- Design and synthesis of biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety as novel antibacterial agents against Gram-positive bacteria
-
Novel biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety were designed, synthesized and evaluated for their antibacterial activity. The key compounds 7 and 9 were synthesized by the knoevenagel condensation of intermediate aldehyde 5 with rhodanine derivatives 6a?6b. The preliminary study showed that compounds 7, 9 and 10e exhibited potent antibacterial activity with MIC values of 0.125 μg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as the positive controls. The most promising compound 10e exhibited potent antibacterial activity against tested clinical isolates of MRSA, MSSA, VRE and LREF with MIC values in the range of 0.125–0.5 μg/mL, and the potency of 10e against clinical isolates of LREF was 64-fold higher than that of linezolid. Moreover, compound 10e was non-cytotoxic with an IC50 value of 91.04 μM against HepG2 cell. Together, compound 10e might serve as a novel antibacterial agent for further investigation.
- Wu, Yachuang,Ding, Xiudong,Xu, Sicong,Yang, Yifeng,Zhang, Xue,Wang, Chu,Lei, Hong,Zhao, Yanfang
-
-
Read Online
- Installation of an aryl boronic acid function into the external section of N-aryl-oxazolidinones: Synthesis and antimicrobial evaluation
-
N-aryl-oxazolidinones is a prominent family of antimicrobials used for treating infections caused by clinically prevalent Gram-positive bacteria. Recently, boron-containing compounds have displayed intriguing potential in the antibiotic discovery setting. Herein, we report the unprecedented introduction of a boron-containing moiety such as an aryl boronic acid in the external region of the oxazolidinone structure via a chemoselective acyl coupling reaction. As a result, we accessed a series of analogues with a distal aryl boronic pharmacophore on the oxazolidinone scaffold. We identified that a peripheric linear conformation coupled with freedom of rotation and no further substitution on the external aryl boronic ring, an amido linkage with hydrogen bonding character, in addition to a para-relative disposition between boronic group and linker, are the optimal combination of structural features in this series for antimicrobial activity. In comparison to linezolid, the analogue comprising all those features, compound 20b, displayed levels of antimicrobial activity augmented by an eight-fold to a thirty-two-fold against a panel of Gram-positive strains, and a near one hundred-fold against Escherichia coli JW5503, a Gram-negative mutant strain with a defective efflux capability.
- Cruz, Cristina D.,Wrigstedt, Pauli,Moslova, Karina,Iashin, Vladimir,M?kkyl?, Heidi,Ghemtio, Léo,Heikkinen, Sami,Tammela, P?ivi,Perea-Buceta, Jesus E.
-
-
- Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity
-
gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-containing oxazolidinone antibiotic, exhibits significant side effects associated with human mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue that when compared to linezolid, maintains comparable (albeit slightly diminished) activity against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-activity-relationship data surrounding oxazolidinone MPS inhibition, and may inspire investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry.
- Sun, Alexander W.,Bulterys, Philip L.,Bartberger, Michael D.,Jorth, Peter A.,O'Boyle, Brendan M.,Virgil, Scott C.,Miller, Jeff F.,Stoltz, Brian M.
-
p. 2686 - 2689
(2019/08/07)
-
- Synthesis and antibacterial activity evaluation of novel biaryloxazolidinone analogues containing a hydrazone moiety as promising antibacterial agents
-
A series of linezolid analogues containing a hydrazone moiety were designed, synthesized and evaluated for their antibacterial activity. Most compounds exhibited more potent antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens as compared with linezolid and radezolid. Compounds 9a, 9c, 9f, 9g, 10m and 10t were more potent against tested clinical isolates of MRSA, MSSA, VRE and LREF as compared to linezolid. Compound 9a exhibited comparable activity with linezolid against human MAO-A for safety evaluation and showed moderate metabolism in human liver microsome. The most promising compound 9a showed remarkable antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens with MIC value of 0.0675 mg/mL, respectively, which was 15- to 30-fold more potent than linezolid.
