title: Design, synthesis, nitric oxide release and antibacterial evaluation of novel nitrated ocotillol-type derivatives.
abstract: Nitric oxide (NO) and its auto-oxidation products are known to disrupt normal bacterial function and NO releasing molecules have the potential to be developed as antibacterial leads in drug discovery. We have designed and synthesized a series of novel nitrated compounds by combining NO releasing groups with ocotillol-type triterpenoids, which have previously demonstrated activity only against Gram-positive bacteria. The in vitro NO release capacity and antibacterial activity were sequentially evaluated and the data showed that most of the synthesized compounds could release nitric oxide. Compound 16a, 17a and 17c, with nitrated aliphatic esters at C-3 position, displayed higher NO release than other analogues, correlating to their good antibacterial activity, in which 17c demonstrated broad-spectrum activity against both Gram positive and -negative bacteria, as well as excellent synergism at sub-minimum inhibitory concentration when using with kanamycin and chloramphenicol. Furthermore, the epifluorescent microscopic study indicated that the ocotillol-type triterpenoid core may induce NO release on the bacterial membrane. Our results demonstrate that nitrated substitutions at C-3 of ocotillol-type derivatives could provide an approach to expand their antibacterial spectrum, and that ocotillol-type triterpenoids may also be developed as appropriate carriers for NO donors in antibacterial agent discovery with low cytotoxicity.
authors.affiliation: School of Pharmacy, Yantai University, Yantai 264005, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Biological Sciences, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Yantai University, Yantai 264005, China; Key Laboratory for The Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Yantai University, Yantai 264005, China.
authors.forename: Zeyun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Yantai University, Yantai 264005, China.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Yantai University, Yantai 264005, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Key Laboratory for The Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, China.
authors.forename: Keguang
authors.initials: K
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jinyi
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Yantai University, Yantai 264005, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Yantai University, Yantai 264005, China.
authors.forename: Guangyao
authors.initials: G
authors.lastname: Lv
authors.affiliation: Biological Sciences, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: Peter John
authors.initials: PJ
authors.lastname: Lewis
authors.affiliation: School of Pharmacy, Yantai University, Yantai 264005, China. Electronic address: qinggmeng@163.com.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Biological Sciences, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia. Electronic address: cma1@newcastle.edu.au.
authors.forename: Cong
authors.initials: C
authors.lastname: Ma
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D036145:Ginsenosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D036145:Ginsenosides; C524540:ocotillol; D009569:Nitric Oxide
keywords: Antibacterial activity; NO release; Ocotillol; Synergistic effect; Triterpenoid