- Synthesis and antibacterial activities of novel pleuromutilin derivatives bearing an aminothiophenol moiety
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We synthesized a series of novel thioether pleuromutilin derivatives incorporating 2-aminothiophenol moieties into the C14 side chain via acylation reactions under mild conditions. We evaluated the in-vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300), Staphylococcus aureus (ATCC 29213) and Escherichia coli (ATCC 25922). The majority of the synthesized derivatives possessed moderate antibacterial activities. Compound 8 was found to be the most active antibacterial derivative against MRSA. We conducted docking experiments to understand the possible mode of interactions between compounds 8, 9b, 11a and 50S ribosomal subunit. The docking results proved that there is a reasonable correlation between the binding free energy and the antibacterial activity. Compound 8 was evaluated for its in-vivo antibacterial activity and showed higher efficacy than tiamulin against MRSA in mouse infection model.
- Zhang, Zhao-Sheng,Huang, Yun-Zhen,Luo, Jian,Jin, Zhen,Liu, Ya-Hong,Tang, You-Zhi
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- Synthesis and antibacterial activity of novel pleuromutilin derivatives
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In this study we describe the design, synthesis, and antibacterial activity of novel pleuromutilin analogs. A series of new compounds containing piperazine and alkylamino or arylamino groups was synthesized. The new compounds were characterized via 1
- Liu, Huixian,Xiao, Sui,Zhang, Depeng,Mu, Shuhua,Zhang, Lifang,Wang, Xiaoyang,Xue, Feiqun
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- Synthesis and biological evaluation of novel thioether pleuromutilin derivatives
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To develop new pleuromutilin derivatives as veterinary antibiotic medicines, we designed and synthesized a series of new thioether pleuromutilin derivatives possessing acylthiazolyl moiety based on previously designed derivatives. The antibacterial properties of the prepared pleuromutilin derivatives were assessed in vitro by the broth dilution method against five kinds of bacteria and the mycoplasma Mycoplasma gallisepticum (MG). All of the tested compounds displayed moderate to good antibacterial activity to meth-icillin-sensitive Staphylococcus aureus (MSSA), methicillin-sensitive Staphylococcus epidermidis (MSSE), methicillin-resistant S. aureus (MRSA), Streptococcus agalactiae (S. aga) and MG. However, the activity to Pyogeniccoccus (Pyogens) was generally poor. Compounds 13i and l showed potent antibacterial activity against MSSE and MRSA which are better than that of valnemulin. The structural modification for pleuromutilin affected the antibacterial activity. Amino substituents in the benzene ring can effectively improve activity. Compared with the analogue 13a that possesses unsubstitution benzoyl group, the nitro, methoxy, hydroxy and dichloro substituent contributed little to antibacterial activity. Increasing a methylene between benzene moiety and carbonyl group decreased the bioactivity of derivative. The analogues that obtained by the reaction of amino acids and intermediate 9 showed moderate activity.
- Mu, Shuhua,Liu, Huixian,Zhang, Lifang,Wang, Xiaoyang,Xue, Feiqun,Zhang, Yue
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- Design, synthesis and antibacterial activities of pleuromutilin derivatives
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We described the design, synthesis and antimicrobial activities of novel pleuromutilin derivatives with substituted piperazine substrate. Minimum inhibitory concentration (MIC) was used to evaluate the activity of the derivatives against six bacteria in?v
- Liu, Hui-Xian,Ma, Dong-Lai,Cui, Ge,Zhang, Yue,Xue, Fei-Qun
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- Design, synthesis and antibacterial evaluation of novel pleuromutilin derivatives possessing piperazine linker
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A series of pleuromutilin derivatives bearing piperazine ring have been reported. The in vitro antibacterial activities of the synthetic derivatives against MRSA (ATCC 43300), Staphylococcus aureus (ATCC 29213), Enterococcus faecalis (ATCC 29212), Enterococcus faecium (ATCC35667) and Escherichia coli (ATCC25922) were evaluated by the broth dilution method. Most of the synthesized derivatives displayed potent activities. Compounds 11c, 12a and 12c were found to be the most active antibacterial derivatives against MRSA (minimum inhibitory concentration = 0.015 μg/mL). The binding of compounds 11c, 12a and 12c to the 50s ribosome were investigated by molecular modeling. Compound 11c possessed lower binding free energy compared with compounds 12a and 12c. Compound 11c was further evaluated in MRSA systemic infection model and displayed superior in vivo efficacy to that of tiamulin.
