Synthesis and Anti-inflammatory evaluations of Novel Catecholopyrimidine derivatives for the treatment of Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting millions of people worldwide. Dysregulated cytokine release from activated immune cells is the major underlying cause of AD. For the past decades, the discovery of phosphodiesterase 4 (PDE4) inhibitors as anti-inflammatory drugs for the treatment of atopic dermatitis (AD) have been investigated. However, a fewer number of drugs only approved by the United States federal drug administration (US-FDA). PDE4 is a major cyclic adenosine monophosphate (cAMP) hydrolyzing enzyme and play an important role in the inflammatory response. PDE4 enzyme is primarily found in inflammatory and immune cells. Selective inhibition of PDE4 enzyme favorably suppresses the production of inflammatory cytokines and subsequently arrest the development of atopic dermatitis via modulating the intracellular cAMP levels. Considering the side effects of corticosteroids, selective inhibition of PDE4 could constitute an effective alternative therapy for the treatment of atopic dermatitis (AD).

In this work, a series of novel catechol based compounds bearing a pyrimidine as the core have been designed and synthesized. In chapter I, introduction to atopic dermatitis and PDE4 enzyme is presented. In chapter II, design, synthesis, molecular docking, in-vitro and in vivo properties of the synthesized compounds is presented. In vitro PDE4 enzyme assay confirmed that compounds 1 and 23 specifically inhibits PDE4B enzyme. The in-vivo animal study of the active compounds 1 and 23 were analyzed using DNCB-induced Balb/c and NC/Nga mice. The animal study confirmed that compound 23 suppressed the levels of pro-inflammatory cytokines such as TNF-α, IL-4, IL-5, and IL-17. Moreover, compound 23 significantly reduced the infiltrative CD4+ T-helper cells, mast cells and IgE levels in atopic tissue. Thus, the in-vitro and in-vivo data suggested that compound 23 specifically inhibited the PDE4B enzyme and the symptoms of the AD in atopic mice. Taken together, this work suggested that compound 23 could be an effective PDE4B inhibitor for the potential treatment of AD.

Keywords: atopic dermatitis

phosphodiesterase-4

molecular docking

catecholopyrimidine

dinitrochlorobenzene.