Jianping Liang

Synthesis and Biological Evaluation of New Pleuromutilin Derivatives as Antibacterial Agents

Several pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant S. aureus, methicillin-resistant S. epidermidis, S. aureus, S. epidermidis, E. coli, and B. cereus were tested by the agar dilution method and Oxford cup assay. All the screened compounds displayed potent activity. Compound 6d was the most active antibacterial agent because of its lowest MIC value and largest inhibition zone. Docking experiments were performed to understand the possible mode of the interactions between the derivatives and 50S ribosomal subunit. Moreover, the absorption, distribution, metabolism, excretion and toxicity properties of the synthesized compounds were analyzed after prediction using the Advanced Chemistry Development/Percepta Platform available online.

Chemical synthesis and biological activities of novel pleuromutilin derivatives with substituted amino moiety.

Novel pleuromutilin derivatives designed based on the structure of valnemulin were synthesized and evaluated for their in vitro antibacterial activities. These pleuromutilin derivatives with substituted amino moiety exhibited excellent activities against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae. Compound 5b showed the highest antibacterial activities and even exceeded tiamulin. Moreover, the docking experiments provided information about the binding model between the synthesized compounds and peptidyl transferase center (PTC) of 23S rRNA.

Synthesis and antibacterial activities of novel pleuromutilin derivatives with a substituted pyrimidine moiety

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.xa0aureus) 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. Inxa0vivo mouse systemic infection experimental results confirmed the therapeutic efficacy of compound 3, with ED50 of 4.22xa0mg/kg body weight against MRSA.

In Vivo Efficacy and Toxicity Studies of a Novel Antibacterial Agent: 14-O-[(2-Amino-1,3,4-thiadiazol-5-yl)Thioacetyl] Mutilin

A new pleuromutilin derivative with excellent antibacterial activity, 14-O-[(2-amino-1,3,4-thiadiazol-5-yl) thioacetyl] mutilin (ATTM), may serve as a possible lead compound for the development of antibacterial drugs. However, in vivo efficacy and toxicity evaluations of this compound have not been performed. In this study, we evaluated the efficacy of ATTM by measuring the survival of mice after a lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA), and the 50% effective dose (ED50) was 5.74 mg/kg by the intravenous route. In an oral single-dose toxicity study, ATTM was orally administered to mice at different doses and the 50% lethal dose (LD50) was calculated to be 2304.4 mg/kg by the Bliss method. The results of the subchronic oral toxicity study in rats showed no mortality, exterior signs of toxicity, or differences in the total weight gain or relative organ weights between the treated groups and control group after administration. The hematological and serum biochemical data showed no differences between the treated and control groups, except for the levels of alkaline phosphatase (ALP), creatinine (CR) and blood glucose (GLU), which were significantly different in the high-dose group. The differences in the histopathological findings between the treated groups and the control group were not considered to be treatment-related. Our results indicated that the no observed adverse effect level (NOAEL) for ATTM was 5 mg/kg in this study.

Review of Platensimycin and Platencin: Inhibitors of β-Ketoacyl-acyl Carrier Protein (ACP) Synthase III (FabH).

Platensimycin and platencin were successively discovered from the strain Streptomyces platensis through systematic screening. These natural products have been defined as promising agents for fighting multidrug resistance in bacteria by targeting type II fatty acid synthesis with slightly different mechanisms. Bioactivity studies have shown that platensimycin and platencin offer great potential to inhibit many resistant bacteria with no cross-resistance or toxicity observed in vivo. This review summarizes the general information on platensimycin and platencin, including antibacterial and self-resistant mechanisms. Furthermore, the total synthesis pathways of platensimycin and platencin and their analogues from recent studies are presented.

Synthesis and antibacterial activities of novel pleuromutilin derivatives

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), methicillin‐resistant S. aureus (MRSA, ATCC 43300), Pasteurella multocida (CVCC 408), Escherichia coli (ATCC 25922), and Salmonella typhimurium (ATCC 14028). Most compounds with quaternary amine showed higher antibacterial activities against both Gram‐positive and Gram‐negative bacteria strains. Among the screened compounds, compound 5a bearing an N,N,N‐trimethyl group at the C‐14 side chain of pleuromutilin was found to be the most active agent. Furthermore, preliminary molecular docking was performed to predict the binding interaction of the compounds in the binding pocket.

Antibacterial activity and pharmacokinetic profile of a promising antibacterial agent: 14-O-[(4-Amino-6-hydroxy-pyrimidine-2-yl)thioacetyl] mutilin