- Gao, Mei-Ling,Zeng, Jie,Fang, Xi,Luo, Jian,Jin, Zhen,Liu, Ya-Hong,Tang, You-Zhi
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- Antibacterial Activity and Structure?Activity Relationship of a Series of Newly Synthesized Pleuromutilin Derivatives
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A series of novel thioether or sulfoxide-type pleuromutilin derivatives containing heteroaromatic substituents at the end of C14 side chain were designed and synthesized. All of the derivatives were evaluated for their in vitro antibacterial activity. Som
- Li, Yun-Ge,Wang, Ju-Xian,Zhang, Guo-Ning,Zhu, Mei,You, Xue-Fu,Hu, Xin-Xin,Zhang, Fan,Wang, Yu-Cheng
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- Design, synthesis, and antibacterial activity of novel pleuromutilin derivatives bearing an amino thiazolyl ring
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A series of novel pleuromutilin derivatives containing the amino thiazolyl ring were designed, synthesized, and evaluated for their antibacterial activities in vitro against Gram-positive clinical bacteria. All the target compounds showed better aqueous s
- Ling, Yong,Wang, Xinyang,Wang, Hui,Yu, Jianghe,Tang, Junming,Wang, Donggeng,Chen, Guangtong,Huang, Jinhua,Li, Yuqin,Zheng, Heng
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- Synthesis and antibacterial activity against MRSA of pleuromutilin derivatives possessing a mercaptoethylamine linker
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Background: Methicillin resistant Staphylococcus aureus (MRSA) usually invalidate powerful antibiotics in the clinic. Pleuromutilin derivatives have been reported to possess antibacterial activity against MRSA. Objective: The antibacterial activities agai
- Zhang, Zhao-Sheng,Huang, Yun-Zhen,Luo, Jian,Wang, Bing-Feng,Jin, Zhen,Liu, Ya-Hong,Tang, You-Zhi
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- Synthesis and pharmacological evaluation of novel pleuromutilin derivatives with substituted benzimidazole moieties
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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 b
- Ai, Xin,Pu, Xiuying,Yi, Yunpeng,Liu, Yu,Xu, Shuijin,Liang, Jianping,Shang, Ruofeng
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- Boron-Pleuromutilins as Anti- Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis
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A series of pleuromutilins modified by introduction of a boron-containing heterocycle on C(14) of the polycyclic core are described. These analogs were found to be potent anti-Wolbachia antibiotics and, as such, may be useful in the treatment of filarial
- Jacobs, Robert T.,Lunde, Christopher S.,Freund, Yvonne R.,Hernandez, Vincent,Li, Xianfeng,Xia, Yi,Carter, David S.,Berry, Pamela W.,Halladay, Jason,Rock, Fernando,Stefanakis, Rianna,Easom, Eric,Plattner, Jacob J.,Ford, Louise,Johnston, Kelly L.,Cook, Darren A. N.,Clare, Rachel,Cassidy, Andrew,Myhill, Laura,Tyrer, Hayley,Gamble, Joanne,Guimaraes, Ana F.,Steven, Andrew,Lenz, Franziska,Ehrens, Alexandra,Frohberger, Stefan J.,Koschel, Marianne,Hoerauf, Achim,Hübner, Marc P.,McNamara, Case W.,Bakowski, Malina A.,Turner, Joseph D.,Taylor, Mark J.,Ward, Stephen A.
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- Design, synthesis and biological evaluation of novel pleuromutilin derivatives as potent anti-MRSA agents targeting the 50S ribosome
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A series of novel pleuromutilin derivatives were designed and synthesized with 1,2,4-triazole as the linker connected to benzoyl chloride analogues under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against four st
- Huang, Si-Yu,Wang, Xiao,Shen, Ding-Yi,Chen, Fang,Zhang, Guang-Yu,Zhang, Zhe,Li, Kang,Jin, Zhen,Du, Dan,Tang, You-Zhi
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- Synthesis and evaluation of novel pleuromutilin derivatives with a substituted pyrimidine moiety
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A series of novel pleuromutilin derivatives possessing 6-hydroxy pyrimidine moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against methicillin-resistant Staphyl
- Yi, Yunpeng,Yang, Guanzhou,Zhang, Chao,Chen, Jiongran,Liang, Jianping,Shang, Ruofeng
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- Design, synthesis and antibacterial activity evaluation of pleuromutilin derivatives according to twin drug theory
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A series of novel pleuromutilin derivatives were designed and synthesized based on the twin drugs theory. Piperazinyl and thioether were used as the linkage to connect the pleuromutilin nuclear and sulfonamide to improve the biological activity and water
- Cui, Ge,Liu, Hui-Xian,Ma, Dong-Lai,Xue, Fei-Qun,Zhang, Yue
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- Antibacterial activity evaluation of synthetic novel pleuromutilin derivatives in vitro and in experimental infection mice
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A series of novel pleuromutilin derivatives embracing 7H-pyrrolo[2,3-d]pyrimidine moiety were synthesized and evaluated for their in vitro antibacterial activity against Gram-positive and Gram-negative pathogens as well as in vivo efficacy in lethal syste
- Deng, Yu,Wang, Xiao-Zhong,Huang, Shu-Heng,Li, Cheng-Hong
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- Design, synthesis, and structure–activity relationship studies of novel pleuromutilin derivatives having a piperazine ring
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A series of novel pleuromutilin derivatives possessing piperazine moieties were synthesized under mild conditions. The in vitro antibacterial activities of these derivatives against Staphylococcus aureus and Escherichia coli were tested by the agar dilution method. Structure–activity relationship studies resulted in compounds 11b, 13b, and 14a with the most potent in vitro antibacterial activity among the series (minimal inhibitory concentration?=?0.0625–0.125?μg/mL). The binding of compounds 11b, 13b, and 14a to the E.?coli ribosome was investigated by molecular modeling, and it was found that there is a reasonable correlation between the binding free energy and the antibacterial activity.
