Efficient synthesis, biological evaluation, and docking study of isatin based derivatives as caspase inhibitors

Figures & data

Figure 1. Some of the reported caspase-3 inhibitors. IC₅₀ = 120 nM; IC₅₀ = 44 nM; IC₅₀ = 2.5 nM. IC₅₀ = 46.7µM; IC₅₀ = 0.086 µM; IC₅₀ = 0.031 µM

Figure 2. 2 D and 3 D representations of 20d interactions with caspase-3 active site.

Scheme 1. (A) Synthesis route for A series. Reagents and conditions. a: CH₂Cl₂, Et₃N; b: NaH, DMF (B) Synthesis route for B series. Reagents and conditions. a: ClSO₃H; b: pyrrolidine or 16, Et₃N, DMF, c: acetic acid; d: 9 or propargyl bromide, NaH, DMF, 0 ˚C; e: p-toluenesulfonyl chloride, pyridine; f: phenol, NaH, THF; g: TFA, CH₂Cl_2.

Table 1. Structures of compounds 11a–k, 19a–k, and 20a–k displaying inhibitory effects on caspase-3 and -7.

^aIC₅₀ values are expressed as Mean ± SD of three experiments. ^bN.D. = Not determined. ^cIC₅₀ amount for Ac-DEVD-CHO is 0.016 ± 0.002 μM. ^dThe values given in bracket are percentage inhibition. ^dSelectivity Index (SI) was calculated as IC₅₀ caspase-7/IC₅₀ caspase-3.

Figure 3. Superimposition of the binding pose for 20d and natural ligand at the 1GFW active site.

Figure 4. 2 D representations of 20d (A) and isatin sulphonamide (B) interactions with caspase-3 active site.

Table 2. The interactions of compound 20d and natural ligand in 1GFW at the active site.

Interaction type	20d	Isatin Sulphonamide
Van der waals	–	–
Conventional hydrogen bond	–	Arg 207, Gly 122
Carbon hydrogen bond	–	His 121
Pi-pi stacked	Phe 256	Phe 256
Pi-pi T-shaped	His 121, Tyr 204	Tyr 204
Pi-alkyl	Trp 206. Tyr 204	Trp 206
Pi-cation	His 121	–
Pi-hydrogen bond	Tyr 204	Cys 163
Pi-sulfur	Cys 163	–