generally unsuccessful (iv) A 4-C(6)H(5)SO(2) substituent provided both electron withdrawal and a van der Waal's interaction of the phenyl group with a hydrophobic surface at the mouth of the active site. The inhibition (K(is) = 12 nM) of human TS by this compound, 7n, showed that C(6)H(5)SO(2) provided virtually as much binding affinity as the CO-glutamate which it had replaced. (v) The series of compounds were poorly water soluble, and also the potent TS inhibition shown by several of them did not translate into good cytotoxicity. Compounds with large cyclic groups linked to position 4 by an SO or SO(2) group did, however, have IC(50)'s in the range 1-5 microM. Of these, 4-(N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylamino )phenyl phenyl sulfone, 7n, had IC(50)'s of about 1 microM and was chosen for further elaboration.

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Section: Methodsmentioning

confidence: 99%

Structure-Based Design of Lipophilic Quinazoline Inhibitors of Thymidylate Synthase

et al. 1996

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“…Hapten S12: 4-amino-N-(3-hydroxypropyl)-benzenesulfonamide. This hapten was obtained following a similar strategy described by Adams et al 27 4-Acetylamino-benzenesulfonyl chloride (11.7 g, 50 mmol) was added portionwise to a solution of 3-amino-1-propanol (7.5 g, 0.1 mol) in 100 mL of water, cooled at 0 C. After shaking for 2 h at room temperature, the reaction mixture was chilled. The white precipitate formed was isolated by filtration and dried, yielding N-[4-(3-hydroxypropylsulfamoyl)phenyl]-acetamide as a white solid (12.05 g, 89%) which did not require further purification.…”

Section: Hapten Synthesismentioning

confidence: 99%

Development of immunoassays to determinate sulfamethoxazole residues in wastewaters

et al. 2009

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Different immunoassays have been developed to monitor sulfamethoxazole (SMX), an antibiotic frequently detected in water. The immunoassays were developed and optimized in two different formats: ELISA in polystyrene 96-well plate and microarray on compact disc (CD) support. Competitive microimmunoassays were performed by direct adsorption of immunoreagents on the polycarbonate surface of a low-reflectivity CD. Results were displayed using nanogold-labeled immunoglobulins and silver staining developer. High sensitivity was achieved with both formats: LD 0.001 ng mL(-1) in the ELISA-plate, and 0.09 ng mL(-1) in the CD format. The novel CD methodology presents advantages such as simplicity, sensitivity, portability, analytical capacity (2560 spots per disc), in addition to reductions in immunoreagents required, costs and time for analysis. Both proposed methods were applied to determine SMX at nanograms per litre level in wastewater samples without previous preconcentration. Finally, the determination of several fortified wastewater samples using the CD format protocol showed a mean recovery of 87%, which confirms that this assay format is a good screening tool to detect sulfamethoxazole in water samples rapidly and reliably.

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“…The procedure employed for the condensation of p-fluoroaniline with p-acetaminobenzenesulfonyl chloride was an adaptation of a more or less general method (1,8,9,10). The amine is generally mixed with the acid chloride in molar proportions in some solvent in which both are soluble.…”

Section: Nfi-p-fluorophenyl-n4-acelylsulfanilamide-mentioning

confidence: 99%