Quantitative structure-activity relationship study of benzylsulfanyl imidazoles as cytokine release inhibitors

J Enzyme Inhib Med Chem. 2007 Feb;22(1):15-21. doi: 10.1080/14756360600952217.

Abstract

Benzylsulfanyl imidazole derivatives (Figure 1) have shown their ability to inhibit the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) from peripheral blood mononuclear cells or human whole blood. Such anticytokine actions of these congeners are quantitatively studied using Fujita-Ban and Hansch type analyses. The Fujita-Ban study resulted in the contributions of different substituents and the parent moiety for the inhibitions of cytokines TNF-alpha and IL-1beta. The substituents that have a higher positive contribution to the given activity, relative to substituents of the parent moiety at different positions were then used to obtain a trend for the active analogues. None of the substituents present at X, Y, 2-R and 3-R, appears to be advantageous over the substituents of the parent moiety for inhibition of both the cytokines. However, the substituents at 4-R, 5-R and 6-R help to improve the inhibitory actions of the compounds for both cytokines. The optimal activities seem to be manifested by compounds in which 4-R, 5-R and 6-R are substituted respectively by OH (or SOCH3 and SO2CH3), Cl and OH for inhibition of TNF-alpha, whereas by SOCH3 (or SO2CH3 and OH), H and OH for inhibition of IL-1beta. The Hansch type analysis, on the other hand, revealed that the F-substituents of the X-position and a less bulky structural moiety such as--S(CH2)2--at the Y-incision are advantageous in improving the inhibitory action towards TNF-alpha. Similarly, a less bulky/polar substituent present at 2-R and not having a hydrogen-bond donor property, while a more hydrophobic substituent at 3-R and hydrogen-bond acceptor substituent at 4-R are helpful in augmenting inhibitory activity of a compound. However, for inhibition of cytokine IL-1beta, it emerged that the X-substituents that transmits a higher negative resonance effect, the Y-substituent that offers less molecular bulk are beneficial. The R-substituents, being more electron donors at the meta-position, less hydrophobic at the para-position and offering smaller refractivity (less bulky and or polar) at the ortho-position are likewise helpful in improving the activity of a compound.

MeSH terms

  • Cytokines / antagonists & inhibitors*
  • Cytokines / metabolism
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology*
  • Quantitative Structure-Activity Relationship

Substances

  • Cytokines
  • Imidazoles