- Luo, Jian,Yang, Qiu-E,Yang, Yuan-Yuan,Tang, You-Zhi,Liu, Ya-Hong
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- Synthesis and antibacterial activities of novel pleuromutilin derivatives with a substituted pyrimidine moiety
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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 m
- Yi, Yunpeng,Xu, Ximing,Liu, Yu,Xu, Shuijin,Huang, Xin,Liang, Jianping,Shang, Ruofeng
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- Synthesis and antibacterial activities of novel pleuromutilin derivatives
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Pleuromutilin derivatives 4a–h, 5a–g, and 6a–d were synthesized and characterized by IR, 1H NMR, and 13C NMR. All synthetic compounds were screened for their in vitro antibacterial activity against Staphylococcus aureus (ATCC 25923),
- Yi, Yunpeng,Fu, Yunxing,Wang, Keli,Shui, Yongzhen,Cai, Jing,Jia, Zhong,Niu, Biao,Liang, Jianping,Shang, Ruofeng
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- Novel pleuromutilin derivatives with substituted 6-methylpyrimidine: Design, synthesis and antibacterial evaluation
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A series of novel pleuromutilin derivatives with substituted 6-methylpyrimidine moieties was designed, synthesized, and evaluated for their antibacterial activities. Most of the tested compounds exhibited potent antibacterial activities against Staphyloco
- Cheng, Feng,Fan, Yuan,Hao, Baocheng,Liu, Yu,Shang, Ruofeng,Shi, Tao,Wang, Hao,Yi, Yunpeng
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- Design, synthesis and biological evaluation of pleuromutilin-Schiff base hybrids as potent anti-MRSA agents in vitro and in vivo
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A series of pleuromutilin derivatives with 1,2,4-triazole-3-substituted Schiff base structure were designed and synthesized under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against 4 strains of Staphylococcus aureus (MRSA ATCC 43300, S.aureus ATCC 29213, S.aureus 144 and S.aureus AD3) and 1 strain of E. coli (ATCC 25922) were evaluated by the broth dilution method. Among these derivatives, compound 60 exhibited superior in vitro antibacterial effect against MRSA (MIC = 0.25 μg/mL) than tiamulin (MIC = 0.5 μg/mL), and compound 60 (?2.28 log10 CFU/mL) also displayed superior in vivo antibacterial efficacy than tiamulin (?1.40 log10 CFU/mL) in reducing MRSA load in the mouse thigh infection model. The time-kill study and the post-antibiotic effect study indicated that compound 60 showed a faster bactericidal kinetic and longer PAE time (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 4.06 and 4.27 h) against MRSA compared with tiamulin (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 1.72 and 2.14 h). Meanwhile, most of these compounds had no significant inhibitory effect on RAW 264.7 cells and HepG2 cells at the concentration of 4 μg/mL. Additionally, the development of resistance study showed that MRSA did not easily develop resistance against compound 60 compared with tiamulin after induction for 8 passages.
- Li, Bo,Zhang, Zhe,Zhang, Jian-Feng,Liu, Jie,Zuo, Xiang-Yi,Chen, Fang,Zhang, Guang-Yu,Fang, Han-Qing,Jin, Zhen,Tang, You-Zhi
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- A click chemistry approach to pleuromutilin derivatives, evaluation of anti-MRSA activity and elucidation of binding mode by surface plasmon resonance and molecular docking
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Novel series of pleuromutilin analogs containing substituted 1,2,3-triazole moieties were designed, synthesised and assessed for their in vitro antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA). Initially, the in vitro antibacterial activities of these derivatives against 4 strains of S. aureus (MRSA ATCC 43300, ATCC 29213, AD3, and 144) were tested by the broth dilution method. Most of the synthesised pleuromutilin analogs displayed potent activities. Among them, compounds 50, 62, and 64 (MIC = 0.5~1 μg/mL) showed the most effective antibacterial activity and their anti-MRSA activity were further studied by the time-killing kinetics approach. Binding mode investigations by surface plasmon resonance (SPR) with 50S ribosome revealed that the selected compounds all showed obvious affinity for 50S ribosome (KD = 2.32 × 10?8~5.10 × 10?5 M). Subsequently, the binding of compounds 50 and 64 to the 50S ribosome was further investigated by molecular modelling. Compound 50 had a superior docking mode with 50S ribosome, and the binding free energy of compound 50 was calculated to be ?12.0 kcal/mol.
