Sulfonamides binding

Fig. 1.14 (a) The pH dependence of the rate constants for the association of carbonic anhydrase B (E) and p-nitrobenzenesnlfonamide (S). The reaction is monitored by nsing stopped-flow and the quenching of a tryptophan fluorescence in the protein which occurs when sulfonamides bind. The full line fits Eqn. (1.226) with k = 3.5 X lO M- s-, pA g = 7.5 and pK =... 

K. K. Kannan, I. Vaara, B. Notstrand, S. Lovgren Borell, K. Fridborg, M. Petef (1977). Structure and function of carbonic anhydrase comparative studies of sulfonamide binding to human erythrocyte carbonic anhydrases B and C. In G. C. K. Roberts (Ed.). Drug Action at the Molecular Level. Baltimore University Park Press, pp. 73-91. 

Drugs with high affinities for plasma albumin can also displace drugs with lower affinities. For example, sulfonamides bind to plasma proteins, but if phenylbutazone, which has a greater affinity for the binding sites, is administered, the concentration of the free sulfonamides in the plasma will increase due to drug displacement. 

Taylor, P. W., and Burgen, A. S. V. Kinetics of carbonic anhydrase inhibitor complex formation. A comparison of anion- and sulfonamide-binding mechanisms. Biochemistry JO, 3859-3866(1971). 

Hsiao CH, Rhodes HJ, Blake ML Fluorescent probe study of sulfonamide binding to povidone. J Pharm Sci 1977 66 1157-1159. 

Testa, B. and Purcell, W.P. (1978). A QSAR Study of Sulfonamide Binding to Carbonic Anhy-drase as Test of Steric Models. EurJ.Med.Chem., 13,509-514. 

The mechanistic interpretation of the rate and equihbrium data for aryl sulfonamide binding to carbonic anhydrase, gathered by Taylor et al. 116, 117, 119) and by others 118, 123, 124, 130), is complicated by the ambiguity inherent in the pH-dependence of the apparent association rate constants for complex formation (Fig. 9). Taylor et al. 119) found that for several aryl sulfonamides the apparent bimolecular association rate constant (Aa) is highly dependent on pH, while the unimolecular dissociation rate constant ( a) is virtually independent of pH in the pH range 5.5 to 10.5. The bell-shaped dependence of on pH (Fig. 9) was found to adhere quantitatively to the theoretical curve predicted for a rate process dependent on two protic ionizations. The first ionization was found to correspond numerically to the aforementioned enzyme pKa of 7. The second ionization was found to correspond closely to the ionization constant of the sulfonamide group of the inhibitor. Furthermore, the visible spectrum of the Co(II) enzyme-sulfonamide complex was found to be independent of pH. This fact, as... 

On the basis of the similarities between the kinetic and thermodynamic characteristics of mono-anion binding and sulfonamide binding it seems probable that both mono-anion binding and sulfonamide binding occur by the same pathway,... 

The mechanism for anion and/or sulfonamide binding shown in Eq. (38) accommodates all of the available kinetic data except for the anomalous behavior of p- (salicyl-5-azo) benzene-sulfonamide. 

The IR studies of Riepe and Wang 125) indicate that CO2 is not coordinated to zinc ion in the enzyme-C02 complex, and CO 2 does not perturb the spectrum of the Co(II) enzyme (72/). (2) Alkylation of His-63 with bromopyruvate 135) only brings about a 70 percent decease in the activity of human carbonic anhy-drase C. Therefore, the chemical integrity of His-63 is not crucial to catalytic activity. (3) It is unlikely that anion or sulfonamide binding could sufficiently perturb the pKa of His-63 to account for the ionization properties of these complexes, and it is not apparent from the X-ray structure of the Co(II) enzyme 41, 106) how the ionization of His-63 can account for the pH-dependence of its visible cobalt(II) spectrum. 

Boriack PA, Christianson DW, Kingery-Wood J, Whitesides JM. Secondary interactions significantly removed from the sulfonamide binding pocket of carbonic anhydrase II influence inhibitor binding constants. J Med Chem 1995 38 2286-2291. 

