title: Novel pleuromutilin derivatives as antibacterial agents: synthesis, biological evaluation and molecular docking studies.
abstract: Owing to the increasingly serious problems caused by multidrug resistance in community-acquired infection pathogens, it has become an urgent need to develop new classes of antibiotics for overcoming the resistance. In this paper, we describe the design and synthesis of novel pleuromutilin derivatives containing the (2-aminothiazol-4-yl)-4-methyl group, as well as their in vitro antibacterial activities against Gram-positive clinical bacteria. Most of the tested compounds displayed strong antibacterial activities against these methicillin-susceptible and methicillin-resistant bacteria. Particularly noteworthy compound 15 and its derivative 16e, both showed potent antibacterial properties (0.0625-0.5μg/mL) that are superior to amoxicillin and tiamulin. Molecular docking studies suggested that the amino thiazole ring on the side chains of the pleuromutilin derivatives can in general be accommodated near the mutilin core in the binding pocket, and thus play an important role in the activity of the whole molecule. The findings reported herein may provide a new insight into the design of novel pleuromutilin derivatives for human clinical use.
authors.affiliation: Department of Pharmacy, School of Medicine, Nantong University, Nantong 226001, PR China.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Ling
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Jianghe
authors.initials: J
authors.lastname: Yu
authors.forename: Junming
authors.initials: J
authors.lastname: Tang
authors.forename: Heng
authors.initials: H
authors.lastname: Zheng
authors.forename: Xi
authors.initials: X
authors.lastname: Zhao
authors.forename: Donggeng
authors.initials: D
authors.lastname: Wang
authors.forename: Guangtong
authors.initials: G
authors.lastname: Chen
authors.forename: Wenqian
authors.initials: W
authors.lastname: Qiu
authors.forename: Jinhua
authors.initials: J
authors.lastname: Tao
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016106:Methicillin Resistance / Q000187:drug effects*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011083:Polycyclic Compounds; D013212:Staphylococcus epidermidis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D000097567:Pleuromutilins
chemical_list: D000900:Anti-Bacterial Agents; D004224:Diterpenes; D011083:Polycyclic Compounds; D000097567:Pleuromutilins