Fig 1.
Known antichagasic agents (1–3) and cysteine protease inhibitors evaluated in the current study (4–12).
Fig 2.
Synthesis of compounds 5 and 6.
Reagents and conditions: (i) SOCl2, MeOH, r.t., 2.5 h, reflux 30 min, r.t. 4 h, 88%; (ii) PhC (= O)CF3, K2CO3, MeOH, 50°C, 18 h, R = H 66%, R = OCH3 58%; (iii) THF, NaBH4, R = H 67%, R = OCH3 56%; (iv) HATU, 1-amino-1-cyclopropanecarbonitrile, DIPEA, DMF, r.t., 24 h, R = H 92%, R = OCH3 90%.
Table 1.
Inhibition of cruzain and cathepsins by nitrile-based cysteine protease inhibitors.
Fig 3.
Concentration-response of anti-trypanosomal activity for compounds 5 and 11 (c = concentration of compound; M = mol/dm3).
Table 2.
Anti-trypanosomal activity of cysteine protease inhibitors.
Fig 4.
Overlay of cathepsin K inhibitors based on cyclohexane dicarboxamide (green) and odanacatib (red) scaffolds generated by alignment of Protein Data Bank (www.rcsb.org) [26] entries 1VSN [27] and 4DMX [24].
Cysteine sulfur with which the nitrile carbon forms a covalent bond is shown as a yellow sphere.