7223-38-3Relevant academic research and scientific papers
A click chemistry approach to pleuromutilin derivatives, evaluation of anti-MRSA activity and elucidation of binding mode by surface plasmon resonance and molecular docking
Zhang, Zhe,Zhang, Zhao-Sheng,Wang, Xiao,Xi, Gao-Lei,Jin, Zhen,Tang, You-Zhi
, p. 2087 - 2103 (2021/12/02)
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.
Design, synthesis and biological activities of novel pleuromutilin derivatives with a substituted triazole moiety as potent antibacterial agents
Zhang, Zhe,Li, Kang,Zhang, Guang-Yu,Tang, You-Zhi,Jin, Zhen
, (2020/07/30)
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).
Design, synthesis and biological evaluation of novel pleuromutilin derivatives containing piperazine and 1,2,3-triazole linker
Zhang, Guang-Yu,Zhang, Zhe,Li, Kang,Liu, Jie,Li, Bo,Jin, Zhen,Liu, Ya-Hong,Tang, You-Zhi
, (2020/11/02)
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.
Design, synthesis,: In silico docking studies and biological evaluation of novel quinoxaline-hydrazide hydrazone-1,2,3-triazole hybrids as α-glucosidase inhibitors and antioxidants
Settypalli, Triloknadh,Chunduri, Venkata Rao,Maddineni, Aruna Kumari,Begari, Nagaraju,Allagadda, Rajasekhar,Kotha, Peddanna,Chippada, Appa Rao
, p. 15435 - 15452 (2019/10/08)
A new series of quinoxaline-hydrazidehydrazone-1,2,3-triazole hybrids, 14a-j, 15a-j and 16a-e, was designed, synthesized and screened for in vitro α-glucosidase and antioxidant activities. For the synthesis of the target compounds, quinoxaline hydrazides were condensed with benzaldehyde triazoles in the presence of AcOH (cat) in ethanol. The key step in the preparation of compounds 8a-j was the Cu(i)-catalyzed [3+2] cycloaddition reaction (CuAAC) with appropriate alkynes (6, 7) and azides, and 13a-j were prepared from simple aldehydes utilizing the same click reaction as the final step. Quinoxaline hydrazides (3, 3a) were synthesized from o-phenylenediamine and pyruvic acid via three-step reactions comprising cyclization, alkylation and hydrazidation. Among these hybrids, 14a (IC50 = 21.92 μg mL-1), 14b (IC50 = 22.32 μg mL-1), 14c (IC50 = 23.58 μg mL-1) and 15a (IC50 = 24.50 μg mL-1) showed good α-glucosidase inhibition compared with the standard acarbose (IC50 = 22.32 μg mL-1). Further, the scavenging abilities of the synthesized compounds as antioxidants were studied using the DPPH, H2O2, and NO methods; as per the obtained results, compounds 14a, 14b, 14c and 15a displayed good antioxidant activity. Docking studies of the active compounds and acarbose as a standard with α-glucosidase (PDB ID: 2ZEO) were performed to determine the molecular interactions between the inhibitors and the active site of the enzyme. Better binding energies of the active compounds than of the standard acarbose were observed. Therefore, our new hybrid molecules may be useful for further optimization in developing new lead molecules with both α-glucosidase inhibition and antioxidant activities.
Pleuromutilin derivative with 2-aminothiophenol and 1,2,3-triazole side chain, preparation and application
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Paragraph 0121-0123, (2019/11/12)
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).
Pleuromutilin derivative containing piperazine and 1, 2, 3-triazole secondary amine side chains, and preparation and applications thereof
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Paragraph 0096-0098, (2019/11/29)
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.
Discovery of highly potent renin inhibitors potentially interacting with the S3' subsite of renin
Sun, Xiaowei,Wen, Xiaoan,Chen, Yan-Yan,Shi, Chen,Gao, Chengzhe,Wu, Yong,Wang, Li-Jun,Yang, Xiu-Hong,Sun, Hongbin
supporting information, p. 269 - 288 (2015/09/21)
To exploit the S3′ subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with modified P2' portion were designed, synthesized and biologically evaluated. Some highly potent renin inhibitors (IC50 50 Combining double low line 0.9 nM) and 39 (IC50 Combining double low line 0.7 nM) were over 2.5-fold more potent than aliskiren (IC50 Combining double low line 2.3 nM). SAR analysis indicated that incorporation of polar hydrophilic moieties into the P2' portion of renin inhibitors generally enhanced the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could provide additional interactions to the S3' subsite of renin active site. Moreover, in vivo evaluation in the double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 1/4mol/kg, respectively. Taken together, the S3' subsite of renin active site merits further consideration for renin inhibitor design.
7-Chloroquinolinotriazoles: Synthesis by the azide-alkyne cycloaddition click chemistry, antimalarial activity, cytotoxicity and SAR studies
Pereira, Guilherme R.,Brand?o, Geraldo Célio,Arantes, Lucas M.,De Oliveira Jr., Háliton A.,De Paula, Renata Cristina,Do Nascimento, Maria Fernanda A.,Dos Santos, Fábio M.,Da Rocha, Ramon K.,Lopes, Júlio César D.,De Oliveira, Alaíde Braga
, p. 295 - 309 (2014/02/14)
Twenty-seven 7-chloroquinolinotriazole derivatives with different substituents in the triazole moiety were synthesized via copper-catalyzed cycloaddition (CuAAC) click chemistry between 4-azido-7-chloroquinoline and several alkynes. All the synthetic compounds were evaluated for their in vitro activity against Plasmodium falciparum (W2) and cytotoxicity to Hep G2A16 cells. All the products disclosed low cytotoxicity (CC50 > 100 μM) and five of them have shown moderate antimalarial activity (IC50 from 9.6 to 40.9 μM). As chloroquine analogs it was expected that these compounds might inhibit the heme polymerization and SAR studies were performed aiming to explain their antimalarial profile. New structural variations can be designed on the basis of the results obtained.
Design, synthesis and antimicrobial activities of some new quinoline derivatives carrying 1,2,3-triazole moiety
Thomas,Adhikari, Airody Vasudeva,Shetty, N. Suchetha
experimental part, p. 3803 - 3810 (2010/09/15)
A new series of [1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3-triazol-4-yl] methanamine derivatives were synthesized starting from 4-methoxyaniline through multi-step reactions. The title compounds 5a-y were prepared by treating the azide intermediate 4 with propargyl bromide and different alkyl/heterocyclic amines in a sequential three component synthesis. All the new compounds were characterized by spectral and elemental analyses. The newly synthesized final compounds were evaluated for their in vitro antibacterial and antifungal activities against pathogenic strains. The preliminary screening results indicated that most of the compounds demonstrated moderate to very good antibacterial and antifungal activities, comparable to the first-line drugs. Twenty five new derivatives of [1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3- triazol-4-yl] methanamine have been synthesized and the most effective compounds have MIC of 6.25 μg/mL, which are in comparable with present antibiotics.
