•PZ-M prepared by mPEG-PLLA significantly increase water solubility of pyrinezolid.•PZ-M possess prolonged blood circulation time and increased oral bioavailability.•PZ-M has the potential to serve as a novel agent for MRSA-related pneumonia.Antibiotic-resistance by bacteria is a growing global concern within the healthcare field, and it has provided an impetus for continued antimicrobial development. Pyrinezolid (PZ), a novel oxazolidinone compound, can effectively inhibit most gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Though PZ is a promising antimicrobial candidate, the druggability of PZ is limited by its poor water solubility. Therefore, the amphipathic mPEG-PLLA copolymer was used to prepare the pyrinezolid micelles (PZ-M). Herein, we described the preparation, pharmacokinetic properties, tissue distribution, efficacy and toxicity of PZ-M. In vivo studies show that PZ-M possess prolonged blood circulation time and increased oral bioavailability compared with free PZ. Meanwhile, PZ-M increase lung PZ exposure and reduce liver and kidney exposure, which indicates that PZ-M may enhance the efficacy in vivo in MRSA-related pneumonia patients and decrease potential renal and hepatic toxicities.Preparation of PZ-M. (A) Chemical structure of pyrinezolid; (B) Schematic diagram of the preparation of PZ-M.Download high-res image (77KB)Download full-size image

A series of novel teraryl oxazolidinone compounds was designed, synthesized, and evaluated for their antimicrobial activity and toxicities. The compounds with aromatic N-heterocyclic substituents at the 4-position of pyrazolyl ring showed better antibacterial activity against the tested bacteria than other compounds with different patterns of substitution. Among all potent compounds, 10f exhibited promising safety profile in MTT assays and in hERG K+ channel inhibition test. Furthermore, its phosphate was found to be highly soluble in water (47.1 mg/mL), which is beneficial for the subsequent in vivo test. In MRSA systemic infection mice models, 10f phosphate exerted significantly improved survival protection compared with linezolid. The compound also demonstrated high oral bioavailability (F = 99.1%). Moreover, from the results of in vivo toxicology experiments, 10f phosphate would be predicted to have less bone marrow suppression.

The asymmetric synthesis of 3-alkyl-3-hydroxyindolin-2-ones via direct aldol reaction of isatin with ketones catalyzed by natural amino acid salts is described, in which the phenylalanine lithium salt was found to be the best catalyst. This strategy was then applied to a variety of isatin and ketone substrates and the corresponding aldol products were obtained in excellent yields (up to 97%) with good to excellent enantioselectivities (up to 90%).(S)-3-Hydroxy-3-(2-oxopropyl)indolin-2-oneC11H13NO370% ee[α]D25 = −11.0 (c 1.0, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)(S)-3-Hydroxy-1-methyl-3-(2-oxopropyl)indolin-2-oneC12H13NO381% ee[α]D25 = −15.2 (c 2.4, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)(S)-1-Benzyl-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC18H17NO387% ee[α]D25 = −16.4 (c 2.8, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)(S)-3-Hydroxy-1-(4-methoxybenzyl)-3-(2-oxopropyl)indolin-2-oneC19H19NO487% ee[α]D25 = −16.3 (c 3.7, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)(S)-3-Hydroxy-5-methyl-3-(2-oxopropyl)indolin-2-oneC12H13NO366% ee[α]D25 = −13.0 (c 1.0, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)(S)-5-Fluoro-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC11H10FNO377% ee[α]D25 = −17.0 (c 1.0, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)(S)-5-Chloro-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC11H10ClNO378% ee[α]D25 = −22.0 (c 1.0, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)

Piperlongumine (PL) shows an inhibitory effect on tumor growth; however, lipophilicity has restricted its further applications. Nanotechnology provides an effective method to overcome the poor water solubility of lipophilic drugs. Polymeric micelles with small particle size can passively target tumors by the enhanced permeability and retention (EPR) effect, thus improving their anti-tumor effects. In this study, to improve the water solubility and anti-tumor activity of PL, PL encapsulated polymeric micelles (PL micelles) were prepared by a solid dispersion method. The prepared PL micelles showed a small particle size and high encapsulation efficiency, which could be lyophilized into powder, and the re-dissolved PL micelles are homogenous and stable in water. In addition, a sustained release behavior of PL micelles was observed in vitro. Encapsulation of PL into polymeric micelles could increase the cytotoxicity, cellular uptake, reactive oxygen species (ROS) and oxidized glutathione (GSSG), and reduce glutathione (GSH) levels in vitro. Encapsulation of PL into polymeric micelles enhanced its inhibitory effect on neovascularization both in vitro and in vivo. Compared with free PL, PL micelles showed a stronger inhibitory effect on the proliferation, migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs). Additionally, in a transgenic zebrafish model, embryonic angiogenesis was inhibited by PL micelles. Furthermore, PL micelles were more effective in inhibiting tumor growth and prolonging survival in a subcutaneous CT-26 murine tumor model in vivo. Therefore, our data revealed that the encapsulation of PL into biodegradable polymeric micelles enhanced its anti-angiogenesis and anti-tumor activities both in vitro and in vivo.

