title: Rational design, synthesis and biological evaluation of 1,3,4-oxadiazole pyrimidine derivatives as novel pyruvate dehydrogenase complex E1 inhibitors.
abstract: On the basis of previous study on 2-methylpyrimidine-4-ylamine derivatives I, further synthetic optimization was done to find potent PDHc-E1 inhibitors with antibacterial activity. Three series of novel pyrimidine derivatives 6, 11 and 14 were designed and synthesized as potential Escherichia coli PDHc-E1 inhibitors by introducing 1,3,4-oxadiazole-thioether, 2,4-disubstituted-1,3-thiazole or 1,2,4-triazol-4-amine-thioether moiety into lead structure I, respectively. Most of 6, 11 and 14 exhibited good inhibitory activity against E. coli PHDc-E1 (IC50 0.97-19.21 μM) and obvious inhibitory activity against cyanobacteria (EC50 0.83-9.86 μM). Their inhibitory activities were much higher than that of lead structure I. 11 showed more potent inhibitory activity against both E. coli PDHc-E1 (IC50<6.62 μM) and cyanobacteria (EC50<1.63 μM) than that of 6, 14 or lead compound I. The most effective compound 11d with good enzyme-selectivity exhibited most powerful inhibitory potency against E. coli PDHc-E1 (IC50=0.97 μM) and cyanobacteria (EC50=0.83 μM). The possible interactions of the important residues of PDHc-E1 with title compounds were studied by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated that 11d had more potent inhibitory activity than that of 14d or I due to its 1,3,4-oxadiazole moiety with more binding position and stronger interaction with Lsy392 and His106 at active site of E. coli PDHc-E1.
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: He
authors.affiliation: Xi'an Modern Chemistry Research Institute, Xi'an 710065, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Xia
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China.
authors.forename: Yanliang
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China.
authors.forename: Jiangtao
authors.initials: J
authors.lastname: Feng
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Peng
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China. Electronic address: he1208@mail.ccnu.edu.cn.
authors.forename: Hongwu
authors.initials: H
authors.lastname: He
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China. Electronic address: fll708@mail.ccnu.edu.cn.
authors.forename: Lingling
authors.initials: L
authors.lastname: Feng
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000458:Cyanobacteria / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D005658:Fungi / Q000187:drug effects; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011743:Pyrimidines; C583463:1,3,4-oxadiazole; D030481:Pyruvate Dehydrogenase (Lipoamide); C030986:pyrimidine
keywords: 1,3,4-Oxadiazole; Antibacterial activity; Cyanobacteria; PDHc-E1 inhibitor