Fluorobenzoyl dipeptidyl derivatives as inhibitors of the Fasciola hepatica cysteine protease cathepsin L1

Figures & data

Scheme 1.  Reagents and conditions: (a) l-Leu or l-Ala, NaOH; (b) C-protected amino acid, DCC, HOBt, TEA, DCM.

Table 1.  In vitro inhibitory activity of N-fluorobenzoyl dipeptidyl benzyl esters 1–12, and compounds 37 and 38, with the Fasciola hepatica cysteine cathepsin L endoprotease FhCL1.

Compound	X	n	IC50 (μM)
1	2-F	1	>100
2	3-F	1	>100
3	4-F	1	43.4
4	Penta-F	1	39.5
5	2-F	2	29.4
6	3-F	2	24.8
7	4-F	2	62.3
8	Penta-F	2	57.7
9	2-F	3	15.3
10	3-F	3	40.1
11	4-F	3	19.3
12	Penta-F	3	21.4
37	—	—	10.0
38	—	—	11.0

Table 2.  In vitro inhibitory activity of N-fluorobenzoyl dipeptidyl nitriles 13–20, and compounds 37 and 38, with the Fasciola hepatica cysteine cathepsin L endoprotease FhCL1.

Compound	X	R1	n	IC50 (μM)
13	2-F	s-Bu	1	3.0
14	4-F	s-Bu	1	2.8
15	2-F	-CH3	1	87.6
16	Penta-F	-CH3	1	68.3
17	2-F	s-Bu	2	24.3
18	4-F	s-Bu	2	21.6
19	2-F	-CH3	2	>100
20	Penta-F	-CH3	2	>100
37	—	—	—	10.0
38	—	—	—	11.0

Figure 1.  Commercially available inhibitor 39.

Figure 2.  Bar chart illustration of percent inhibition of 39, 21, 27, and 36 toward cathepsin L at varying concentrations (μM).

Table 3.  In vitro inhibitory activity of N-fluorobenzoyl dipeptidyl nitriles 21–36, and compounds 37 and 38, with the Fasciola hepatica cysteine cathepsin L endoprotease FhCL1.

Compound	X	IC50 (μM)	Compound	X	IC50 (μM)
21	3-F	3.1	30	2,4,5-F	4.5
22	2,3-F	3.4	31	3,4,5-F	3.4
23	2,4-F	5.5	32	2,3,4,5-F	3.4
24	2,5-F	3.1	33	Penta-F	4.4
25	2,6-F	3.7	34	2-CF3	4.1
26	3,4-F	3.1	35	3-CF3	9.1
27	3,5-F	3.0	36	4-CF3	3.2
28	2,3,6-F	6.0	37	—	10.0
29	2,3,4-F	4.1	38	—	11.0