•Twenty novel derivatives were synthesized and evaluated in vitro and in vivo.•6k, 6o and 6p displayed excellent neuroprotective effects in vitro.•6k, 6o and 6p displayed antidepressant-like potency in forced swim test.•6k showed a better general locomotor activity in open field test.•6k possesses good safety profile in in vitro cytotoxicity evaluation.In this study, a series of novel naphthalene compounds were synthesized and screened for their antidepressant-like activities in vitro and in vivo. Their values for two descriptors (ClogP, tPSA) of the blood–brain barrier (BBB) were calculated for early assessment of the central nervous system (CNS) drug-likeness. Seven of them (6d, 6i, 6k, 6o, 6p, 6s and 6t) demonstrated potential protective effects on corticosterone-induced lesion of PC12 cells although they cannot repair the irreversible oxidant injury to PC12 cells by hydrogen peroxide. Compounds with promising neurorestorative activities (6k, 6o and 6p) were further evaluated for their in vivo effects by forced swim test (FST) and open field test (OFT) in C57 mice models. The FST results showed that compounds 6k, 6o and 6p remarkably reduced the immobility time of the tested mice. Among them, compound 6k was the most potent one, much more effective than Agomelatine and comparable to Fluoxetine. The OFT results showed that mice treated with compound 6k traveled a longer distance than those treated with Agomelatine or Fluoxetine, indicating a better general locomotor activity. The paper also proposed a possible binding mode of compound 6k with glucocorticoid receptor by docking study. The in vitro cytotoxicity data on HEK293 and L02 cells suggested compound 6k to be a promising antidepressant candidate for subsequent investigation.

A concise, environmentally benign, and cost-effective route was developed for the large-scale preparation of 1, a novel oxazolidinone antibacterial candidate. The key intermediate 2-(1-(2-fluoro-4-nitrophenyl)-1H-pyrazol-4-yl)pyridine 7 was prepared with high purity by mild deamination of the regioisomeric mixture 21. The mixture was prepared from a nucleophilic SNAr reaction by selective C–N coupling of the secondary amine functionality of 4-(pyridin-2-yl)-1H-pyrazol-3-amine 14 with 1,2-difluoro-4-nitrobenzene 10 in optimized conditions with the primary amine group remaining intact. The gaseous nitrogen release rate and reaction mixture temperature of the deamination step can be well controlled by altering the feeding manner, thereby providing safety guarantees. The optimized synthetic strategy of 1 with an overall yield of 27.6%, including seven sequential transformations by only five solid–liquid isolations, significantly improved the product separation workup. The strategy bypassed time-consuming and laborious procedures for any intermediate involved as well as for the final API. This study presents a process enabling the rapid delivery of a multikilogram quantity of API with high purity.

In this work, nineteen analogues of Agomelatine were readily synthesized through structural modification of the acetamide side-chain starting from the key common intermediate 2-(7-methoxynaphthalen-1-yl) ethanamine (3), which was prepared from commercially available compound 2-(7-methoxynaphthalen-1-yl) acetonitrile (2) in two steps. Corticosterone-induced PC12 pheochromocytoma cells phenotypic in vitro model was utilized to evaluate their potential antidepression activities. Imide compound 4a and acylamino carboxylic acid analogue 5b showed good protective effects on traumatic PC12 cells with protection rates of 34.2% and 23.2%, respectively. Further in vivo assessments in C57 mice FST (forced swim test) model demonstrated that compound 4a significantly reduced the immobility time of the tested subjects, indicating antidepressant-like activity. Preliminary toxicity assays conducted on human normal liver L02 cells and embryonic kidney 293 cells suggested a relatively low safety risk for compound 4a compared with the marketed drugs Agomelatine and Fluoxetine. The promising antidepressant-like efficacy of compound 4a, together with the relatively low toxicity to the normal tested cells and high liability of diffusion through the blood–brain barrier (BBB), presents us insights of exploration of me-better drug candidates of Agomelatine.