- Zhang, Zhe,Zhang, Zhao-Sheng,Wang, Xiao,Xi, Gao-Lei,Jin, Zhen,Tang, You-Zhi
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p. 2087 - 2103
(2021/12/02)
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- Pleuromutilin derivative with 1, 3, 4-oxadiazole side chain and preparation and application thereof
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The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with a 1, 3, 4-oxadiazole side chain and preparation and application thereof The pleuromutilin derivative with the 1, 3, 4-oxadiazole side chain is a compound shown in a formula 2 or a pharmaceutically acceptable salt thereof, and a solvent compound, an enantiomer, a diastereoisomer and a tautomer of the compound shown in the formula 2 or the pharmaceutically acceptable salt thereof or a mixture of the solvent compound, the enantiomer, the diastereoisomer and the tautomer in any proportion, including a racemic mixture. The pleuromutilin derivative has good antibacterial activity, is especially suitable for being used as a novel antibacterial agent for systemic system infection of animals or human beings, and has good water solubility.
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Paragraph 0056; 0070; 0090-0091
(2021/07/24)
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- Synthesis, biological activities and docking studies of pleuromutilin derivatives with piperazinyl urea linkage
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Antibiotics resistance is becoming increasingly common, involving almost all antibiotics on the market. Diseases caused by drug resistant bacteria, such as MRSA, have high mortality and negatively affect public health. The development of new drugs would be an effective means of solving this problem. Modifications based on bioactive natural products could greatly shorten drug development time and improve success rate. Pleuromutilin, a natural product from the basidiomycete bacterial species, is a promising antibiotic candidate. In this study, a series of novel pleuromutilin derivatives possessing piperazinyl urea linkage were efficiently synthesised, and their antibacterial activities and bactericidal properties were evaluated via MIC, MBC and Time-kill kinetics assays. The results showed that all compounds exhibited potent activities against tested strains, especially MRSA strains with MIC values as low as 0.125 μg/mL; 8 times lower than that of marketed antibiotic Tiamulin. Docking studies indicate substituted piperazinyl urea derivatives could provide hydrogen bonds and initiate π-π stacking between molecules and surrounding residues.
- Zhang, Yuanyuan,Xie, Chuan,Liu, Yang,Shang, Feng,Shao, Rushiya,Yu, Jing,Wu, Chunxia,Yao, Xinghui,Liu, Dongfang,Wang, Zhouyu
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p. 764 - 775
(2021/03/29)
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- Design, synthesis, in vitro and in vivo evaluation against MRSA and molecular docking studies of novel pleuromutilin derivatives bearing 1, 3, 4-oxadiazole linker
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A class of pleuromutilin derivatives containing 1, 3, 4-oxadiazole were designed and synthesized as potential antibacterial agents against Methicillin-resistant staphylococcus aureus (MRSA). The ultrasound-assisted reaction was proposed as a green chemistry method to synthesize 1, 3, 4-oxadiazole derivatives (intermediates 85–110). Among these pleuromutilin derivatives, compound 133 was found to be the strongest antibacterial derivative against MRSA (MIC = 0.125 μg/mL). Furthermore, the result of the time-kill curves displayed that compound 133 could inhibit the growth of MRSA in vitro quickly (- 4.36 log10 CFU/mL reduction). Then, compound 133 (- 1.82 log10 CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (- 0.82 log10 CFU/mL) in reducing MRSA load in mice thigh model. Besides, compound 133 exhibited low cytotoxicity to RAW 264.7 cells. Molecular docking studies revealed that compound 133 was successfully localized in the binding pocket of 50S ribosomal subunit (ΔGb = -10.50 kcal/mol). The results indicated that these pleuromutilin derivatives containing 1, 3, 4-oxadiazole might be further developed into novel antibiotics against MRSA.
- Liu, Jie,Zhang, Guang-Yu,Zhang, Zhe,Li, Bo,Chai, Fei,Wang, Qi,Zhou, Zi-Dan,Xu, Ling-Ling,Wang, Shou-Kai,Jin, Zhen,Tang, You-Zhi
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- Design, synthesis, and biological activity evaluation of a series of pleuromutilin derivatives with novel C14 side chains
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In this work, according to the ‘me-too me-better’ design strategy, a peculiar side chain different from lefamulin at C14 position of pleuromutilin was introduced. A series of novel thioether pleuromutilin derivatives containing cyclohexane in the C14 chain was synthesized by ten-step synthesis reaction. All derivatives were characterized by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometer (HRMS). Furthermore, majority of derivatives displayed moderate antibacterial activity in vitro. However, the compound 2C and 2J exhibited comparable or superior antibacterial activity to lefamulin. The summarized structure-activity relationship not only made the variety of pleuromutilin derivatives more diverse, but also provided new ideas for its design and development.
