Synthesis and antibacterial activities of N-substituted-glycinyl 1H-1,2,3-triazolyl oxazolidinones.

A series of 1H-1,2,3-triazolyl piperazino oxazolidinone analogs with optionally varied glycinyl substitutions were synthesized and their antibacterial activity assessed against a panel of susceptible and resistant Gram-positive and selected Gram-negative bacteria including clinical isolates. The N-aroyl- and N-heteroaroyl-glycinyl (MIC: 0.06-4 µg/ml) derivatives were more potent than the N-acylglycinyl (2-8 µg/ml) derivatives against all Gram-positive bacteria tested. Nitro substitution on aryl and heteroaryl rings significantly enhanced activity against Gram-positive bacteria, as noted with the 3,5-dinitrobenzoyl (6m and 6n) and 5-nitro-2-furoyl (6u and 6v) derivatives with MIC ranges of and 0.25-0.5 and 0.06-0.5 µg/ml, respectively. These nitro analogs also showed more potent extended activity against Moraxella catarrhalis, with MICs ranges of 0.25-1 µg/ml, compared to linezolid (MIC: 8 µg/ml). Hence, the presence of the N-aroyl and/or N-heteroaroyl glycinyl structural motifs as spacer group could significantly enhance the antibacterial activities of 1H-1,2,3-triazolyl oxazolidinone class of compounds.

Effects of varied substituents on the antibacterial activity of triazolylmethyl oxazolidinones.

A number of 1,2,3-triazolylmethyl piperazino oxazolidinone derivatives with optionally varied substituents at the 4N-piperazine position were synthesized and their antibacterial activity evaluated against a panel of susceptible and resistant Gram-positive and selected Gram-negative bacteria. Substitution with 5-membered heteroaroyl and dinitrobenzoyl moieties potentiated activity against staphylococci and enterococci strains. Furthermore, the compounds having dinitrobenzoyl 7n, 7o, and 5-nitrofuroyl 7t substitutions were four- to eightfold more potent than linezolid against M. catarrhalis. However, substitution of guanidino and other water-solubilizing functionalities at the 4N-piperazine position resulted in compounds that are devoid of antibacterial activity.

Antimycobacterial Activities of Novel 5-(1H-1,2,3-Triazolyl)Methyl Oxazolidinones.

The antibacterial activities of a series of triazolyl oxazolidinones against Mycobacterium tuberculosis strain in vitro and in vivo in a mice model are presented. Most active compounds were noncytotoxic against VERO cells with acceptable selectivity indexes (SI) as measures of compound tolerability. Structure activity relationships (SARs) revealed that analogs with alkylcarbonyl (IC(90): < 0.2 to 0.422 µg/mL) and arylcarbonyl (IC(90): < 0.2 to 2.103 µg/mL) groups at the piperazine 4N-position-displayed potent antimycobacterium activities, comparable to the methanesulfonyl (IC(90): < 0.2 µg/mL) analog, linezolid (IC(90): < 0.2 µg/mL), and isoniazid (IC(90): < 0.034 µg/mL). The furanylcarbonyl derivative also displayed potent activity, while the arylsulfonyl analogs were inactive. Of the triazolyl oxazolidinones, the morpholino (PH-27) derivative with medium bioavailability in plasma was most active in vivo, but relatively less efficacious than isoniazid.

The effect of systematic structural modifications on the antibacterial activity of novel oxazolidinones.

A novel series of tetraethylene glycol (TEG) triazolyl and squaramide containing oxazolidinones were synthesized and tested for their antibacterial activity against a selected panel of Gram-positive and Gram-negative bacteria. The 4-TEG-triazolyl derivatives were prepared by 'click reaction'. The introduction of the TEG and squaramide groups did not favor antibacterial activity. The three nucleoside-containing oxazolidinones were also prepared by 'click' methodology resulted in weak antibacterial activity.

Assessment of the stability of novel antibacterial triazolyl oxazolidinones using a stability-indicating high-performance liquid chromatography method.

OBJECTIVES: To evaluate the stability of 12 triazolyl oxazolidinone (TOZ) derivatives in simulated gastric and intestinal fluids as well as in human plasma at 37 ± 1°C. MATERIALS AND METHODS: A stability-indicating high-performance liquid chromatography (HPLC) procedure with a C(8) column (250 × 40 mm, 5 µm particle size) and a mobile phase of acetonitrile/H(2)O (50/50 v/v) at 1.0 ml/min was used. Accelerated stability studies were conducted at 37 ± 1°C in 0.1 M HCl solution as simulated gastric fluid and in phosphate buffer solution (pH about 7.4) as simulated intestinal fluid. The stability of TOZs in human plasma at a simulated biological temperature of 37 ± 1°C was evaluated as well. RESULTS: The stability studies indicated that the examined TOZs were stable in the above media, with the exception of compounds 1a [tert- butyl 4-(4-((R)-5-((1H-1,2,3-triazol-1-yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate] and 1b [tert-butyl 4-(2-fluoro-4-((R)-5-((4-methyl-1H-1,2,3-triazol- 1-yl)methyl)-2-oxooxazolidin-3-yl)phenyl) piperazine-1-carboxylate], which underwent degradation in simulated gastric fluid. The degradation kinetics revealed degradation parameters (k(deg), t(1/2), t(90)) of 0.180 h(-1), 3.85 h, and 0.58 h for 1a and of 0.184 h(-1), 3.76 h and 0.57 h for 1b, respectively. Furthermore, the degradation products were identified by mass-spectrometric analysis at mass-to-charge ratios 347.5 and 361.5, respectively, and proton nuclear magnetic resonance analysis. CONCLUSION: With the exception of compounds 1a and 1b, the TOZs are stable in simulated gastric and intestinal fluids as well as in human plasma. Being carbamate derivatives, compounds 1a and 1b underwent fast and complete degradation in simulated gastric fluid. The obtained results should be considered for future studies of formulation of structurally related TOZs in oral dosage forms.

Synthesis and antibacterial activity of novel 5-(4-methyl-1H-1,2,3-triazole) methyl oxazolidinones.

A series of 5-(4-methyl-1,2,3-triazole)methyl oxazolidinones were synthesized and tested for their antibacterial activity against a panel of Gram-positive and Gram-negative clinical isolates in comparison with linezolid and vancomycin. Most of the compounds demonstrated strong to moderate in vitro antibacterial activity against susceptible and resistant Gram-positive pathogenic bacteria. Antibacterial activity varied with substitutions at the phenyl C4 position with bulky alkylcarbonyl and alkoxycarbonyl substitutions on the piperazine N4 being detrimental to antibacterial activity. Whereas the presence of the 4-methyl-1,2,3-triazole moiety in the acyl-piperazine containing analogs resulted in increased protein binding, and decreased antibacterial activity particularly against Streptococcus pneumoniae strains.