title: Identification of fused bicyclic derivatives of pyrrolidine and imidazolidinone as dengue virus-2 NS2B-NS3 protease inhibitors.
abstract: A series of fused ring derivatives of pyrrolidine and imidazolidinone were designed, synthesized, characterized and assayed against the DENV-2 NS2B-NS3 protease and wild-type DENV-2 virus. The linear dipeptide compound 1 and the non-peptidic fused ring compound 2 show comparable activities against DENV-2 NS2B-NS3 protease and wild-type DENV-2 virus in a viral replication assay. The preliminary SAR reveals that a substituent and its stereochemistry at C-3 position, substitution (X) at N-2 arene and a linker (Y) between C-3 position and its attached arene are important for the fused-ring scaffold of pyrrolidino [1,2-c]imidazolidinone to block the active site of NS2B-NS3 protease. This promising structural core will facilitate the discovery of non-peptidic, potent NS2B-NS3 protease inhibitors to stop dengue virus infections.
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, Jiangsu, PR China.
authors.forename: Zhibing
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Institute of Protein Research, Tongji University, Shanghai 200092, PR China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Shao
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364 D-69120, Heidelberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Graf
authors.affiliation: Institute of Protein Research, Tongji University, Shanghai 200092, PR China.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364 D-69120, Heidelberg, Germany.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klein
authors.affiliation: College of Sciences, Nanjing Agricultural University, Nanjing 210095, Jiangsu, PR China. Electronic address: wangjing@njau.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, Jiangsu, PR China. Electronic address: gczhou@njtech.edu.cn.
authors.forename: Guo-Chun
authors.initials: GC
authors.lastname: Zhou
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D003500:Cyclization; D003716:Dengue Virus / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D048289:Imidazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D048289:Imidazolidines; D011759:Pyrrolidines; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases
keywords: Dengue virus NS2B-NS3 protease inhibitor; HQRJJHXKCFABSI-KBPBESRZSA-N; Linker; Stereochemistry; Structure-activity relationship (SAR); Substitution and substituent; pyrrolidino[1,2-c]imidazolidinone