- Li, Yun-Ge,Wang, Ju-Xian,Wang, Yu-Cheng,You, Xue-Fu,Zhang, Fan,Zhang, Guo-Ning,Zhu, Mei
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- Pleuromutilin derivative with amide side chain as well as preparation and application of pleuromutilin derivative
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The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with an amide side chain as well as preparation and application of the pleuromutilin derivative. The pleuromutilin derivative with an amide side chain is a compound shown as a formula 2 (See the specification) or a pharmaceutically acceptable salt thereof, and a solvate, an enantiomer,a diastereoisomer, a tautomer or a mixture of the solvate, the enantiomer, the diastereoisomer and the tautomer of the compound of formula 2 or the pharmaceutically acceptable salt thereof in any proportion, including a racemic mixture. The compound not only has good in-vitro antibacterial activity and water solubility, but also has the advantage of low preparation cost compared with valnemulin and retapamulin, so that the compound is particularly suitable for being used as a novel antibacterial agent for preventing and treating human or animal bacterial infectious diseases, particularly infectious diseases caused by drug-resistant staphylococcus aureus.
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Paragraph 0095; 0114-0115
(2020/09/09)
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- Pleuromutilin derivative with triazole side chain, and preparation method and application thereof
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The invention relates to the technical field of medicinal chemistry, in particular to a pleuromutilin derivative with a triazole side chain, and a preparation method and application thereof. The pleuromutilin derivative disclosed by the invention has the triazole side chain and a pleuromutilin parent nucleus structure; and in-vitro experiment results and animal experiment results show that the pleuromutilin derivative disclosed by the invention has good antibacterial activity on Staphylococcus aureus, and is particularly applicable as a novel antibacterial drug for systemic infections of animals or human beings.
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Paragraph 0102; 0109-0110
(2020/03/02)
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- Pleuromutilin derivative with 1,2,4-triazole Schiff base as well as preparation and application of pleuromutilin derivative
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The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with 1,2,4-triazole Schiff base as well as preparation and application of the pleuromutilin derivative. The pleuromutilin derivative with 1,2,4-triazole Schiff base is a compound represented by a formula 2 or a pharmaceutically acceptable salt thereof, and a solvate, an enantiomer, a diastereoisomer, a tautomer or a mixture of the solvate, the enantiomer, the diastereoisomer and the tautomer of the compound of formula 2 or the pharmaceutically acceptable salt thereof, the compoundnot only has good in-vitro antibacterial activity, but also has the advantage of low preparation cost compared with valnemulin and retapamulin, so that the compound is particularly suitable for beingused as a novel antibacterial drug for preventing and treating human or animal bacterial infectious diseases, particularly infectious diseases caused by drug-resistant staphylococcus aureus.
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Paragraph 0102-0103
(2020/10/04)
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- Pleuromutilin derivative containing N - type alkylated pyrimidine side chain and application thereof (by machine translation)
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The invention discloses a pleuromutilin derivative containing N - type alkylated pyrimidine side chains and application thereof, and the pleuromutilin derivative has the following structural formula. In the formula, R is each independently. or. The pleuro
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Paragraph 0017
(2020/07/02)
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- Design, synthesis and biological activities of novel pleuromutilin derivatives with a substituted triazole moiety as potent antibacterial agents
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A series of novel pleuromutilin derivatives possessing 1,2,3-triazole moieties were synthesized via click reactions under mild conditions. The in vitro antibacterial activities of these derivatives against 4 strains of S. aureus (MRSA ATCC 43300, ATCC 29213, AD 3, and 144) and 1 strain of E. coli (ATCC 25922) were tested by the broth dilution method. The majority of the synthesized derivatives displayed potent antibacterial activities against MRSA (MIC = 0.125–2 μg/mL). It was also found that most compounds had no significant inhibitory effect on the proliferation of RAW264.7 cells at the concentration of 8 μg/mL. Among these derivatives, compound 32 (~1.71 log10 CFU/g) containing dimethylamine group side chain displayed more effective than tiamulin (~0.77 log10 CFU/g) at the dose of 20 mg/kg in reducing MRSA load in thigh infected mice. Additionally, compound 32 (the survival rate was 50%) also displayed superior in vivo efficacy to that of tiamulin (the survival rate was 20%) in the mouse systemic model. Structure-activity relationship (SAR) studies resulted in compound 32 with the most potent in vitro and in vivo antibacterial activity among the series. Moreover, compound 32 was evaluated in CYP450 inhibition assay and showed moderate in vitro inhibition of CYP3A4 (IC50 = 6.148 μM).
- Zhang, Zhe,Li, Kang,Zhang, Guang-Yu,Tang, You-Zhi,Jin, Zhen
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- Design, synthesis and biological evaluation of novel pleuromutilin derivatives containing piperazine and 1,2,3-triazole linker
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A series of novel pleuromutilin derivatives containing piperazine ring, 1, 2, 3-triazoles and secondary amines on the side chain of C14 were synthesized under mild conditions via click reaction. The in vitro antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213, 144 and AD3) and one strain of Escherichia coli (ATCC 25922) were evaluated by the broth dilution method. Among these derivatives, 22–[2-(4-((4-nitrophenyl piperazine)methyl)-1,2,3-triazol-1-yl)-1-(piperazine-1-yl) ethyl-1-one] deoxy pleuromutilin (compound 59) showed the most prominent in vitro antibacterial effect against MRSA (MIC = 1 μg/mL). Furthermore, compound 59 displayed more rapid bactericidal kinetic than tiamulin time-kill studies and possessed a longer PAE than tiamulin against MRSA in vitro. In addition, in vivo antibacterial activities of compound 59 against MRSA were further evaluated employing thigh infection model. And compound 59 (-8.89 log10 CFU/mL) displayed superior activities than tiamulin. Compound 59 was further evaluated in CYP450 inhibition assay and the results showed that it exhibited low to moderate inhibitory effects on CYP1A2, CYP2E1, CYP2D6 and CYP3A4 enzymes. The PK properties of compound 59 were then measured. The half-life (t1/2), clearance rate (Cl) and the area under the plasma concentration time curve (AUC0→∞) of compound 59 were 0.74 h, 0.29 L/h/kg and 46.28 μg·h/mL, respectively.
