Synthesis and Pharmacological Evaluation of Novel Pleuromutilin Derivatives with Substituted Benzimidazole Moieties.
A series of novel pleuromutilin derivatives with substituted benzimidazole moieties were designed and synthesized from pleuromutilin and 5-amino-2-mercaptobenzimidazole through sequential reactions. All the newly synthesized compounds were characterized by IR, NMR, and HRMS. Each of the derivatives was evaluated in vitro for their antibacterial activity againstEscherichia coli(E. coli) and five Gram (+) inoculums. 14-O-((5-amino-benzimidazole-2-yl) thioacetyl) mutilin (3) was the most active compound and showed highest antibacterial activities. Furthermore, we evaluated the inhibition activities of compound3on short-termS. aureusand MRSA growth and cytochrome P450 (CYP). The bioassay results indicate that compound3could be considered potential antibacterial agents but with intermediate inhibition of CYP3A4.
Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, 335 Jiangouyan, Lanzhou 730050, China. ai_xin2015@163.com.
Xin
X
Ai
College of Life Science and Engineering, Lanzhou University of Technology, 287 Langongping Road, Lanzhou 730050, China. puhl02@163.com.
Xiuying
X
Pu
Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, 335 Jiangouyan, Lanzhou 730050, China. yiyunpeng88@163.com.
Yunpeng
Y
Yi
Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, 335 Jiangouyan, Lanzhou 730050, China. yangguang8684@163.com.
Yu
Y
Liu
Yancheng Shunbao Chemical Co., Ltd., Yancheng 224555, China. xu@youhuapharm.com.
Shuijin
S
Xu
Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, 335 Jiangouyan, Lanzhou 730050, China. liangjp1963@163.com.
Jianping
J
Liang
Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, 335 Jiangouyan, Lanzhou 730050, China. shangrf1974@163.com.
Ruofeng
R
Shang
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry; D004926:Escherichia coli / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests / Q000379:methods; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011083:Polycyclic Compounds; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D000097567:Pleuromutilins
D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004224:Diterpenes; D011083:Polycyclic Compounds; D000097567:Pleuromutilins
CYP3A4; antibacterial activity; inhibition; pleuromutilin derivatives; synthesis