Design, synthesis and biological evaluation of 1-benzyl-5-oxopyrrolidine-2-carboximidamide derivatives as novel neuroprotective agents.

A series of 1-benzyl-5-oxopyrrolidine-2-carboximidamide derivatives were designed and synthesized. Their protective activities against N-methyl-d-aspartic acid (NMDA)-induced cytotoxicity were investigated in vitro. All of the compounds exhibited neuroprotective activities, especially 12k, which showed higher potency than reference compound 1 (ifenprodil). Further investigation showed that 12k could attenuate Ca2+ influx and suppress the NR2B upregulation induced by NMDA. The docking results indicated that 12k could fit well into binding site of 1 in the NR2B-NMDA receptor. Additionally, 12k exhibited excellent metabolic stability. Furthermore, the results of behavioral tests showed that compound 12k could significantly improve learning and memory in vivo. These results suggested that 12k is a promising neuroprotective drug candidate and that the NR2B-NMDA receptor is a potential target of 12k.

Computational investigation of the antagonism effect towards GluN2B-Containing NMDA receptor: Combined ligand-based and target-based approach.

The interaction of GluN2B-Containing NMDA Receptor with 18 antagonists were investigated by a combined ligand-based and target-based approach. First, two distinct pharmacophore models were generated for antagonists which cluster in two groups with Catalyst (HipHop module). The pharmacophore of "ifenprodil group" antagonists includes three hydrophobic groups, one H-bond donor and one H-bond acceptor, the pharmacophore of "EVT101 group" antagonists involves one aromatic ring, two hydrophobic groups and one H-bond acceptor. Docking results and pharmacophore model confrontation allow the pharmacodynamic characteristics to be weighted and structural information integrated. Which results in the proposal of two interaction models inside the GluN2B binding cavity for two groups of antagonists. The interaction model of "ifenprodil group" antagonists consists of one hydrophobic group, one H-bond donor, one H-bond acceptor and an aromatic ring, while on the other hand, the interaction model of "EVT101 group" antagonists includes three hydrophobic groups and an aromatic ring.

Pyrrolo[2,1-c][1,4] benzodiazepine-3,11-diones protect SHSY-5Y cells from Cd-induced apoptosis involving suppression of endoplasmic reticulum stress.

Cadmium (Cd) is a potent toxic heavy metal, some studies showed that Cd-induced apoptosis is through ER stress pathway. Compounds of pyrrolo[2,1-c][1,4]benzodiazepine (PBD)-3,11-diones were discovered as potent neuroprotective agents against Cd-induced toxicity in SH-SY5Y cells for the first time. In this study, twenty-six PBD-3,11-dione derivatives were synthesized and evaluated for their neuroprotective activity against Cd-induced toxicity by CCK-8 assay. Their preliminary SARs studies indicated that various substituents were tolerated on the benzene ring, and alkyl heterocycles groups at the N10-position of the PBD-3,11-dione scaffold were important for the activities. Among them, compound 13c exhibited the best activity (cell viability = 68.6%, 25 µM). Furthermore, we found that the compound 13c could inhibit cadmium-induced cell apoptosis with the downregulation of the ER stress markers GRP78, CHOP, cleaved-caspase12 and cleaved-caspase3 through western blotting. The results of in silico evaluation of ADME/T properties showed that 13c exhibited medium BBB penetration level and promising toxicity profiles. These results proved the potential of 13c as a promising lead compound against Cd-induced neurotoxicity.

Design, synthesis and bioevaluation of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives as potent neuroprotective agents.

Diverse of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives were designed, synthesized and evaluated for their neuroprotective activity against NMDA-induced cytotoxicity in vitro, and 5q exhibited excellent neuroprotective activity. The compound 5q was selected for further investigation. We found that 5q could attenuate Ca2+ influx induced by NMDA, meanwhile, 5q could suppress the NR2B up-regulation and increase p-ERK1/2 expression. The molecular docking results showed that 5q might fit well in the binding pocket of 4 and interact with some key residues in the binding pocket of 1 simultaneously. Besides, 5q exhibited acceptable metabolic stability. These results suggested that 5q was a promising lead for further development of new potent and orally bioavailable NR2B-selective NMDAR antagonists.

Allergy-preventive effects of linarinic acid and its tetrahydropyrrolo[2,1-b]quinazoline derivatives isolated from Linaria vulgaris.

Linarinic acid, (-)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid (4a), was isolated from the ethanol extract of Linaria vulgaris Mill. In our previous study, a series of tetrahydropyrrolo[2,1-b]quinazoline derivatives 4b, 4c, 5a, 5b, 6a and 6b that were structurally related to 4a and evaluated as neuroprotective agents were synthesized. The aim of the present study was to investigate the novel features of these compounds. We examined their allergy-preventive effects using an in vivo assay system we developed previously, that monitors a decrease in blood flow in the tail vein of mice subjected to sensitization with hen egg-white lysozyme. We observed that 4a and its three derivatives, amide (6a), ester (5a), bromine (4b), and alcohol substituent (6b), showed significant allergy-preventive activities. The study confirmed the allergy-preventive activity of tetrahydropyrrolo[2,1-b]quinazoline derivatives by comprehensively monitoring the specific blood flow decrease occurring in the induction phase of allergy. This finding may aid in the development of new agents for the treatment of allergic diseases such as atopic dermatitis, allergic asthma, and hay fever.