Biological Activity of Drugs. X. Relation of Structure to the Bacteriostatic Activity of Sulfonamides. (1)

Yamazaki, Masaru; Kakeya, Nobuharu; Morishita, Takashi; Kamada, Akira; Aoki, Masaru

doi:10.1248/cpb.18.702

Cited by 19 publications

(8 citation statements)

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“…Several investigators have noted that the potency of the sulfonamides may be directly related to their ability to ionize at physiologic pH (32)(33)(34). Since these drugs penetrate cellular membranes with difficulty, the best inhibitors of intact organisms were those that were half-ionized at physiologic pH, i.e., their pKa was between 6 and 7.4.…”

Section: Discussionmentioning

confidence: 99%

Interaction of sulfonamide and sulfone compounds with Toxoplasma gondii dihydropteroate synthase.

Allegra¹,

Boarman²,

Kovacs³

et al. 1990

J. Clin. Invest.

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Toxoplasma gondii is a common protozoan disease that often causes life-threatening disease, particularly among patients with the acquired immunodeficiency syndrome. This study demonstrates that the dihydropteroate synthase in T. gondii is kinetically distinct from the enzyme characterized from other sources and can be highly purified with a high yield using sequential dye-affinity chromatography. Conditions have been identified that allow for stabilization of the purified enzyme, and its physical characteristics have been elucidated. The molecular weight of the native protein was 125,000 and the protein appeared to contain both dihydropteroate synthase and 6-hydroxymethyl-dihydropterin pyrophosphokinase activities. The sulfonamide class of compounds vary in inhibitory potency by more than three orders of magnitude. Sulfathiazole, sulfamethoxazole, and sulfamethazine, with 50% inhibitory concentrations (IC50's) of 1.7, 2.7, and 5.7 MM, respectively, represent the most potent of this class of inhibitors. Several sulfone analogues, including dapsone, were identified as highly potent inhibitors with ICN's < 1 uM. The results of these cell-free experiments were corroborated by investigating the metabolic inhibition produced by the various inhibitors in intact organisms. The qualitative and quantitative relations among the inhibitors were preserved in both the cell-free and intact cell assay systems. These studies suggest that the sulfones may be important therapeutic agents for the treatment of toxoplasmosis. (J. Clin. Invest. 1990. 85:371-379.) antimetabolites.enzymology-protozoan * sulfonamides

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Section: Discussionmentioning

confidence: 99%

Interaction of sulfonamide and sulfone compounds with Toxoplasma gondii dihydropteroate synthase.

Allegra¹,

Boarman²,

Kovacs³

et al. 1990

J. Clin. Invest.

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“…The addition of p and p 2 terms to Eqns 5, 7 and 9 did not improve the correlation because of the high colinearity of the variables pK a and p. On the other hand, Fujita and Hansch (1967) stated that the addition of p and p 2 to pK a resulted in a small, but statistically significant (P 5 0.1), improvement of the relationship between pK a and log 1/[HA] for a comparable nonhomologous series of N1-heterocyclic sulfanilamides. These authors as well as Yamazaki et al (1970a) also showed that if the antibacterial activity was expressed as the concentration of the neutral form, better correlations with pK a were obtained than applying the concentration of the ionized form. However, the conclusion, therefore, that the neutral form would be more active than the ionized form is premature as will be discussed below.…”

Section: Empirical Relationshipsmentioning

confidence: 94%

“…Previous studies using bacterial cultures (whole cell systems) or cell-free folate synthesizing enzyme systems, showed that the inhibitory activity of sulfonamides depends on electronic influences and not on the hydrophobicity of these compounds. If the bacteriostatic potency, expressed in terms of total concentration, was related to electronic parameters, linear, parabolic and bilinear relationships were obtained (Bell & Roblin, 1942;Cowles, 1942;Brueckner, 1943;Yamazaki et al, 1970a; #1997 Blackwell Science Ltd, J. vet. Pharmacol.…”