- Wu, Yachuang,Ding, Xiudong,Ding, Liang,Zhang, Yongsheng,Cui, Lei,Sun, Lu,Li, Wei,Wang, Di,Zhao, Yanfang
-
p. 247 - 258
(2018/09/18)
-
- Oxazolidinone compound containing combined aromatic hydrazine and its preparation method
-
The invention relates to oxazolidinone compound containing combined aromatic hydrazine shown in general formula I, its optical isomer, pharmaceutical acceptable salt and/or solvent compound, and it preparation method, and the drug composition containing the compound, wherein the substituent groups R1, R2, R3, X and A rings have the meaning given in the specification. The invention further relatesto the compound, the substituent group, solvent compound or application of its prodrug using as antibacterial drug in treatment, and application of treating gram positive bacterial infection and mycobacterium tuberculosis infection especially.
- -
-
-
- Heterocycle-containing biaryl oxazolidinone compound and preparation method thereof
-
The invention relates to a heterocycle-containing biaryl oxazolidinone compound with the structural formula as shown in the figure I in the specification, or an optical isomer and a pharmaceutically acceptable salt and/or solvate thereof, a preparation method for the heterocycle-containing biaryl oxazolidinone compound as well as the optical isomer and the pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutical composition containing the compound. According to the heterocycle-containing biaryl oxazolidinone compound, the substituent groups R1, R2, R3, R4 and A-ring have the meanings given in the specification. The invention also relates to application of the compound as well as the pharmaceutically acceptable salt and solvate or a prodrug thereof as an antibacterial drug in treatment, especially in treatment of gram-positive bacterial infection and mycobacterium tuberculosis infection. (Please see the figure I in the specification for the structural formula of theheterocyclic ring-containing biaryl oxazolidinone compound.).
- -
-
-
- Compound design guidelines for evading the efflux and permeation barriers of Escherichia coli with the oxazolidinone class of antibacterials: Test case for a general approach to improving whole cell Gram-negative activity
-
Previously we reported the results from an effort to improve Gram-negative antibacterial activity in the oxazolidinone class of antibiotics via a systematic medicinal chemistry campaign focused entirely on C-ring modifications. In that series we set about testing if the efflux and permeation barriers intrinsic to the outer membrane of Escherichia coli could be rationally overcome by designing analogs to reside in specific property limits associated with Gram-negative activity: i) low MW (7.4 1), and iii) zwitterionic character at pH 7.4. Indeed, we observed that only analogs residing within these limits were able to overcome these barriers. Herein we report the results from a parallel effort where we explored structural changes throughout all three rings in the scaffold for the same purpose. Compounds were tested against a diagnostic MIC panel of Escherichia coli and Staphylococcus aureus strains to determine the impact of combining structural modifications in overcoming the OM barriers and in bridging the potency gap between the species. The results demonstrated that distributing the charge-carrying moieties across two rings was also beneficial for avoidance of the outer membrane barriers. Importantly, analysis of the structure-permeation relationship (SPR) obtained from this and the prior study indicated that in addition to MW, polarity, and zwitterionic character, having ≤4 rotatable bonds is also associated with evasion of the OM barriers. These combined results provide the medicinal chemist with a framework and strategy for overcoming the OM barriers in GNB in antibacterial drug discovery efforts.
- Spaulding, Andrew,Takrouri, Khuloud,Mahalingam, Pornachandran,Cleary, Dillon C.,Cooper, Harold D.,Zucchi, Paola,Tear, Westley,Koleva, Bilyana,Beuning, Penny J.,Hirsch, Elizabeth B.,Aggen, James B.
-
p. 5310 - 5321
(2017/11/13)
-
- TOPICAL FORMULATIONS OF BIARYL HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF
-
The present invention relates to topical formulations of biaryl heterocyclic compounds and methods of use thereof for treating acne and other skin infections caused or mediated by Streptococcus pyogenes, Streptococcus agalactiae, Haemophilus influenza, Trichomonas vaginalis, Klebsiella sp., Enterobacter sp., Proteus sp., Propionibacterium acnes, Gardnerella vaginalis, or Staphylococcus aureus (including Methicillin-resistant Staphylococcus aureus (MRSA)) in a patient in need thereof. In certain embodiments, the acne or other skin infection is caused or mediated by Propionibacterium acnes, Gardnerella vaginalis, or Staphylococcus aureus.