- Zhang, Guang-Yu,Zhang, Zhe,Li, Kang,Liu, Jie,Li, Bo,Jin, Zhen,Liu, Ya-Hong,Tang, You-Zhi
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- Pleuromutilin compounds for treating novel coronavirus pneumonia secondary bacterial infectious diseases
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The present invention relates to novel pleuromutilin compounds, and a pharmaceutical composition and a use method thereof. Furthermore, the present invention also relates to a therapeutic method for treating bacterial infections, including infections caused by resistant microorganisms including multiple resistant microorganisms. The method and the compounds for treating secondary bacterial infectious diseases of novel coronavirus (COVID-19 or SARS-Cov-2) pneumonia, and the pharmaceutical composition of the compounds are especially provided, and provide scientific and technological support forwin-win new coronapneumonia epidemic prevention and control obstructing warfare.
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Paragraph 0095-0097; 0110-0112
(2020/09/23)
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- Chemoselective reduction of aldehydes: Via a combination of NaBH4 and acetylacetone
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A bench-stable combination of NaBH4-acetylacetone was developed for the efficient chemoselective reduction of aldehydes in the presence of ketones. This method offers a useful synthetic protocol for distinguishing carbonyl reaction sites, and its synthetic utility is reflected by its moisture tolerance and high efficiency in a variety of complex settings.
- Sui, Guoqing,Lv, Qingyun,Song, Xiaoqing,Guo, Huihui,Dai, Jiatong,Ren, Li,Lee, Chi-Sing,Zhou, Wenming,Hao, Hong-Dong
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supporting information
p. 15793 - 15796
(2019/10/19)
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- Pleuromutilin derivative with 2-aminothiophenol and 1,2,3-triazole side chain, preparation and application
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The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with 2-aminothiophenol and a 1,2,3-triazole side chain, preparation and application. The pleuromutilin derivative with 2-aminothiophenol and the 1,2,3-triazole side chain is a compound of a formula 2 or a pharmaceutically acceptable salt of the compound, and a solvent compound, an enantiomer, a diastereomer and a tautomer of the compound of the formula 2 or the pharmaceutically acceptable salt of the compound or a mixture of the compound of the formula 2 or the pharmaceutically acceptable salt of the compound in any ratio, and includes a racemic mixture, and the compound has good inhibition to methicillin-resistant staphylococcus aureus activity, and is especially suitable forbeing used as a novel antibacterial drug for prevention and treatment of infectious diseases caused by human or animals or methicillin-resistant staphylococcus aureus or multi-drug resistant bacteria.(Please see the specification for the formula).
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Paragraph 0076; 0091; 0092
(2019/11/12)
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- Pleuromutilin derivative containing piperazine and 1, 2, 3-triazole secondary amine side chains, and preparation and applications thereof
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The invention belongs to the field of pharmaceutical chemistry, and especially relates to a pleuromutilin derivative containing piperazine and 1, 2, 3-triazole secondary amine side chains, and preparation and applications thereof. The pleuromutilin derivative containing piperazine and 1, 2, 3-triazole secondary amine side chains is a compound represented by formula 2 or a pharmaceutically acceptable salt of the compound, or a solvate, an enantiomer, a diastereomer, a tautomer of the compound represented by formula 2 or the pharmaceutically acceptable salt of the compound, or a mixture of the above substances at a random ratio comprising a racemic mixture. The compound possesses excellent in vitro antibacterial activity, the cost is lower than that of valnemulin and retapamulin, so that thecompound is especially suitable to be taken as a novel antibacterial drug in prevention and treatment of human or animal bacterial infectious diseases, especially infectious diseases caused by medicine resistant Staphylococcus aureus.
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Paragraph 0091; 0092
(2019/11/29)
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- Semi-synthesis, antibacterial activity, and molecular docking study of novel pleuromutilin derivatives bearing cinnamic acids moieties
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To develop new antibiotics owning a special mechanism, we used the molecular assembly method to synthesize a series of novel pleuromutilin derivatives containing a cinnamic acid scaffold at the C-14 side chain. We evaluated their antibacterial activity an
- Deng, Yu,Tang, Da,Wang, Qiu-ru,Huang, Sheng,Fu, Li-zhi,Li, Cheng-hong
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- Pleuromutilin compound and preparation method and application thereof
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The invention belongs to the technical field of drug synthesis, and concretely relates to a pleuromutilin compound and a preparation method and an application thereof. The pleuromutilin compound has astructure shown in formula I, and is prepared by reacti
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Paragraph 0059; 0065; 0066; 0067; 0068
(2019/01/05)
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- PLEUROMUTILIN DERIVATIVES AND USES THEREOF
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Provided herein are pleuromutilin derivatives and analogs that are useful antimicrobial agents against Acinetobacter baumannii and Mycobacterium.
