Structure-activity relationship studies in substituted sulfamoyl benzamidothiazoles that prolong NF-κB activation

• Published in: Bioorganic & medicinal chemistry 2021-08, Vol.43, p.116242-116242, Article 116242
• Main Authors: Shukla, Nikunj M., Chan, Michael, Lao, Fitzgerald S., Chu, Paul J., Belsuzarri, Masiel, Yao, Shiyin, Nan, Jason, Sato-Kaneko, Fumi, Saito, Tetsuya, Hayashi, Tomoko, Corr, Maripat, Carson, Dennis A., Cottam, Howard B.
• Format: Article
• Language: English
• Subjects: Adjuvant; Affinity probe; Animals; Benzamides - chemistry; Benzamides - pharmacology; Cell Line; Dose-Response Relationship, Drug; Humans; Immunization; LPS; Mice; Molecular Structure; MPLA; NF-kappa B - metabolism; NF-κB; Structure-Activity Relationship; Thiazoles; Thiazoles - chemistry; Thiazoles - pharmacology; Toll-like receptor; Vaccine
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2021.116242

[Display omitted] In the face of emerging infectious diseases, there remains an unmet need for vaccine development where adjuvants that enhance immune responses to pathogenic antigens are highly desired. Using high-throughput screens with a cell-based nuclear factor κB (NF-κB) reporter assay, we identified a sulfamoyl benzamidothiazole bearing compound 1 that demonstrated a sustained activation of NF-κB after a primary stimulus with a Toll-like receptor (TLR)-4 agonist, lipopolysaccharide (LPS). Here, we explore systematic structure–activity relationship (SAR) studies on compound 1 that indicated the sites on the scaffold that tolerated modification and yielded more potent compounds compared to 1. The selected analogs enhanced release of immunostimulatory cytokines in the human monocytic cell line THP-1 cells and murine primary dendritic cells. In murine vaccination studies, select compounds were used as co-adjuvants in combination with the Food and Drug Administration approved TLR-4 agonistic adjuvant, monophosphoryl lipid A (MPLA) that showed significant enhancement in antigen-specific antibody titers compared to MPLA alone. Additionally, our SAR studies led to identification of a photoaffinity probe which will aid the target identification and mechanism of action studies in the future.