ABSTRACT. Diastereoselective reduction of 2,3-dioxo-4-carboxy-5-(substituted)pyrrolidine 1 by NaBH4/AcOH and heterogenous hydrogenation were reported. Stereochemical assignment and diastereomeric ratios of the products were determined using 1 H NMR and single crystal X-ray analyses. The steric factors of the C-5 substituents of the pyrrolidinone was shown to have an interesting influence on both the yield and diastereoselectivity of the reduced product.

2-Aryl-4,5-dioxopyrrolidine-3-carboxylate and 5-aryl-2,4-dioxopyrrolidine-3-carboxylate derivatives were successfully synthesized via carbonyl-based multiple component reaction and Dieckmann cyclization, respectively. Successive functional group transformations which include decarboxylation and hydrazonation afforded 2-oxo-5-aryl-3-hydrazone and 2-oxo-5-aryl-4-hydrazone derivatives. Compound 3d exhibited activity against human histiocytic lymphoma (U937) and neuroblastoma (SH-SY5Y) cell lines while compound 6 showed neuroprotective ability from oxidative stress medium induced with H2O2.

This study was carried out to determine the antinociceptive activity of a novel synthetic oxopyrrolidine-based compound, (2R,3R,4S)-ethyl 4-hydroxy-1,2-dimethyl-5-oxopyrrolidine-3-carboxylate (ASH21374), and to elucidate the involvement of the opioid, vanilloid, glutamate, and nitric oxide - cyclic guanosine monophosphate (NO/cGMP) systems in modulating the observed antinociception. ASH21374, in the doses of 2, 10, and 100 mg/kg body mass, was administered orally to mice 60 mins prior to exposure to various antinociceptive assays. From the results obtained, ASH21374 exhibited significant (P < 0.05) antinociceptive activity in the abdominal constriction, hot-plate, and formalin tests that was comparable with 100 mg/kg acetylsalicylic acid or 5 mg/kg morphine, respectively. ASH21374 also attenuated capsaicin- and glutamate-induced paw licking. Pre-treatment with 5 mg/kg naloxone significantly (P < 0.05) inhibited the activity in all assays, while pretreatment with 10 mg/kg β-funaltraxamine, 1 mg/kg naltrindole, or 1 mg/kg nor-binaltorphimine significantly (P < 0.05) reversed the activity in the abdominal constriction test. l-Arginine, N(G)-nitro-l-arginine methyl esters (l-NAME), methylene blue, and their combinations, failed to inhibit the ASH21374 antinociceptive activity. In conclusion, ASH21374 demonstrated antinociceptive activities on the peripheral and central nervous systems, mediated through the activation of opioid receptors, inhibition of the glutamatergic system, and attenuation of vanilloid-mediated nociceptive transmission. Further studies have been planned to determine the pharmacological potential of ASH21374.

A series of novel potentially biologically active fused [5:7] oxazepanone γ-lactams were synthesized and described. A series of functional group transformations, namely amination, syn-hydrogenation and intramolecular annulation reactions were used to obtain the [5:7] oxazepanone γ-lactams in reasonable yields. In the diastereoselective fused-annulation for the formation of the secondary ring, steric constrain and cisgeometrical configuration of C-3 and C-4 substituents were observed as the predetermined factors. These ring annulations were purposely constructed to suit the physicochemical enhancement of the biological activity of the title compounds via SAR study of γ-lactams.

The asymmetric unit of the title compound, C14H17NO4·1.25H2O, consists of four substituted pyrrolidone mol­ecules (two pairs of enanti­omers) and five water mol­ecules. The five-membered rings each have an envelope conformation, with the C atom bonded to the ester group as the flap. The mean planes of the five-membered rings of the four pyrrolidone mol­ecules make dihedral angles of 60.87 (5), 64.45 (5), 62.03 (5) and 65.79 (5)° with respect to the phenyl rings. In the crystal, the pyrrolidone and water mol­ecules are connected through O—H⋯O hydrogen bonds, forming a layer parallel to the ab plane. The two-dimensional network is further stabilized by inter­molecular C—H⋯O hydrogen bonds.