Small molecule prevents inflammation in microglia by targeting the NLRP3 inflammasome

Abstract

Abstract Uncontrolled CNS inflammation forms the pathophysiological basis of numerous disorders, including Alzheimer’s disease (AD). Evidence strongly suggests that the inhibition of the NLRP3 inflammasome is a promising strategy for the treatment of AD. A variety of natural products including curcumin, resveratrol, and isoliquiritigenin have displayed encouraging in vitro NLRP3 inhibitory activity. These natural products, however, are reported to display low chemical and/or enzymatic stability and therefore are not considered as promising leads for drug discovery. Using computer-assisted drug design methods and classical medicinal chemistry approaches, we developed a small library of tertiary sulfonylurea compounds that resembled the 3D-structure of the aforementioned natural products without the moieties responsible for the reported chemical and enzymatic instability. The compounds were synthesized, characterized, and tested for their inflammasome inhibitory activity. Preliminary studies indicated two of our compounds decreased the NLRP3 expression in a dose-dependent manner. These compounds reduced the production of inflammatory markers, such as, IL-1b, TNF-a, and caspase 1. These compounds lower the levels of inducible nitric oxide synthase and NO biosynthesis. MTT assays revealed that the sulfonylurea compounds did not affect N9 cell viability. Using computational chemistry and pharmacophore modeling, our efforts are currently on structural modifications to improve their biological activity and penetration the blood-brain barrier.