Abstract
The treatment of Human African trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important; pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp., has been identified as a candidate target, and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from Trypanosoma brucei (J. Med. Chem.2010, 53, 221–229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. Eight compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus, although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development.
Highlights
The crude material was purified by HPLC, fractions containing the required product were collected and freeze dried to give lilac colored solid (60 mg, 16%), mp > 230 oC. 1H NMR (DMSO-d6): 11.16 (1H, s), 10.31 (1H, s), 7.84 (2H, d, J = 8.0 Hz), 7.10 (2H, d, J = 8.0 Hz), 6.96 (1H, d, J = 2.4 Hz), 6.13 (2H, br), 2.29 (3H, s)
The crude material was purified by HPLC, fractions containing the required product were collected and freeze dried to give lilac colored solid (72 mg, 20%) with no distinct melting point. 1H NMR (DMSO-d6): 10.78 (1H, s), 10.47 (1H, s), 7.28-7.09 (6H, m), 6.38 (2H, d, J = 2.0 Hz), 2.92-2.81 (4H, m)
The crude material was purified by HPLC, fractions containing the required product were collected and freeze dried to give pale yellow solid (40 mg, 35%), mp 130-134 oC. 1H NMR (DMSO-d6): 11.90 (1H, s, NH, exchangeable), 7.48-7.44 (2H, dd, J = 3.2 Hz & J = 8.7 Hz), 7.31 (2H, t, J = 9.0 Hz), 7.17 (4H, br, 2 x NH2, exchangeable), 7.07 (1H, d, J = 1.9 Hz)
Summary
General 1H and 13C NMR spectra were measured on a Bruker DPX- 400 MHz spectrometer with chemical shifts given in ppm (δ values), relative to proton and carbon traces in solvent. The crude material was purified by HPLC, fractions containing the required product were collected and freeze dried to give pale yellow solid (50 mg, 29%), mp 200-203 oC 1H NMR (DMSO-d6): 11.91 (1H, s), 7.48-7.34 (5H, m), 7.20 (4H, br), 7.08 (1H, d, J = 1.8 Hz.) IR (KBr): 1694, 1651, 1543, 1453, 1390, 1207, 1131, 826, 800, 759, 725 cm.-1 HRESIMS: Found: 226.1082 Calculated for C12H12N5 226.1087. The organic layer was collected, washed with a saturated solution of sodium hydrogen carbonate followed by brine the organic layer was dried (Na2SO4), filtered and the solvent removed under reduced pressure to give the required product (3.090 g, 91%) as a yellow solid after trituration with n-hexane.
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