A variety of new mono-oxazolidinone molecules by modifying the C-ring of Linezolid, a marketed antibiotic for MRSA, were synthesized and tested for their in vitro antibacterial activities against several Staphylococcus aureus, Mycobacterium smegmatis and two Gram-negative bacteria strains (Escherichia coli and Pseudomonas aeruginosa). Among them, compounds 4–7 displayed moderate antimicrobial activities. After development of a second oxazolidinone ring in the western part of the mono-oxazolidinone compounds 4–7 by a ring closure reaction with N,N′-carbonyldiimidazole (CDI), we found thus obtained bis-oxazolidinone compounds 22–25 possess excellently inhibitory activities against H37Rv but poor or no effects on other test bacteria. Among them, bis-oxazolidinone compound 22 and 24 are the most potent two compounds with a same MIC value of 0.125 μg/mL against H37Rv virulent strain. Compound 22 also exhibited extremely low cytotoxicity on monkey kidney Vero cells with a selective index (IC50/MIC) over 40,000, which suggested bis-oxazolidinone compound 22 is a promising lead compound for subsequent investigation in search of new antitubercular agents.

In this work, a novel oxazolidinone compound FYL-67 was synthesized, and the obtained FYL-67 could form nanoassemblies in aqueous solution by a self-assembly method without using any carrier, organic solvent, or surfactant. The prepared FYL-67 nanoassemblies had a particle size of 264.6 ± 4.3 nm. The FYL-67 nanoassemblies can be lyophilized into a powder form without any cryoprotector or excipient, and the re-dissolved FYL-67 nanoassemblies are stable and homogeneous. The in vitro release profile showed a significant difference between rapid release of free FYL-67 and much slower and sustained release of FYL-67 nanoassemblies. In vitro susceptibility tests were conducted in three strains of methicillin-susceptible Staphylococcus aureus (MSSA) and three strains of methicillin-resistant Staphylococcus aureus (MRSA), using linezolid as a positive control. FYL-67 nanoassemblies exhibited excellent in vitro activity, with a minimum inhibitory concentration (MIC) value of 0.5 μg mL−1 against MRSA. In the in vitro post-antibiotic effect (PAE) evaluation, FYL-67 nanoassemblies showed a more powerful effect than linezolid. Besides, in vitro cytotoxicity tests indicated that FYL-67 nanoassemblies had a very low cytotoxicity on HEK293 cells and L02 cells. Furthermore, in both MSSA and MRSA systemic infection mouse models, FYL-67 nanoassemblies showed a lower ED50 than linezolid. In a murine model of MRSA systemic infection, FYL-67 nanoassemblies displayed an ED50 of less than 4.0 mg kg−1, which is 2.3-fold better than that of linezolid. Our findings suggested that the FYL-67 nanoassemblies may be a potential drug candidate in MRSA therapy.

Small molecules with oxathiazol-2-one moiety were recently reported as potent inhibitors of Mycobacterium bovis var. bacilli Calmette–Guérin (BCG), among which HT1171 was the most potent and selective proteasome inhibitor. Herein we synthesized a series of novel compounds by bioisosteric replacement of the oxathiazol-2-one ring with 3H-1,2,4-dithiazol-3-one, and also fifteen 1,3,4-oxathiazol-2-one molecules in order for potency comparison and structure–activity relationship elucidation since their antibacterial effects on the virulent strains were not evaluated before. All the compounds were assessed for antitubercular activities on the virulent H37Rv strain by a serial dilution method. Among the tested compounds, 3H-1,2,4-dithiazol-3-one compound 4n was found to be the most active with a lowest MIC90 value of 1 μg/mL. Furthermore, the cytotoxicities of all the compounds against normal human liver cell line L02 were determined by an MTT method. Compound 4n displayed a lower inhibitory ratio than HT1171 at the concentration of 100 μM, indicating its better safety profile.The readily available 3H-1,2,4-dithiazol-3-one molecule compound 4n was shown to be potent against the virulent Mycobacterium tuberculosis H37Rv strain by a microdilution method, demonstrating a better safety profile on human normal liver L02 cells than the lead compound HT1171, which was reported as a potent proteasome inhibitor of Mycobacterium bovis var. bacilli Calmette–Guérin (BCG).

A series of compounds with a diphenyl ether nucleus were synthesized by incorporating various amines into the diphenyl ether scaffold with an amide bond. Their antitubercular activities were evaluated against Mycobacteriumtuberculosis H37Rv by a microdilution method, with MIC values ranging from 4 to 64 μg/mL. Through structure–activity relationship studies, the two chlorine atoms at 3 and 4 positions in the phenyl ring of R2 group were found to play a significant role in the antitubercular activity. The most potent compound 6c showed an MIC value of 4 μg/mL and a good safety profile in HepG2 cell line by the MTT assay. Compound 6c was further found to be effective in a murine model of BCG infection, providing a good lead for subsequent optimization.A series of compounds with a diphenyl ether nucleus were synthesized and screened for antitubercular activity against Mycobacteriumtuberculosis H37Rv, among which compound 6c was the most potent with MIC value of 4 μg/mL. It was further found to be effective in attenuating the pathological changes caused by BCG infection in vivo.