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Page/Page column 49; 50
(2018/09/18)
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- An antimycobacterial pleuromutilin analogue effective against dormant bacilli
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Pleuromutilin is a promising pharmacophore to design new antibacterial agents for Gram-positive bacteria. However, there are limited studies on the development of pleuromutilin analogues that inhibit growth of Mycobacterium tuberculosis (Mtb). In screenin
- Lemieux, Maddie R.,Siricilla, Shajila,Mitachi, Katsuhiko,Eslamimehr, Shakiba,Wang, Yuehong,Yang, Dong,Pressly, Jeffrey D.,Kong, Ying,Park, Frank,Franzblau, Scott G.,Kurosu, Michio
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supporting information
p. 4787 - 4796
(2018/08/27)
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- Synthesis and biological activity evaluation of novel heterocyclic pleuromutilin derivatives
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A series of pleuromutilin derivatives were synthesized by two synthetic procedures under mild reaction conditions and characterized by Nuclear Magnetic Resonance (NMR), Infrared Spectroscopy (IR), and High Resolution Mass Spectrometer (HRMS). Most of the derivatives with heterocyclic groups at the C-14 side of pleuromutilin exhibited excellent in vitro antibacterial activities against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and vancomycin-resistant Enterococcus (VRE) in vitro antibacterial activity. The synthesized derivatives which contained pyrimidine rings, 3a, 3b, and 3f, displayed modest antibacterial activities. Compound 3a, the most active antibacterial agent, displayed rapid bactericidal activity and affected bacterial growth in the same manner as that of tiamulin fumarate. Moreover, molecular docking studies of 3a and lefamulin provided similar information about the interactions between the compounds and 50S ribosomal subunit. The results of the study show that pyrimidine rings should be considered in the drug design of pleuromutilin derivatives.
- Yi, Yunpeng,Fu, Yunxing,Dong, Pengcheng,Qin, Wenwen,Liu, Yu,Liang, Jiangping,Shang, Ruofeng
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supporting information
(2017/06/28)
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- A Swedish he Moline synthesis method
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The present invention provides a synthesis method for Retapamulin. The method comprises: using pleuromutilin as a starting material of one segment; obtaining PLM-TS by condensation reaction between the starting material and toluenesulfonyl chloride; using tropenol as a raw material of the other segment; obtaining TRP-MS by reaction between the raw material and toluenesulfonyl chloride; after performing substitution reaction between TRP-MS that uses water as a solvent and potassium ethyl xanthate, performing acidification between the substance and sulfuric acid to obtain an intermediate TRP-XAN; TRP-XAN undergoing hydrolysis in an ethanol NaOH solution; performing acidification between the substance and sulfuric acid to obtain an intermediate TRP-THI; the two segments TRP-THI and PLM-TS undergoing condensation reaction under alkaline conditions to obtain the final product, Retapamulin. The synthesis method for Retapamulin provided by the present invention is simple, environmentally friendly, easy in controlling the quality of intermediates of all steps, and suitable for the Retapamulin synthesis process in industrialized production.
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Paragraph 0054; 0055; 0065; 0066; 0076; 0077
(2017/07/11)
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- With pyrimidine side chain pleuromutilin derivative and its application
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The invention discloses a pleuromutilin derivative with a pyrimidine side chain. The structural formula of the derivative is shown in the specification, wherein R1 is C1-C4 alkoxy groups or hydroxyl groups; R2 is an amino group or an amide group; R3 is hy
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Paragraph 0025-0027
(2017/08/25)
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- Pleuromutilin antibiotic as well as preparation method and application thereof
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The invention discloses a method for synthesizing pleuromutilin antibiotic. The method comprises the following steps: (1) reacting paratoluensulfonyl chloride and pleuromutilin so as to produce p-tosylation pleuromutilin; (2) dissolving the p-tosylation p
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Paragraph 0031; 0035; 0036; 0037
(2017/12/28)
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- Synthesis method of valnemulin hydrochloride
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The invention discloses a synthesis method of valnemulin hydrochloride. The synthesis method comprises the following three steps: synthesis of dimethylcysteamine pleuromulin from pleuromulin, synthesis of D-valine dane salt from D-valine and synthesis of
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Paragraph 0059; 0060; 0072; 0073; 0085; 0086; 0098; 0099
(2017/04/03)
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- BORON-CONTAINING SMALL MOLECULES
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Compounds, pharmaceutical formulations, and methods of treating bacterial infections are disclosed.
