Synthesis and biological evaluation of novel benzoxazinyl-oxazolidinones as potential antibacterial agents.

A number of benzoxazinyl-oxazolidinones bearing 3-trizolylmethyl or 3-carboxamide side chain were designed and synthesized with the aim to develop antibacterial agents with improved properties. In vitro antibacterial activities of these novel compounds were evaluated against a panel of resistant and susceptible Gram-positive bacteria. Most analogues bearing 3-trizolylmethyl showed good to moderate antibacterial activities. Compound 12a exhibited a fourfold increase in activity compared with linezolid against all the tested strains, which was identified to be a promising antibacterial agent for further evaluation.

Discovery of potent dipeptidyl peptidase IV inhibitors derived from ß-aminoamides bearing substituted [1,2,3]-triazolopiperidines for the treatment of type 2 diabetes.

A series of novel [1,2,3]-triazolopiperidine derivatives 5a-5y were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes, most of the compounds exhibited excellent in vitro potency (IC(50)<50n M) against DPP-4. Among these, compound 5d with potent in vitro activity against DPP-4 and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in ICR mice. On the base of these properties, compound 5d was selected as a potential new candidate for the treatment of type 2 diabetes.

Insulin-releasing activity of a series of phenylalanine derivatives.

A series of phenylalanine derivatives were synthesized and their biological activities were evaluated. Compounds (S)-3 and (R)-3 exhibited more potent insulin-releasing activity than that of nateglinide, compound (S)-3 also showed insulin-sensitizing activity in vitro. Both compounds were tested for hypoglycemia effect in vivo.

Synthesis and biological evaluation of new N-linked 5-triazolylmethyl oxazolidinones.

A new series of oxazolidinones bearing N-linked 5-triazolylmethyl group have been synthesized and their in vitro antibacterial activities (MIC) were evaluated against a spectrum of resistant and susceptible Gram-positive organisms. Some of the analogues in this series displayed activity superior to linezolid and vancomycin. Furthermore, in vivo efficacies and pharmacokinetic properties of the selected compounds were also disclosed herein; the selected compounds showed reasonable bioavailability as well as in vivo efficacy comparable to that of linezolid.

Synthesis and antibacterial activity of oxazolidinones containing triazolyl group.

A new series of oxazolidinones containing triazolyl group has been synthesized and tested for in vitro antibacterial activity by MIC determination against a panel of resistant and susceptible Gram-positive organisms. Most of the analogs in this series displayed activity superior to linezolid and vancomycin in vitro. Further, in vivo efficacies of the selected oxazolidinones were also disclosed herein.

Solubility-driven optimization of (pyridin-3-yl) benzoxazinyl-oxazolidinones leading to a promising antibacterial agent.

The solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-oxazolidinones is described, which resulted in the development of a new series of benzoxazinyl-oxazolidinone analogues with high antibacterial activity against Gram-positive pathogens, including that against linezolid-resistant strains and low hERG inhibition. With regard to structure-activity relationship (SAR) trends among the various substituents on the pyridyl ring, relatively small and nonbasic substituents were preferable to sterically demanding or basic substituents. Oxazolidinone ring substitution on the pyridyl ring generated analogues with antibacterial activity superior to imidazolidinone ring. Solubility was enhanced by the incorporation of polar groups, especially when compounds were converted to their prodrugs. Among the prodrugs, compound 85 exhibited excellent solubility and a good pharmacokinetic profile. In a MRSA systemic infection model, compound 85 displayed an ED50 = 5.00 mg/kg, a potency that is 2-fold better than that of linezolid.

Design, synthesis, and structure-activity relationship studies of highly potent novel benzoxazinyl-oxazolidinone antibacterial agents.

A series of novel benzoxazinyl-oxazolidinones bearing nonaromatic heterocycle or aryl groups were designed and synthesized. Their in vitro and in vivo antibacterial activities were investigated. Most of the (3S, 3aS) biaryl benzoxazinyl-oxazolidinones exhibited potent activity against Gram-positive pathogens. SAR trends were observed; a pyridyl C ring was preferable to other 5- or 6-member aryl C rings, while fluorine substitution on the B ring generated derivatives with reduced activity. Various substituent group positions on the pyridyl ring were also evaluated. The resulting compounds displayed excellent activity against linezolid-resistant strains. Compound 45 exhibited excellent in vitro activity, with a MIC value of 0.25-0.5 µg/mL against MRSA and an activity against linezolid-resistant strains of 8-16-fold higher potency than linezolid. In a MRSA systemic infection model, compound 45 displayed an ED(50) < 5.0 mg/kg, a potency that is nearly 3-fold better than that of linezolid. This compound also showed excellent pharmacokinetic profiles, with a half-life of more than 5 h as well as an oral bioavailability of 81% in rats.