Synthesis and antibacterial activities of novel oxazolidinones having spiro[2,4]heptane moieties

The synthesis of a new series of oxazolidinones having spiro[2,4]heptane moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the oxazolidinone ring was investigated. A particular compound Ih having fluoro group showed the most potent antibacterial activity.     

Synthesis and antibacterial activity of novel oxazolidinones bearing N-hydroxyacetamidine substituent

Novel oxazolidinone antibacterials containing N-hydroxyacetamidine moiety are synthesized with the diversity at C-5 terminus. These compounds have been evaluated against a panel of clinically relevant gram-positive and gram-negative pathogens. Most of the analogs in this series displayed activity superior to Linezolid and in vivo efficacies of selected oxazolidinones are also disclosed herein.     

Synthesis and in vitro antibacterial activity of novel methylamino piperidinyl oxazolidinones

Design and synthesis of a few novel methylamino piperidinyl substituted oxazolidinones are reported. Their antibacterial activities have been evaluated in a MIC assay against broader panel of both susceptible and resistant Gram-positive strains. (S)-N-{3-[3-Fluoro-4-(methyl-{1-[3-(5-nitrofuran-2-yl)-acryloyl]-piperidin-4-yl}-amino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 4i has shown comparable antibacterial activity to linezolid and eperezolid in the MIC assay, additionally compound 4i showed good antibacterial activity with an in vitro MIC value of 2-4 microg/mL against linezolid resistant Staphylococcus aureus (linezolid 16 microg/mL).     

Synthesis and antibacterial activity of pyrroloaryl-substituted oxazolidinones

A novel series of oxazolidinones containing a pyrroloaryl substituent was synthesized and screened against a representative panel of susceptible and resistant Gram-positive bacteria. Several members of this series were found to have antibacterial activity comparable to or better than linezolid.     

Synthesis and antibacterial activity of 5-substituted oxazolidinones

A series of 5-substituted oxazolidinones with varying substitution at the 5-position of the oxazolidinone ring were synthesized and their in vitro antibacterial activity was evaluated. The compounds demonstrated potent to weak antibacterial activity. A novel compound (PH-027) demonstrated potent antibacterial activity, which is comparable to or better than those of linezolid and vancomycin against antibiotic-susceptible standard and clinically isolated resistant strains of gram-positive bacteria. Although the presence of the C-5-acetamidomethyl functionality at the C-5 position of the oxazolidinones has been widely claimed and reported as a structural requirement for optimal antimicrobial activity in the oxazolidinone class of compounds, our results from this work identified the C-5 triazole substitution as a new structural alternative for potent antibacterial activity in the oxazolidinone class.     

Synthesis and antibacterial evaluation of isoxazolinyl oxazolidinones: Search for potent antibacterial

A series of (5S) N-(3-{3-fluoro-4-[4-(3-aryl-4,5-dihydro-isoxazole-5-carbonyl)-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide(6a–o) were synthesized and their in vitro antibacterial activity against various resistant Gram-positive and Gram-negative bacteria were evaluated. Most of the synthesized compounds showed 2 to 10 fold lower MIC values compared to linezolid against Staphylococcus aureus ATCC 25923, ATCC 70069, ATCC 29213, Bacillus cereus MTCC 430, Enterococcus faecalis MTCC439, Klebsiella pneumoniae ATCC 27736, and Streptococcus pyogens.     

Synthesis and biological activity of novel oxazolidinones

A number of 5-substituted derivatives of Ranbezolid, a novel oxazolidinone were synthesized. Antibacterial activity of the compounds against a number of sensitive and resistant bacteria showed promising results.     

Synthesis and antibacterial activity of new N-linked 5-triazolylmethyl oxazolidinones

A new series of N-linked 5-triazolylmethyl oxazolidinones with varying substitution at the piperazine nitrogen 4-position were synthesized and tested against a panel of Gram-positive and Gram-negative bacteria including clinical isolates. Most of the compounds showed excellent antibacterial activity against susceptible and resistant Gram-positive organisms. One of the compounds showed enhanced antibacterial activity against Moraxella catarrhalis.     

Synthesis and antibacterial activity of dihydro-1,2-oxazine and 2-pyrazoline oxazolidinones: novel analogs of linezolid

The synthesis and antibacterial activity of oxazolidinones containing dihydro-1,2-oxazine and 2-pyrazoline ring systems are described. Linezolid analogs utilizing dihydro-1,2-oxazines as morpholine mimics were prepared utilizing a nitrosoamine/diene 4+2 cycloaddition strategy. Pyrazolidine, hexahydro-pyridazine, and 2-pyrazoline analogs more closely related to eperezolid were also prepared. The most active of these new oxazolidinones were the dihydro-1,2-oxazine 6 and the 2-pyrazoline 20 both of which had potency similar to linezolid against a panel of Gram-positive bacteria.     

