Table 1.

Impact of size and hydrophobicity of carboxamide derivatives derived from the DECL hit (A127/B178) on Sirt6 deacylase activity.

Cmpd	Substituent R =	Inhibition c = 10 μM
1	H	0%
2-Me		40%[a]
2-Pr		60% (IC50 = 8.9 μM)[b] pIC50 (5.1 ± 0.03)
2-MeOEt		9%
2-PhEt		29%
2-Bn		30%[a]
2-Pip		28%
2-Ph		53% (IC50 = 9.3 μM) pIC50 (5.0 ± 0.05)
2-CyBu		64% (IC50 = 8.2 μM) pIC50 (5.1 ± 0.05)
3		3%
Nicotinamide (1000 μM)		92%

^[a]Sirt6 activity measured at c = 40 μM.

^[b]Previously measured IC₅₀ = 6.7 μM Ref.^[20] The biochemical assay used to assess the in vitro activity of the compounds was done in duplicate and repeated twice on different days.