In subsequent studies attempting to find a correlation of physicochemical properties and antimicrobial activity, other parameters have been employed, such as Hammett O values, electronic distribution calculated by molecular orbital methods, spectral characteristics, and hydrophobicity constants. No new insight on the role of physiochemical properties of the sulfonamides has resulted. Acid dissociation appears to play a predominant role, since it affects aqueous solubiUty, partition coefficient and transport across membranes, protein binding, tubular secretion, and reabsorption in the kidneys. An exhaustive discussion of these studies has been provided (10). 

In a few cases, A/ -heterocycHc sulfanilamides have been prepared by the condensation of an active heterocycHc haHde with the sulfonamide nitrogen of sulfanilamide or its A/-acetyl derivative in the presence of an acid-binding agent. Sulfapyridine, sulfadiazine, and sulfapyrazine have been made by this method (1), but the most important appHcation is probably for the synthesis of sulfachlorapyridazine (9) and sulfamethoxypyridazine (10) (45). 

Sulfaphenazole (684) and sulfazamet (685) are both examples of relatively short acting sulfonamides (B-80MI40406) and their antibacterial activity has been tested against Escherichia coli, the former being more effective than the latter. Sulfaphenazole also displaces sulfonyl ureas from protein binding sites on human serum albumin and consequently increases the concentration of the free (active) drug and produces a more intense reaction that may result in hypoglycemia. 

The investigation of minor groove-binding polyamides was greatly accelerated by the implementation of solid-phase synthesis [48]. Originally demonstrated on Boc-y9-Ala-PAM resin with Boc-protected monomers, it was also shown that Fmoc chemistry could be employed with suitably protected monomers and Fmoc-y9-Ala-Wang resin (Fig. 3.8) [49]. Recently, Pessi and coworkers used a sulfonamide-based safety-catch resin to prepare derivatives of hairpin polyamides [50]. Upon activation of the linker, resin-bound polyamides were readily cleaved with stoichiometric quantities of nucleophile to provide thioesters or peptide conjugates. 

Another important function of albumin is its ability to bind various ligands. These include free fatty acids (FFA), calcium, certain steroid hormones, bilirubin, and some of the plasma tryptophan. In addition, albumin appears to play an important role in transport of copper in the human body (see below). A vatiety of drugs, including sulfonamides, penicilhn G, dicumarol, and aspirin, are bound to albumin this finding has important pharmacologic implications. 

The macrolide erythromycin inhibits protein synthesis and resistance is induced by N -dimethyl-ation of adenine within the 23S rRNA, which results in reduced affinity of ribosomes for antibiotics related to erythromcin (Skinner et al. 1983). Sulfonamides function by binding tightly to chromosomal dihydropteroate synthetase and resistance to sulfonamides is developed in the resistance plasmid through a form of the enzyme that is resistant to the effect of sulfonamides. 

Chakraborty, S., Sengupta, C., Roy, K. Exploring QSAR with E-state index Selectivity requirements for COX-2 versus COX-1 binding of terphenyl methyl sulfones and sulfonamides. Eioorg. Med. Chem. Lett. 2004, 14, 4665-4670. 

Chloro- and sulfonamide-substituted aromatic amides showed decreased binding affinity and in vivo potency compared to the simple aliphatic amides. Side chains with an additional (CH2)i-2 linker between the amide and the phenylsulfonamide group resulted in partial or absent in vivo effects [113]. The (CH2)-linked compound, (153), showed around 80-fold selectivity for CB2 over CBi binding [107]. 

Host factors can help to ensure selection of the most appropriate antimicrobial agent. Age is an important factor in antimicrobial selection. With regard to dose and interval, renal and hepatic function varies with age. Populations with diminished renal function include neonates and the elderly. Hepatic function in the neonate is not fully developed, and drugs that are metabolized or eliminated by this route may produce adverse effects. For example, sulfonamides and ceftriaxone may compete with bilirubin for binding sites and may result in hyperbilirubinemia and kernicterus. Gastric acidity also depends on... 

Jones-Hertzog, D.K. Jorgensen, W.L., Binding affinities for sulfonamide inhibitors with human thrombin using Monte Carlo simulations with a linear response method, J. Med. Chem. 1997, 40, 1539-1549... 

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