Synthesis of novel sulfonamide analogs containing sulfamerazine/sulfaguanidine and their biological activities

Sulfamerazine and sulfaguanidine are clenched with p-nitrobenzoyl chloride and the products obtained are reduced to Na_xS in ethanol–water. Novel sulfonamides (6a–g and 9a–g) were synthesized by the reaction of these reduced products (4 and 8) with various sulfonyl chlorides (5a–g). The structures of these compounds were characterized using spectroscopic analysis (IR, ¹H-NMR, ¹³C-NMR and HRMS) technique. Antimicrobial activity of sulfonamides (3, 4, 7, 8, 6a–g and 9a–g) was evaluated by the agar diffusion method. These compounds showed antimicrobial activity against tested microorganism strains (Gram-positive bacteria, clinic isolate and yeast and mold). Compounds 9d, 9e, 9a, 6d and 6e showed particularly antimicrobial activity against tested Gram-positive (Bacillus cereus and B. subtilis) and Gram-negative (Enterobacter aerogenes) bacteria.     

Synthesis and antibacterial activity of novel oxazolidinones with methylene oxygen- and methylene sulfur-linked substituents at C5-position

Novel oxazolidinone derivatives of the lead compound RBx 8700, containing methylene oxygen- and methylene sulfur-linked substituents at the C5-position, were synthesized. Antibacterial screening of these compounds against a panel of resistant and susceptible Gram-positive and fastidious Gram-negative bacteria gave compounds 2 and 4 as new antibacterial agents.     

Synthesis of novel selenium containing sulfa drugs and their antibacterial activities

Synthesis of 3-[4-(N-substituted sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyri-do[3′,2′:4,5]selenolo[3,2-d]pyrimidines,7-[4-(N-substituted sulfamoyl)phenyl]-7,8-dihydro-8-oxo-3,4-diphenylpyrimido[4′,5′:4,5]selenolo [2,3-c]pyridazines and 1-[4-(N-substituted sulfamoyl)phenyl]-1,11-dihydro 11-oxo-4-methylpyrimido[4′,5′:4,5]selenolo[2,3-b]quinolines is reported. 4-Amino-N-pyrimidine-2-ylbenzene sulfonamide (a), 4-amino-N-(2,6-dimethylpyrimidin-4-yl)benzene sulfonamide (b), N-[(4-aminophenyl)sulfonyl] acetamide (c) with N-ethoxymethyleneamino of selenolo pyridine, selenolo pyridazine and selenolo quinoline derivatives respectively were obtained starting from 1-amino-N ⁴-substituted sulfanilamides. Spectroscopic data (IR, ¹H NMR, ¹³C NMR and Mass spectral) confirmed the structure of the newly synthesized compounds. Substituted pyrimidines, pyridazines and quinolines were screened for antibacterial activity against gram-positive and gram-negative bacteria. Selenolo derivative of N-[(4-aminophenyl)sulfonyl] acetamide (substitutent of sulfacetamide c) showed strong bactericidal effect against all the tested organisms. Selenolo[3,2-d]pyrimidin (substitutent a) showed a good bactericidal effect against Serratia marcescens, Staphylococcus aureus and Escherichia coli. Compounds selenolo[2,3-c]pyridazine (substitutent b), selenolo[2,3-b]quinoline(substitutents c)) exhibited a moderate bactericidal effect against Serratia marcescens. None of the synthesized seleno pyridazines has a considerable antimicrobial activity against the tested organisms. The minimum inhibitory concentration (MIC) of the most active compound-3-[4-(N-acetyl sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyrido[3′,2′:4,5]selenolo [3,2-d]pyrimidine was 10 mg ml⁻¹.     

Synthesis and structure-activity studies of antibacterial oxazolidinones containing dihydrothiopyran or dihydrothiazine C-rings

A new series of antimicrobial oxazolidinones bearing unsaturated heterocyclic C-rings is described. Dihydrothiopyran derivatives were prepared from the saturated tetrahydrothiopyran sulfoxides via a Pummerer-rearrangement/elimination sequence. Two new synthetic approaches to the dihydrothiazine ring system were explored, the first involving a novel trifluoroacetylative-detrifluoroacetylative Pummerer-type reaction sequence and the second involving direct dehydrogenation of tetrahydrothiopyran S,S-dioxide intermediates. Final analogs such as 4 and 13 represent oxidized congeners of recent pre-clinical and clinical oxazolidinones.     