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Paragraph 0226
(2017/09/19)
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- With 2 - amino qiuqiu mellow side chain pleuromutilin derivative and its preparation and use (by machine translation)
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The invention belongs to the field of pharmaceutical chemistry, discloses a with 2 - amino qiuqiu mellow side chain of pleuromutilin compound and its preparation and use. The compound has the formula 2 formulae 3 structure shown. Wherein R1 , R
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Paragraph 0057; 0058
(2017/06/02)
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- A side chain with alkaline spat pleuromutilin derivative and its preparation method and application (by machine translation)
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The invention belongs to the field of pharmaceutical chemistry, has disclosed a kind of alkaline side chain pleuromutilin derivative and its preparation method. The having alkaline side chain pleuromutilin derivatives of structural formula such as formula
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Paragraph 0059-0060
(2017/10/13)
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- Pleuromulin derivative with acyl piperazine side chain and preparing method and application of pleuromulin derivative
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The invention belongs to the field of medicinal chemistry, and discloses a pleuromulin-like compound and with an acyl piperazine side chain and a preparing method and application of the pleuromulin-like compound. The pleuromulin derivative is a compound and an officinal salt of which the structure can be shown in the formula 3, formula 4 or formula 5, wherein R1, R2, and R3 are independently chosen from one of hydrogen atom, hydroxide radical, amidogen, sulfydryl, hydroxymethyl, amine methyl, nitro, halogen, trihalogenated methyl, methyl, natural amino acid acylamino, and alkoxy of which the number of carbon atoms is 1-6. The pleuromulin-like compound and with the acyl piperazine side chain has good property of inhibiting staphylococcus aureus and mycoplasma activities, and is particularly suitable for being used as a novel anti-microbial agent to prevent infectious diseases of human or animal caused by infection of mycoplasma or multidrug resistant microorganisms.
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Paragraph 0069; 0077; 0078
(2017/07/20)
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- Pleuromutilin derivative with 2-amino mercaptoethanol side chains and preparing method and application of pleuromutilin derivative
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The invention belongs to the field of medicinal chemistry, and discloses a pleuromutilin derivative with 2-amino mercaptoethanol side chains and a preparing method and application of the pleuromutilin derivative. The pleuromutilin derivative is a compound
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Paragraph 0052; 0053
(2017/04/29)
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- SMALL-MOLECULES ACTIVE AGAINST GRAM-NEGATIVE BACTERIA
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Disclosed are novel compounds that accumulate in Gram-negative bacteria. Also disclosed are method of antimicrobial treatment using the compounds.
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Page/Page column 89; 91
(2017/10/06)
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- BORON-CONTAINING SMALL MOLECULES
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Compounds, pharmaceutical formulations, and methods of treating bacterial infections are disclosed.
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Paragraph 0226
(2017/09/15)
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- 2 - mercapto-acetyl amine pleuromutilin derivatives and preparation method and medical use
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The invention discloses 2-mercaptoacetamide pleuromutilin derivatives and pharmaceutically acceptable salts thereof, a preparation method for the derivatives and the salts thereof, a pharmaceutical composition containing the derivatives and medical applic
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Paragraph 0115
(2017/08/18)
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- Of the skeleton with dithiazo Pleuromutilin derivatives and the preparation method, application
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The invention discloses a pleuromutilin derivative with a thiadiazole skeleton and a preparation method thereof. The preparation method comprises the following steps: 1, synthesizing 22-O-(4-tosyl)acetoxyl mutilin; 2, synthesizing 14-O-( iodoacetyl)mutili
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Paragraph 0064; 0069; 0070
(2016/12/01)
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- Pleuromutilin antibiotics
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The present invention relates to pleuromutilin antibiotics represented by a general formula (I), pharmaceutically acceptable salts, prodrugs, solvates or stereoisomers thereof, wherein R, R, R, R, m, X and Y are defined in an instruction. The present invention further relates to preparation methods of the compounds, drug compositions containing the compounds, drug preparations containing the compounds, and applications of the compounds in preparation of drugs for treatment and/or prevention of diseases caused by microorganisms.
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Paragraph 0280-0282
(2017/01/23)
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- The side chains of the piperazine with a pleuromutilin derivatives and process for their preparation and use (by machine translation)
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The invention belongs to the field of medicinal chemistry, discloses a piperazine chain Pleuromutilin derivatives and process for their preparation and use. The derivative has formula 2 or formula 3 the structure of the shown, wherein R 1 is hydrogen, methoxy, methyl, hydroxy, nitro or Cl, R 2 is hydrogen, methoxy, methyl, hydroxy, nitro or Cl, R 3 is hydrogen, methoxy, methyl, hydroxy, nitro or Cl, R 4 is phenyl or methyl. The invention has the advantages of the side chains of the piperazine Pleuromutilin derivatives not only has good in vitro antibacterial activity, also has and compares the Warney wonderful forestswitzerland it moline preparing the advantages of low cost, which is especially suitable to be used as a novel antibacterial drugs are used for human or animal bacterial infectious diseases. (by machine translation)
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Paragraph 0045; 0046
(2016/11/02)
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