Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists

doi:10.1038/s41467-021-24536-4

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Nat Commun. 2021; 12: 4351.

Published online 2021 Jul 16. doi: 10.1038/s41467-021-24536-4

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Table 1

Analysis of the structure–activity relationship of the tetrasubstituted imidazole analogs.


Compounds	R¹	R²	R³	R⁴	R⁵	TLR7 Inhibition^[a]	TLR8 Inhibition^[a]
1a	–CN	–OH	–H	–H	–H	1.0±0.2	1.1±0.2
1b		–OH	–H	–H	–H	0.8±0.1	1.0±0.2
1c	–CONH₂	–OH	–H	–H	–H	1.0±0.1	0.7±0.1
1d	–CHO	–OH	–H	–H	–H	1.2±0.2	1.2±0.2
1e	–COOCH₃	–OH	–H	–H	–H	0.9±0.2	0.9±0.2
1f	–CH₂OH	–OH	–H	–H	–H	0.9±0.2	1.0±0.2
1g	–CH₂OCH₃	–OH	–H	–H	–H	0.9±0.2	1.0±0.3
1h	–CH₃	–OH	–H	–H	–H	0.9±0.1	0.8±0.2
1i	–CH₂F	–OH	–H	–H	–H	0.8±0.2	1.0±0.2
1j	–C(CH₃)₂OH	–OH	–H	–H	–H	0.8±0.1	0.9±0.1
1k	–CH(CH₃)₂	–OH	–H	–H	–H	0.7±0.1	0.9±0.2
1l	–Ph	–OH	–H	–H	–H	0.8±0.1	0.6±0.0
1m	–H	–OH	–H	–H	–H	1.0±0.1	1.1±0.3
1n	–Cl	–OH	–H	–H	–H	1.1±0.2	0.6±0.1
1o	–Br	–OH	–H	–H	–H	0.8±0.2	0.3±0.2
1p (CU-CPD107)	–I	–OH	–H	–H	–H	1.0±0.2	0.1±0.1
1q	–COOH	–OH	–H	–H	–H	0.9±0.2	0.9±0.2
2a	–H	–H	–H	–H	–H	0.6±0.2	0.8±0.1
2b	–Cl	–H	–H	–H	–H	0.6±0.2	0.5±0.2
2c	–Br	–H	–H	–H	–H	0.1±0.1	0.0±0.1
2d	–I	–H	–H	–H	–H	0.1±0.2	0.0±0.0
3a	–I	–OH	–H	–H	–Ph	0.4±0.0	0.3±0.1
3b	–I	–OH	–H	–Ph	–H	0.7±0.1	0.1±0.1
3c	–I	–OH	–CH₃	–H	–H	1.0±0.0	0.9±0.1
3d	–I	–OH	–H	–CH₃	–H	1.0±0.1	0.8±0.1
3e	–I	–OH	–H	–H	–CH₃	1.0±0.0	0.9±0.1

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^[a]The values reported represent the fraction of signaling observed using SEAP assay in HEK-Blue hTLR7 and hTLR8 cells compared to uninhibited R848 signaling, which was normalized to 1.0. Data are representative of the average and standard deviation of at least three independent experiments.