Synthesis and antibacterial activity of oxazolidinones containing pyridine substituted with heteroaromatic ring

A series of oxazolidinone derivatives, which morpholino group of linezolid was replaced with heteroaromatic ring substituted pyridine moiety, were newly synthesized, and their substituted effects on in vitro and in vivo antibacterial activities were evaluated against four problematic gram-positive strains including drug resistant strains and two gram-negative strains. Most compounds exhibited the enhanced in vitro activities with 4-16-fold and three compounds exerted more than 2-fold increased in vivo efficacies than linezolid.     

Synthesis and antibacterial activity of arylpiperazinyl oxazolidinones with diversification of the N-substituents

A series of 4-arylpiperazin-1-yl-3-phenyloxazolidin-2-one derivatives with diversification of the N-substituents such as methylene O-linked heterocycles, thioamide, dithiocarbamate, thiourea, and thiocarbamate were synthesized and evaluated as antibacterial agents. Their in vitro activities (MIC) were evaluated against MRSA and VRE resistant Gram-positive strains such as Staphylococcus and Enterococcus. Most of the compounds were more potent in vitro but less active in vivo than linezolid.     

Synthesis of novel dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties as potential antibacterial agents

Three novel series of dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties were designed, synthesized and evaluated in terms of their antibacterial and antifungal activities. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-negative bacterial strains with minimum inhibitory concentration values in the range of 1–64?µg/mL. Compounds 4b and 4c presented the most potent inhibitory activity against Gram-positive bacteria (S. aureus 4220, MRSA 3167, QRSA 3519) and Gram-negative bacteria (E. coli 1924), with minimum inhibitory concentration values of 1 or 2?µg/mL. Compared with previous studies, these compounds exhibited a broad spectrum of inhibitory activity. The cytotoxic activity of the compounds 4a, 4b, 4c and 11n were assessed in L02 cells. In vitro enzyme study implied that compound 4c exerted its antibacterial activity through DHFR inhibition.     

Synthesis and SAR of novel oxazolidinones: discovery of ranbezolid

Novel oxazolidinones were synthesized containing a number of substituted five-membered heterocycles attached to the 'piperazinyl-phenyl-oxazolidinone' core of eperezolid. Further, the piperazine ring of the core was replaced by other diamino-heterocycles. These modifications led to several compounds with potent activity against a spectrum of resistant and susceptible gram-positive organisms, along with the identification of ranbezolid (RBx 7644) as a clinical candidate.     

Synthesis and SAR of novel conformationally-restricted oxazolidinones possessing gram-positive and fastidious gram-negative antibacterial activity. Part 1: Substituted pyrazoles

A novel series of conformationally-restricted oxazolidinones was synthesized which possess a fused pyrazole ring substituted with various alkyl, aryl and heteroaryl substituents. A number of analogs exhibited potent activity against both gram-positive and fastidious gram-negative organisms.     

Synthesis and antibacterial activity of potent heterocyclic oxazolidinones and the identification of RBx 8700

Several potent oxazolidinone antibacterial agents were obtained by systematic modification of the linker between the five-membered heterocycle and the piperazinyl ring of RBx 7644 (Ranbezolid, 1) and its thienyl analogue 2, leading to the identification of an expanded spectrum compound RBx 8700 (6b).     

Synthesis, characterization, and antibacterial activities of novel methacrylate polymers containing norfloxacin

A novel methacrylate monomer containing a quinolone moiety was synthesized and homopolymerized in N,N-dimethylformamide (DMF) by using azobisisobutyronitrile (AIBN) as an initiator. The new monomer was copolymerized with poly(ethylene glycol) methyl ether methacrylate (MPEGMA) in DMF using the same initiator. The monomer, homopolymer, and copolymer were characterized by elemental analysis, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), size exclusion chromatography (SEC), FTIR, (13)C NMR, and (1)H NMR. The antibacterial activities of the monomer as well as polymers were investigated against Staphylococcus aureus and Escherichia coli, which are representative of Gram-positive and Gram-negative bacteria, respectively. All compounds showed excellent antibacterial activities against these two types of bacteria. The antibacterial activities were determined using the shaking flask method, where 25 mg/mL concentrations of each compound were tested against 10(5) CFU/mL bacteria solutions. The number of viable bacteria was calculated by using the spread plate method, where 100 microL of the incubated antibacterial agent in bacteria solutions were spread on agar plates and the number of viable bacteria was counted after 24 h of incubation period at 37 degrees C.