title: Synthesis and antibacterial activities of novel pleuromutilin derivatives with a substituted pyrimidine moiety.
abstract: The alarming growth of multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) has become a major global health hazard. Therefore, urgent demand for new antibiotics with a unique mechanism of action is very necessary. The present study reports the design, synthesis, and antibacterial studies of a series of novel pleuromutilin derivatives with substituted 6-amino pyrimidine moieties. Most of the tested compounds exhibited highly potent anti-MRSA or Staphylococcus aureus (S. aureus) activities. 14-O-[(4,6-Diamino -pyrimidine-2-yl) thioacetyl] mutilin (3) and 14-O-[(2-((3R)-3-Hydroxymethylpiperidine-1-yl)-acetamido-6-aminopyrimidine-2-yl) thioacetyl] mutilin (5h) were the most active compounds and showed higher antibacterial activities. Compound 3 displayed rapid bactericidal activity and affected bacterial growth with the same manner as tiamulin fumarate. Docking experiments for compounds 3 and 5h carried out on the peptidyl transferase center (PTC) of 23S rRNA provided the information about the binding model. In vivo mouse systemic infection experimental results confirmed the therapeutic efficacy of compound 3, with ED50of 4.22 mg/kg body weight against MRSA.
authors.affiliation: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, China; Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, 335 Jiangouyan, Lanzhou, 730050, China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Yi
authors.affiliation: Institut Pasteur, Unité de Pathogenèse des infections vasculaires, Département de Biologie Cellulaire et Infection, Paris, 75015, France.
authors.forename: Ximing
authors.initials: X
authors.lastname: Xu
authors.affiliation: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, China; Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, 335 Jiangouyan, Lanzhou, 730050, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Yancheng YouHua Pharmaceutical & Chemical Technology Co., Ltd., Yancheng, 224555, China.
authors.forename: Shuijin
authors.initials: S
authors.lastname: Xu
authors.affiliation: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, China; Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, 335 Jiangouyan, Lanzhou, 730050, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, China; Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, 335 Jiangouyan, Lanzhou, 730050, China. Electronic address: liangjp1963@163.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Liang
authors.affiliation: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, China; Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, 335 Jiangouyan, Lanzhou, 730050, China. Electronic address: shangrf1974@163.com.
authors.forename: Ruofeng
authors.initials: R
authors.lastname: Shang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004224:Diterpenes / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D062105:Molecular Docking Simulation; D011083:Polycyclic Compounds; D011743:Pyrimidines / Q000737:chemistry; D012338:RNA, Ribosomal, 23S / Q000378:metabolism; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects; D000097567:Pleuromutilins
chemical_list: D000900:Anti-Bacterial Agents; D004224:Diterpenes; D011083:Polycyclic Compounds; D011743:Pyrimidines; D012338:RNA, Ribosomal, 23S; D000097567:Pleuromutilins; C030986:pyrimidine
keywords: Antibacterial activity; Molecular docking; Pleuromutilin derivatives; Synthesis