Section: Empirical Relationshipsmentioning

confidence: 99%

“…Brueckner (1943) assumed different intra and extracellular pH values to explain the observed effects. Yamazaki et al showed that bilinear correlations between pK a and log 1/MIC were more appropriate than parabolic relationships (Yamazaki et al, 1970a). After reinvestigation of the data of Bell and Roblin (1942) and those of Seydel (1971) and Miller et al (1972), Silipo and Vittoria suggested bilinear relationships between pK a and inhibitory activities in whole cell and cell-free systems (Silipo & Vittoria, 1979).…”

Section: Empirical Relationshipsmentioning

confidence: 99%

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Structure‐activity relationships between antibacterial activities and physicochemical properties of sulfonamides

Mengelers¹,

Hougee²,

Janssen

et al. 1997

Vet Pharm & Therapeutics

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Relationships between the antimicrobial activities of sulfonamides and physicochemical properties including the acid dissociation constant (pKa) and the hydrophobicity constant (pi) were determined. The minimal inhibitory concentrations (MIC) of sulfonamides against Actinobacillus pleuropneumoniae, a gram-negative veterinary pathogen, were used. High performance liquid chromatography was applied for the determination of the electronic and hydrophobic parameters. Empirically determined relationships pointed out the dominant role of the degree of ionization on the antimicrobial activity. The data indicate that hydrophobic properties of sulfonamides, characterized by pi, are of minor importance for the in vitro antibacterial activity. Because of the restricted pKa range (4.9-7.7) it could not be established whether the relationship between pKa and activity was linear or bilinear. Whenever o,m-disubstituted sulfonamides were included correlations decreased substantially. Relationships based on multicompartment equilibrium models were derived and indicated a bilinear relation between pKa and MIC. Model-based equations showed that the antibacterial activity was governed by the extracellular ionic concentration of the sulfonamides whenever different intra and extracellular pH values were assumed in the equilibrium model. The antimicrobial activities of the sulfonamides against gram-positive organisms were also related to the degree of ionization of the sulfonamides in the agar medium.

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“…In the absence of a specific transport mech anism, the possibility of a selective, geneti cally coded influence must be discounted from the outset. The completely opposite tendency of the pH effect on the antibac terial effectiveness [Yamazaki et al, 1970] is also striking in this connection; a further indication that no relationship exists between the degree of accumulation and the biologi cal action. It has in the interim proved pos sible to attribute a sulfonamide resistance transmissible by plasmid to the presence of sulfonamide-insensitive enzymes [dihydropteroate synthase, see Wise and AbouDonia, 1975],…”

Section: Discussionmentioning

confidence: 66%

pH Dependency in Uptake of Sulfonamides by Bacteria

Büttner¹,

Büttner²

1980

Chemotherapy

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Sulfonamide-sensitive cells of Escherichia coli were incubated under standardized conditions with various sulfonamides and the quantity of sulfonamide uptake into the bacteria measured. The test substances reached a higher concentration inside the bacteria than in the incubation medium, the degree of accumulation varying for the individual substances despite uniformly applied incubation conditions. In all cases a pH dependency was detected which varied with the pK_a values of the substances tested. On the basis of the pK_a dependency of the pH effect, the sulfonamide uptake can be interpreted as being a passive diffusion process. Knowing the intracellular pH value, which was determined by the DMO method, it was then possible to calculate the theoretically expected value for the accumulation as a concentration coefficient. Since the calculated and experimentally determined values differ approximately by a factor of 2, an intracellular binding of the sulfonamides is assumed. The same results were obtained in cells of sulfonamide-resistant E. coli strains.

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Biological Activity of Drugs. X. Relation of Structure to the Bacteriostatic Activity of Sulfonamides. (1)

Cited by 19 publications

References 0 publications

Interaction of sulfonamide and sulfone compounds with Toxoplasma gondii dihydropteroate synthase.

Interaction of sulfonamide and sulfone compounds with Toxoplasma gondii dihydropteroate synthase.

Structure‐activity relationships between antibacterial activities and physicochemical properties of sulfonamides

pH Dependency in Uptake of Sulfonamides by Bacteria

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