The translational challenge in Chagas disease drug development

Structure-Guided Design and Synthesis of a Pyridazinone Series of Trypanosoma cruzi Proteasome Inhibitors

“…Flash column chromatography was performed using pre-packed silica gel cartridges (230−400 mesh, 40−63 μm, from Redisep) using a Teledyne ISCO Combiflash Companion, or Combiflash Retrieve. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance DPX 500 spectrometer ( 1 H at 500.1 MHz, 13 C at 125.8 MHz). Chemical shifts (δ) are expressed in ppm recorded using the residual solvent as the internal reference in all cases.…”

“…The crude residue was adsorbed onto silica gel (1 g), then purified by flash chromatography (0−60% EtOAc in cyclohexane) to give 11 as a pale yellow solid, (123 mg, 23%). 1 13 N-[3-(Cyclopropylcarbamoyl)-4-fluorophenyl]-1-[(4methoxyphenyl)methyl]-6-oxo-pyridazine-3-carboxamide (12). 12 was synthesized from 29c and 33 by an analogous method to 5 to yield a white solid (40 mg, 46%).…”

“…1 H NMR (500 MHz, CDCl 3 ) δ 10.47 (s, 1H), 8.42 (d, J = 3.9 Hz, 1H), 7.95 (m, 3H), 7.41 (d, J = 8.7 Hz, 2H), 7.31 (m, 1H), 7.08 (d, J = 9.7 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 5.30 (s, 2H), 3.73 (s, 3H), 2.85 (m, 1H), 0.71 (m, 2H), 0.55 (m, 2H). 13 (13). To a solution of 29d (147 mg, 0.57 mmol), HATU (255 mg, 0.67 mmol), and DIPEA (0.270 mL, 1.545 mmol) in DMF (5 mL) was added 33 (100 mg, 0.515 mmol) and stirred for 16 h. The RM was added to ice-cold water, and the resulting solid was collected, washed with cold EtOAc, then cold 50% EtOAc in pet ether, and then pentane, and dried to give 13 (105 mg, 46%).…”

“…1 H NMR (500 MHz, DMSO-d 6 ) δ 12.81 (s, 1H), 8.88 (s, 1H), 8.60 (m, 1H), 8.30 (s, 1H), 8.00 (d, J = 10.8 Hz, 1H), 7.94 (d, J = 9.6 Hz, 1H), 7.66 (d, J = 7.3 Hz, 1H), 7.46 (t, J = 6.9 Hz, 1H), 7.11 (d, J = 9.6 Hz, 1H), 5.30 (s, 2H), 3.91 (s, 3H), 3.06 (m, 1H), 0.78 (d, J = 5.2 Hz, 2H), 0.68 (s, 2H). 13 N-(4-Fluoro-3-((trans-3-methoxycyclobutyl)carbamoyl)phenyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide (19). 19 was synthesized from 28c and 34 by an analogous method to 11, with purification by flash chromatography (0−100% EtOAc in cyclohexane) and subsequent trituration with ether yielding a white solid (250 mg, 95%).…”

“…1 H NMR (500 MHz, DMSO-d 6 ) δ 10.49 (s, 1H), 8.25 (m, 1H), 8.08 (dd, J = 6.4, 2.8 Hz, 1H), 7.98 (m, 1H), 7.94 (d, J = 9.7 Hz, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.34 (t, J = 9.6 Hz, 1H), 7.08 (d, J = 9.7 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 5.30 (s, 2H), 3.73 (s, 3H), 3.59 (t, J = 4.5 Hz, 4H), 3.40 (q, J = 6.4 Hz, 2H), 2.48 (t, J = 6.8 Hz, 2H), 2.43 (s, 4H). 13…”