- -
-
-
- Preparation method of biaryl oxazolidone intermediate
-
The invention relates to a preparation method of a biaryl oxazolidone intermediate (5S)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxooxazolidine-5-ol]methyl]acetamine (I). According to the method, the intermediate is prepared with m-fluoroaniline as an initial raw material through amino protection, iodination and cyclization sequentially. Compared with a reported preparation method of the biaryl oxazolidone intermediate, the method adopts a short route, increases the yield, greatly reduces the cost and is more suitable for industrial production.
- -
-
-
- METHOD FOR TREATING, PREVENTING, OR REDUCING THE RISK OF SKIN INFECTION
-
The present invention relates to methods for treating acne and other skin infections caused or mediated by Propionibacterium acnes, Gardnerella vaginalis, or Staphylococcus aureus in a patient with a safe and effective amount of a topically applied oxazolidinone antibiotic compound.
- -
-
-
- Synthesis and in vitro activity of novel 1,2,4-triazolo[4,3-a]pyrimidine oxazolidinone antibacterial agents. Part II
-
The synthesis and antibacterial activity of 1,2,4-triazolo[4,3-a]pyrimidine oxazolidinones is reported. Compound 3e with a 2,4-disubstituted thiophene ring was found to be a potent inhibitor of Gram-positive pathogens and was 4-16-fold more potent than Linezolid.
- Khera, Manoj Kumar,Cliffe, Ian A.,Prakash, Om
-
p. 5266 - 5269
(2011/10/02)
-
- Process for the synthesis of triazoles
-
The present invention relates to processes for the preparation of triazoles. These compounds are useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents.
- -
-
Page/Page column 37-38
(2010/09/18)
-
- OXAZOLIDINONE DERIVATIVES AS ANTIMICROBIALS
-
The present invention relates to certain substituted phenyl oxazolidinones and to processes for the synthesis of the same. This invention also relates to pharmaceutical compositions containing the compounds of the present invention as antimicrobials. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria, for example, multiple-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms, for example, Bacterioides spp. and Clostridia spp. species, and acid fast organisms, for example, Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
- -
-
Page/Page column 93
(2010/10/20)
-
- OXAZOLIDINONE DERIVATIVES AND THEIR USE AS ANTIBACTERIAL AGENTS
-
A compound of the formula (I), or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof: (I)wherein in (I) C is for example wherein A and B are independently selected from i) ii) and m is 1 or 2;R2b and R6b, R2a and R6a, R3a and R5a, are for example selected from H, F, OMe and Me;R2b' and R6b', R2a' and R6a', R3a', R5a' are for example selected from H, OMe and Me;R1a is for example optionally substituted (1-10C)alkyl;R1b is for example selected from NR5C(=W)R4, a) , or b) wherein HET-1 is for example isoxazolyl and HET-2 is for example triazolyl or tetrazolyl.Methods for making compounds of the formula (I), compositions containing them and their use as antibacterial agents are also described.
- -
-
-
- HYDROXYMETHYL SUBSTITUTED DIHYDROISOXAZOLE DERIVATIVES USEFUL AS ANTIBIOTIC AGENTS
-
Compounds of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, (I) R1a is NH(C=W)R5 or (a); W is O or S; R2 and R3 are for example H or F; R1 is for example hydrogen, or halogen; R5 is selected from hydrogen, (2-6C)alkyl (optionally substituted); R6 and R7 are independently selected from hydrogen, and (1-4C)alkyl (optionally substituted); wherein R4 is either a hydroxymethyl substituent on C-4' of the isoxazoline ring; or R4 is a hydroxymethyl substituent on C-5' of the isoxazoline ring and the stereochemistry at C-5' of the isoxazoline ring and at C-5 of the oxazolidinone ring is selected, such that the compound of formula (I) is a single diastereomer; are useful as antibacterial agents; and processes for their manufacture and pharmaceutical compositions containing them are described.
- -
-
-
- Novel oxazolidinone derivatives and a process for the preparation thereof
-
The present invention relates to novel oxazolidinone derivatives, their pharmaceutically acceptable salts and a process for the preparation thereof. More particularly, the present invention relates to oxazolidinone derivatives having pyridine or pyrimidine moeity substituted by heterocycle and heteroaromaticcycle at 4-position of phenyl ring. The compounds of the present invention have wide antibacterial spectrum, superior antibacterial activity and low toxicity, such that the compound of this invention can be used as an antibacterial agent.
- -
-
-