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

Small Molecule Calcium Channel Activator Potentiates Adjuvant Activity

“… 32 We examined the same compounds in two screens for NF-κB activation after 5 and 12 h of incubation and found an active cluster of compounds with a conserved aminothiazole scaffold. 35 As proof of concept, compound 50 ( N -(4-(4-bromophenyl)thiazol-2-yl)-4-( N , N -dimethylsulfamoyl)benzamide) and compound 2D216 ( N -(4-(2,5-dimethylphenyl)thiazol-2-yl)-4-(piperidin-1-ylsulfonyl)benzamide ( Figure 1 A), which generated the highest levels of NF-κB reporter signals at 5 and 12 h respectively, were examined as potential co-adjuvants in mice with a prototypic TLR4 agonist, LPS, and ovalbumin (OVA) as a test antigen. Injection with compound 2D216 as a co-adjuvant resulted in greater levels of both antigen-specific IgG1 and IgG2c antibodies compared to LPS as a single adjuvant, whereas injection with compound 50 increased IgG1 but not IgG2c levels ( Figure 1 B,C).…”

“…In a prior structure–activity relationship (SAR) study, we examined which elements of the 2D216 scaffold are necessary for enhancement of NF-κB activity. 35 This exploratory SAR probed six different sites on the scaffold 35 and we selected a set of representative compounds (structural differences shown in color; Figure 7 A). Some of these compounds retained NF-κB activity such as 2D291 , which had a 2-bromo-5-methyl substituent on the C4-position of the thiazole ring, 2F86 bearing a 2-methyl-5-ethyl substituent on the C4-position of the thiazole ring, 2F84 with a 5-ethyl substituent on the C5-position of the thiazole ring, and 2E151 , a C4-propyl piperidine-bearing analog.…”

“…To identify small molecules that would enhance the potency of approved TLR adjuvants, we previously conducted a HTS using LPS as a primary stimulus and tested a large library of compounds for ones that protracted the NF-κB signal in reporter cells . We examined the same compounds in two screens for NF-κB activation after 5 and 12 h of incubation and found an active cluster of compounds with a conserved aminothiazole scaffold . As proof of concept, compound 50 ( N -(4-(4-bromophenyl)­thiazol-2-yl)-4-( N , N -dimethylsulfamoyl)­benzamide) and compound 2D216 ( N -(4-(2,5-dimethylphenyl)­thiazol-2-yl)-4-(piperidin-1-ylsulfonyl)­benzamide (Figure A), which generated the highest levels of NF-κB reporter signals at 5 and 12 h respectively, were examined as potential co-adjuvants in mice with a prototypic TLR4 agonist, LPS, and ovalbumin (OVA) as a test antigen.…”

“…Compounds 37 , 38 , 2D216 , 50 , 171 , 172 , 173 , and 174 were purchased from Life Chemicals Inc. (Canada). 2D216 ( 1 ) was later resynthesized along with compounds 2D291 ( 12d ), 2F86 ( 12u ), 2F84 ( 18r ), 2E151 ( 54h ), 2D224 ( 34c ), 2E121 ( 42c ), 2A250 ( 45c ), and 2E91 ( 54i ) as reported in our structure–activity relationship (SAR) studies’ publication along with its purity and identity analysis . The numbers in the brackets for each synthesized compound refer to the compound number in the published manuscript.…”

“…2D216 (1) was later resynthesized along with compounds 2D291 (12d), 2F86 (12u), 2F84 (18r), 2E151 (54h), 2D224 (34c), 2E121 (42c), 2A250 (45c), and 2E91 (54i) as reported in our structure−activity relationship (SAR) studies' publication along with its purity and identity analysis. 35 The numbers in the brackets for each synthesized compound refer to the compound number in the published manuscript. Purity for all the purchased compounds was verified to be more than 97% by LC−MS.…”