Identification of sulphonamide-tethered N-((triazol-4-yl)methyl)isatin derivatives as inhibitors of SARS-CoV-2 main protease

Figures & data

Figure 1. Structures of isatin and some reported main SARS-CoV protease inhibitors (I and II), as well as the target triazolo isatins (6a-d and 10a-b).

Scheme 1. Reagent and conditions: (i) Dry dioxane, K₂CO₃, stirring r.t., 12 h; (ii) NaN₃, DMF, stirring r.t., 8 h; (iii) Dry acetonitrile, K₂CO₃, Stirring r.t., 10 h; (iv) DMF/H₂O, CuSO₄.5H₂O, sodium ascorbate, heating at 60 °C, 7 h.

Scheme 2. Reagent and conditions: (i) Dry dioxane, K₂CO₃, stirring r.t., 12 h; (ii) NaN₃, DMF, stirring r.t., 8 h; (iii) 5a or 5c, DMF/H₂O, CuSO₄.5H₂O, sodium ascorbate, heating at 60 °C, 7 h.

Table 1. In vitro inhibitory effect of target triazolo isatins (6a-d and 10a-b) against 3CL-Pro, using (GC376) as a standard drug.

Comp.	R	^aIC50 (μM)
6a		0.562 ± 0.005
6b		0.249 ± 0.006
6c		0.939 ± 0.007
6d		1.054 ± 0.053
10a		12.28 ± 0.73
10b		17.075 ± 0.815
GC376		0.063 ± 0.001

^a Mean from two different assays.

Figure 2. CC₅₀ and IC₅₀ values for isatin derivative 6b.

Figure 3. Redocking of the co-crystalised ligand GC-14 into SARS-CoV-2 Mpro binding site.

Figure 4. Compound 6b (in green) in 3D style overlaid with GC-14 (in blue).

Figure 5. 2D and 3D interaction diagram of compound 6b with SARS CoV-2 Mpro binding site.

Figure 6. RMSD analysis for the MD simulations.

Figure 7. RMSF analysis for the MD simulations.