Studies on the Inhibitory Effects of Analogues of Dapsone on Neutrophil Function In-vitro

Abstract

We have compared twelve sulphone analogues of dapsone in terms of inhibition both of zymosan-mediated human neutrophil respiratory burst and inhibition of interleukin-1-stimulated neutrophil adhesion to transformed human umbilical vein endothelial cells. Overall, there was a good correlation between the respective rank orders of compound potency in the two test systems. The most effective compounds in terms of respiratory burst and adherence inhibition were the 2-nitro-4-amino-, 2-hydroxy-4-aminopropyl-, and 2-methoxy-4-aminoethyl- derivatives. In general, potency was inversely associated with lipophilicity; compounds with bulky side-chains, e.g. the 2-methyl-4-aminopentyl, 2-methyl-4-aminohexyl and the 2-hydroxymethyl-4-aminoethyl derivatives, were less potent. A 2-hydroxy-4-amino- derivative was the exception, however, with low lipophilicity and relatively low potency. All of the compounds tested showed comparable or greater inhibition in both the neutrophil-mediated assays compared with dapsone. Some of the compounds might, because of their good tissue penetration and lower toxicity than dapsone, have the potential to undergo further development.

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

“…These derivatives are of interest with respect to their toxic properties because of their increased antibacterial and antiin¯ammatory activities [3,19,20]. The two compartment system as described in the experimental section was used to determine the % methaemoglobin produced by 100 mM of the test substances.…”

“…Preliminary animal and in vitro studies [16,18] have indicated that a number of these analogues are far less toxic than dapsone. In consequence a series of these dapsone analogues have been toxicologically tested using human and rat tissues and their inhibitory effects on neutrophil function determined in vitro [19,20].…”

“…The antiin¯ammatory activities, expressed as inhibition of the neutrophil zymosan-mediated respiratory burst (cellbr), the inhibition of neutrophil interleukin-1 stimulated cell adhesion (celladh) and the methaemoglobin formation of sulphones have been studied on a smaller set of 11 derivatives [20]. First a PC-analysis has been performed to analyze for possible multiple intercorrelations amongst the three test systems.The result shows that with 2 PC's 89% of the total information can be extracted.…”

“…Chemiluminescence readings were taken in intervals. Before analysis samples of puri®ed neutrophiles or whole blood were incubated with the compounds (0.5, 1.0, or 1.5 mM) for 30 min at 37 C. For details see [20].…”

Management of Oro-Cutaneous Manifestations in Behçet disease and Recurrent Oral Aphthosis, review article

“…70 Other studies have suggested that dapsone inhibits leukotrine B4 binding to neutrophils, 71 , and inhibits the neutrophil response to some chemotactic stimuli 72 such as inhibiting inter-leukin 1-stimulated neutrophil adhesion to endothelial cells. 73 The fact that dapsone is retained in the skin and that trace concentrations of the drug may present in the skin up to 3 weeks after discontinuation of dapsone therapy may account for the observation that parameters tended to reach pretreatment values only at about one month after discontinuation of the drug. The frequency of dapsone side effects are much low than what has been reported if is used in ordinary 100mg daily dose.…”