Graphical abstract Figure. No caption available. &NA; A new pleuromutilin derivative, 14‐O‐[(4‐Amino‐6‐hydroxy‐pyrimidine‐2‐yl)thioacetyl] mutilin (APTM), has been synthesized and proved most potent antibacterial agent in in vitro assays, suggesting that further development of this compound may lead to a promising antibacterial drug. In this study, we further evaluated the cytotoxicity, antibacterial efficacy and the pharmacokinetic profile of APTM. In BRL 3A cells, 50% of viability was obtained when 363 &mgr;g/mL of APTM was used, while retapamulin and tiamulin fumarate needed 49 and 28 &mgr;g/mL, respectively, to reach this viability. Compared to tiamulin fumarate, APTM showed higher inhibition efficacy and faster bactericidal activity against S. aureus and lower 50% effective dose (ED50) in mice after a lethal challenge with methicillin‐resistant Staphylococcus aureus (MRSA). Docking experiment for APTM showed a similar binding pattern with tiamulin. Furthermore, a simple, accurate and sensitive HPLC method for the determination of APTM in rabbit plasma was developed and successfully applied to pharmacokinetic study, in which the half life (t1/2), clearance rate (Cl) and the area under the plasma concentration–time curve (AUC0→∞) were 3.37 h, 0.35 L/h/kg and 70.68 &mgr;g·h/m, respectively.

Flavonoids and Phenolics from the Flowers of Limonium aureum

Plants of the Limonium aureum (L.) Hill ex Kuntze (Plumbaginaceae) are rich sources of flavonoids and phenolics [1, 2]. Plants of the Limonium aureum were reported to possess blood invigorating and activating properties and hemostatic and anticancer activity [3]. We studied the flavonoid and phenolic compositions of the flowers of Limonium aureum collected from the north of China, in September 2010 (Gansu region, PRC). Air-dried flowers (1.0 kg) were exhaustively extracted with ethanol. The extract was evaporated to a thick consistency and diluted with 400 mL water. The flavonoids and phenolics were extracted with ethyl acetate and chromatographed over polyamide, silica gel, and Sephadex LH-20 in our continuing chemical examination of this plant. The compounds were isolated from the flowers of Limonium aureum and identified by UV, mass, and NMR spectra and comparison with authentic samples. Eriodictyol, white needle crystals, mp 266–267 C. UV (MeOH, max, nm): 286, 321. 1H NMR and 13C NMR confirmed the identity of the compound as eriodictyol [4]. Luteolin, mp 330–332 C. UV (MeOH, max, nm): 255, 270, and 350. MS (EI): 287 (18), 286 (100), 258 (12), 153 (20), 134 (6), 129 (10), 62 (21), and 44 (47). Authentic samples were used to identify luteolin [5]. Apigenin, mp 346–347 C. UV (MeOH, max, nm): 267, 334. MS (EI): 270 (100), 242 (13), 153 (15), 152 (10), 121 (11), 96 (3), 69 (4) and 43 (7). Authentic samples were used to identify apigenin [6]. 5,7-Dihydroxychromone, white needle crystals, mp 245–247 C. 1H NMR (400 MHz, DMSO-d6, , ppm, J/Hz): 6.07 (1H, d, J = 6, H-6), 6.13 (2H, d, J = 2.0, H-3), 6.24 (2H, d, J = 2.4, H-8), 7.78 (1H, d, J = 6, H-2), 10.30 (1H, s, H-7), 12.50 (1H, s, H-5). 13C NMR (100 MHz, DMSO-d6, , ppm): 93.7 (C-8), 98.9 (C-6), 105.0 (C-10), 110.3 (C-3), 155.6 (C-2), 157.6 (C-4), 161.5 (C-5), 164.0 (C-7), 181.0 (C-4), characterized as 5,7-dihydroxychromone [7]. Quercetin 3-O-D-xyloside, yellow powder, mp 202–204 C. 1H NMR (400 MHz, DMSO-d6, , ppm, J/Hz): 2.95–3.44 (sugar H), 5.35 (1H, d, J = 7.0, H-1 ), 6.19 (1H, br.s, H-6), 6.39 (1H, br.s, H-8), 6.85 (1H, d, J = 8.5, H-5 ), 7.54 (1H, dd, J = 2.0, 8.5, H-6 ), 7.56 (1H, d, J = 2.0, H-2 ). 13C NMR (100 MHz, DMSO-d6, , ppm): 66.0 (C-5 ), 70.3 (C-4 ), 74.6 (C-2 ), 76.9 (C-3 ), 94.1 (C-8), 99.2 (C-6), 102.3 (C-1 ), 104.4 (C-10), 116.3 (C-2 ), 116.6 (C-5 ), 121.0 (C-1 ), 121.9 (C-6 ), 133.2 (C-3), 146.3 (C-3 ), 150.1 (C-4 ), 156.1 (C-2), 156.1 (C-9), 162.6 (C-5), 164.2 (C-7), 177.2 (C-4), characterized as quercetin-3-O-D-xyloside [8]. Myricetin 3-O-D-xylopyranoside, mp 186–187 C. UV spectrum (MeOH, max, nm): 256, 284, 360. 1H NMR (400 MHz, CD3OD, , ppm, J/Hz): 3.50 (1H, dd, J = 3, H-5 ), 3.67 (1H, dd, J = 3, H-4 ), 3.80–3.87 (2H, m, H-2 , 3 ), 5.19 (1H, d, J = 5.8, H-1 ), 6.22 (1H, d, J = 2), 6.41 (1H, d, J = 2), 7.33 (2H, s); acid hydrolysis produced myricetin and xylose, characterized as myricetin 3-O-D-xylopyranoside [9].