3-(5-Hydroxyphenyl)-5-Phenyl-2-Pyrazolines as Toll-Like Receptor 7 Agonists

Abstract

Toll-like receptor 7 (TLR7) is an attractive target for developing immune modulators to enhance innate immunity against ssRNA virus infections, including hepatitis C and COVID-19. Ten 3-(5-hydroxyphenyl)-5-phenyl-2-pyrazolines were tested using TLR7 reporter cells, overexpressing TLR7 and the NF-κB-inducible SEAP reporter gene to discover a novel TLR7 agonist enhancing innate immunity. Of these, 2-(3-(2-hydroxynaphthalen-1-yl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (compound 6) showed the best TLR7 agonistic activity, and further experiments were carried out to study the immune-modulatory capability of compound 6. Treatment with compound 6 rapidly induced phosphorylation of IRAK4, IKKα/β, IκBα, and p65/RelA in THP1 monocytic cells. In addition, it increased the expression of NF-κB-regulated innate cytokines, such as TNFα and IL1β, in THP1 monocytic cells. These data suggest that compound 6 induces an innate immune response by agonizing TLR7 activity in THP1 human monocytic cells. Therefore, compound 6 can be used as an innate immune modulator to develop antiviral agents and vaccine adjuvants.