138384-97-1Relevant articles and documents
Structure-activity relationship studies in substituted sulfamoyl benzamidothiazoles that prolong NF-κB activation
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.
, (2021/07/19)
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.
Crystal-Structure-Based Design and Synthesis of Benzindole-Containing Inhibitors of Thymidylate Synthase
Varney, Michael D.,Marzoni, Gifford P.,Palmer, Cindy L.,Deal, Judith G.,Webber, Stephanie,et al.
, p. 663 - 676 (2007/10/02)
The X-ray crystal-structure-based design, synthesis, and biological activity of a novel family of benzindole-containing inhibitors of thymidylate synthase (TS) are described.The structure-activity of the lead compound was studied by conceptually dividing the molecule into four regions and independently optimizing the substituents for each region.Combination of favored substituents for each region led to inhibitors with Ki's against the human enzyme in the range of 10-20 nM.Thymidine shift experiments suggested that the cytotoxic properties of the best enzyme inhibitors were due to TS targeting in cells.The inhibitors were synthesized from substituted 6-aminobenzindol-2(1H)-ones by alkylation with both a simple alkyl group and a substituted benzylic portion.The 2,6-diaminobenzindoles were prepared from the corresponding lactams by conversion to the thiolactam, alkylation to the methylated thiolactam, and then displacement with a substituted or unsubstituted amine.
