Leyla H. Sharaf

Pleuromutilin antibacterial agents: patent review 2001 - 2006

Derivatives of the naturally occurring pleuromutilin, of which certain analogs were successfully developed in veterinary medicine, have regained interest in the past few years as promising antibacterial agents with potential for human use. This review provides an overview of patents related to pleuromutilin derivatives during 2001 – 2006. Representative compounds along with their antibacterial activities are selected for this purpose, and a section focuses on pleuromutilins in clinical development and practice, in particular retapamulin. Most of the patents reveal the usefulness of different analogs as antibacterial agents effective against multi-drug-resistant organisms, whereas one patent disclosed the in vitro effectiveness of pleuromutilins against Helicobacter pylori. Few patents disclosed novel formulations, methods of preparation in order to improve efficacy, delivery, stability upon storage and synthesis of pleuromutilins.

Oxazolidinone antimicrobials: a patent review (2012-2015)

ABSTRACT Introduction: Antimicrobial resistance in Gram-positive bacteria is a major health care issue. This review summarizes patent publications from 2012 to 2015 that divulged novel oxazolidinones as antibacterial agents. Areas covered: A total of 25 patents obtained from Espacenet, WIPO Patentscope and FreePatentsOnline, and AcclaimIP search engines were reviewed. The patents were scrutinized based on the novelty of the compounds, their antibacterial activity (MIC, µg/mL), and the process of preparation. The oxazolidinones with promising antibacterial activity were classified according to the following structural diversities, as biaryl heterocyclic, fused heteroaryl rings containing oxazolidinones, and others. The biaryl heterocyclic, fused heteroaryl, benzoxazine, and the 1H-pyrazol-1-yl containing oxazolidinone derivatives demonstrated potent antibacterial activities superior to linezolid against Gram-positive bacteria. Some derivatives were effective against standard strains of Gram-negative bacteria, namely Moraxella catarrhalis ATCC A894, and Escherichia coli ATCC 25922. In addition, a patent disclosed a structural isomer of linezolid with marginal activity against the aerobic Gram-negative bacteria MDR Stenotrophomonas (Xanthomonas) maltophilia, while linezolid and vancomycin did not inhibit growth. Finally, some derivatives showed activity against respiratory infectious diseases’ causative agents, such as B. anthracis, B. mallei, Y. pestis, and M. pneumoniae. Expert opinion: Overall, there is limited in vivo data to support the potential clinical advancement of the currently reported novel derivatives.

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 C8 column (250 × 40 mm, 5 µm particle size) and a mobile phase of acetonitrile/H2O (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 (kdeg, t1/2, t90) 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.

Evaluation of the monoamine oxidases inhibitory activity of a small series of 5-(azole)methyl oxazolidinones.

Oxazolidinone class of compounds continue to generate interest as promising agents effective against sensitive and resistant Gram-positive pathogenic bacteria strains. Recent focus is to develop new potent derivatives with improved broad-spectrum activity and safety profile superior to linezolid. An important toxicity issue for this class of compounds arises from the structural similarity with toloxatone, a known MAO inhibitor. Herein, we report the evaluation of a small series of 5-(1H-1,2,3-triazolyl)-, 5-(4-methyl-1H-1,2,3-triazolyl)-, 5-(5-methyl-1H-1,2,3-triazolyl)- and 5-imidazolyl-methyl oxazolidinone analogs with and without antibacterial activity for their effects as inhibitors of monoamine-A and -B (MAO-A and -B) oxidases. Substitutions at the oxazolidinone C-5 position significantly affected antibacterial activity and MAO inhibition. The N-substituted-glycinyl 1H-1,2,3-triazolyl methyl oxazolidinones with potent antibacterial activity demonstrated only weak to moderate affinity for MAO-A and -B, supporting further investigation for this group of compounds.

5-Hydroxymethyl-oxazolidin-2-one antibacterials: Actelion Pharmaceuticals: WO2008062379

The application, WO2008062379, claims chimeric compounds comprising chemically linked 5-hydroxymethyl-oxazolidinone and tetracyclic-quinolone moieties. The claimed compounds are potent expanded-range antibacterial agents against selected Gram-positive and Gram-negative bacteria, which may exhibit dual mode of action as inhibitors of topoisomarases IV and protein synthesis. The structures of the compounds suggest that the linkers are chemically and biochemically stable. This application represents part of recently initiated research efforts at Actelion.