Quantitative Structure–Activity and Structure–Toxicity Relationships of 4‐Aminodiphenyl Sulphone Derivatives with Antiinflammatory Activity

Abstract

It has been shown that dapsone and its derivatives are not only potential inhibitors of bacterial and plasmodial folate synthesis but also possess antiin¯ammatory activity. The application of dapsone is, however, limited by its toxic side effects at higher dose manifested especially by its potential to produce methaemoglobin. We have analyzed the structural dependence of this property on a set of 29 derivatives. A highly signi®cant nonlinear dependence on the lipophilicity could be derived. Two exceptions to the general relation were found and the mechanism for these could be derived. It was also shown that the bilinear dependence is not due to lipophilicity mediated diffusion into erythrocytes. It was found that the diffusion is linearly dependent on lipophilicity. Principal Component (PC)-Analysis revealed that the antiin¯ammatory activities, determined as inhibition of zymosane stimulated cell burst and cell adhesion are orthogonal to methaemoglobin formation and cell death potential of the studied derivatives. The antiin¯ammatory activity seems to depend on electronic and steric effects of the 2 H -substituents. The orthogonality of substituent in¯uences on the toxic and wanted effects opens up the possibility to further optimize the selectivity of aminodiphenylsulphones.

QSRR: Quantitative Structure-(Chromatographic) Retention Relationships

“…Wachall et al, 350 in the study of imidazole-substituted biphenyls, potential agents for the treatment of prostate cancer, obtained correlations between biological activity and TLC retention coefficient, R M , determined on octadecylbonded silica plates. Seydel et al 351 studied the toxicity of 4-aminodiphenylsulfone derivatives used in the therapy of bacterial infections, malaria, and toxoplasmosis. It was found that methemoglobin production, reflecting compounds toxicity, significantly correlated with lipophilicity parameters determined chromatographically.…”

Validação lateral em relações quantitativas entre estrutura e atividade farmacológica, QSAR

“…O exemplo mais notável é aquele mostrado pelas sulfas, que descrevem a potência através de um coeficiente negativo para a partição 16,18,19 . Seydel e colaboradores, no entanto, encontraram outro exemplo no caso de hidrazidas do ácido nicotínico atuando frente a M. tuberculosis.…”

QSAR Study of the Fungicidal Activity of Thiophosphorylglycinamide Derivatives. Comparison of Principal Component Analysis and Spectral Mapping Technique

“…Principal component analysis (PCA) as a versatile and easy to carry out multivariate method has been frequently employed for the elucidation of the relationship between biological activity and molecular characteristics [6]. PCA has been successfully used for improving ligand selectivity in receptor-based drug design [7], for the study of the substituent effects of meta and para benzene derivatives [8], for the characterization of amino acids [9], for the evaluation of aquatic toxicity of xenobiotics [10], and for the study of the structure-activity and structure-toxicity relationships of anti in¯ammatory drugs [11]. PCA forms clusters of variables and observations taking into consideration simultaneously the strength and selectivity of the biological effect under investigation that is PCA cannot be employed when the separation of the strength and selectivity of the effect is required.…”