Tautomerism of 1-phenyl-3-methyl-4-benzyl-5-pyrazolone

First-in-Class Selective Inhibitors of the Lysine Acetyltransferase KAT8

“…These compounds were selective over KAT3B and KAT2B, although they displayed 2.4- to 3.7-fold lower KAT8 inhibitory potency compared to 19 . Similarly, addition of a methyl substituent on the exocyclic double bond ( 30 ) or its reduction ( 31 and 32 , both were observed in 1 H-NMR experiments in DMSO as the 5-hydroxypyrazole prevalent tautomeric forms) , slightly decreased KAT8 inhibitory potency, while keeping the selectivity over KAT3B and KAT2B. Hence, the presence of the exocyclic double bond and, consequently, the α,β-unsaturated system is not crucial for KAT8 inhibition.…”

“…The crude was then again triturated with diethyl ether (1.5 mL), filtered under vacuum, and washed over filter with petroleum ether to yield the final compound 31 as gray powder. 1 H-NMR (400 MHz; DMSO- d 6 ) for prevalent enol form , δ 2.05 (s, 3H, C H 3 ), 3.54 (s, 2H, C H 2 ), 5.68 (s, 1H, C H pyrrole proton), 5.86 (s, 1H, C H pyrrole proton), 6.56 (s, 1H, C H pyrrole proton), 7.92 (d, 2H, C H phenyl proton), 8.00 (d, 2H, C H phenyl proton), 10.46 (s, 1H, N H ), 11.03 (br s, 1H, O H ), 12.79 (br s, 1H, COO H ). 13 C-NMR (100 MHz, DMSO- d 6 ) δ 12.8, 20.1, 104.8, 107.2, 110.0, 116.3 (2C), 117.5, 126.0, 130.0, 130.5 (2C), 141.6, 149.3, 157.9, 166.9 .…”

“…The crude was then again triturated with diethyl ether (1.5 mL), filtered under vacuum, and washed over filter with petroleum ether to yield the final compound 31 as gray powder. 1 H-NMR (400 MHz; DMSO-d 6 ) for prevalent enol form 42,43 equiv), and PyBOP (0.406 mmol, 1.2 equiv) in dry DMF (3.5 mL) was stirred at rt under a nitrogen atmosphere for 1 h. Then, ammonia (for compound 37) or an appropriate commercially available primary/secondary amine (for compounds 38−41) (0.389 mmol, 1.15 equiv) was added and the reaction mixture was stirred at rt under a nitrogen atmosphere for 3.5−4.5 h. After completion, the reaction mixture was quenched by adding water (45 mL) and the resulting precipitate was filtered and washed over the filter with water. The crude product was purified by silica gel column chromatography eluting with the appropriate chloroform/methanol (for compounds 37 and 40), chloroform/methanol/ammonia (for compound 41), or ethyl acetate/dichloromethane (for compound 38 and 39) mixture to afford the desired final compounds 37−41. )…”

“…-hydroxy-3-methyl-1H-pyrazol-1-yl)benzoic Acid (MC4247, 32). 1 H-NMR (400 MHz; DMSO-d 6 ) for the prevalent enol form 42,43 δ 2.08 (s, 3H, CH 3 ), 3.62 (s, 2H, CH 2 ), 7.16 (t, 1H, J = 6.8 Hz, CH phenyl proton), 7.22−7.29 (m, 4H, CH phenyl protons), 7.92 (d, 2H, J = 8.8 Hz, CH carboxyphenyl protons), 7.99 (d, 2H, J = 8.8 Hz, CH carboxyphenyl protons), 11.22 (br s, 1H, OH), 12.65 (br s, 1H, COOH). 13 C-NMR (100 MHz, DMSO-d 6 ) δ 13.1, 27.3, 106.7, 117.1 (2C), 125.8, 128.1 (2C), 128.3 (2C), 130.5 (2C), 137.1, 140.9, 149.8, 157.3, 166.9.…”

“…Moreover, we investigated the influence of bulkier substitutions on the C3 of the 5-pyrazolone ring by replacing the methyl group with isopropyl (33), phenyl (34), and benzyl (35) moieties. Finally, we applied various modifications to the benzoic acid portion, by either changing the position of the carboxylic group from para to meta (36) or replacing it with various amides (37−41), sulfonic acid (42), or sulfonamide (43) functions.…”