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

  • Eur J Med Chem. 2018 May 10;151:27-38. doi: 10.1016/j.ejmech.2018.03.052.
Linkui Zhang  1 ,  Ying Zhao  1 ,  Jian Wang  1 ,  Donglin Yang  1 ,  Chenwen Zhao  1 ,  Changli Wang  2 ,  Chao Ma  3 ,  Maosheng Cheng  4
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
  • 2. Department of Pharmacy, General Hospital of Shenyang Military Area Command, 83 Wenhua Road, Shenhe District, Shenyang, 110840, PR China.
  • 3. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: [email protected].
  • 4. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: [email protected].
PMID: 29604542 DOI: 10.1016/j.ejmech.2018.03.052
Abstract

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.

Keywords
Ca(2+) influx; NR2B-selective NMDAR antagonists; Neuroprotective activity; p-ERK1/2.
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