Structural confirmation of position isomers 2-(2-methylaminoprolyl)benzofuran and 5-(2-methylaminopropyl)benzofuran: a combined mass spectrometric and computational study.

RATIONALE: Phenylethylamines are one of the most common types of new psychoactive substances, following synthetic cannabinoids and synthetic cathinones. They are regulated in many countries because of their strong hallucinogenic effects, which can cause serious nerve damage. There is a wide variety of phenylethylamines, exhibiting rapid renewal and extremely similar structures, therefore accurate qualitative analysis of isomers is a difficult problem in current drug analysis. METHODS: The dissociation pathways of the position isomers 2-(2-methylaminoprolyl)benzofuran (2-MAPB) and 5-(2-methylaminopropyl)benzofuran (5-MAPB) were investigated by gas chromatography-mass spectrometry and liquid chromatography coupled to high-resolution quadrupole Orbitrap MS. The dissociation patterns of the phenethylamine-based designer drugs 2-MAPB and 5-MAPB were explored and extended in this work based on MS combined with density functional theory studies. RESULTS: For electron ionization mass spectrometry (EI-MS) analysis, the dissociation patterns of 2-MAPB were similar to those of 5-MAPB. For electrospray ionization mass spectrometry (ESI-MSn ) analysis, the hydrogen atom on amino group was facile to form a intramolecular hydrogen bond with the oxygen atom on the parent nucleus of benzofuran in the structure of 2-MAPB, leading to higher abundance of the product ion at m/z 58. However, there was a conjugated system between the positive charge formed by the cleavage of the 5-MAPB side chain and the benzofuran ring, enabling the 5-MAPB to generate a product ion at m/z 131. Computational study showed that energy barrier and spin density difference distribution jointly control the selective dissociation in EI-MS, while different types of orbital interaction induced by intramolecular hydrogen bond led to different dissociation results in ESI-MSn . CONCLUSIONS: These different dissociation patterns could be used to distinguish 2-MAPB from 5-MAPB. This could assist forensic laboratories in the differentiation and characterization of potential isomers in these kinds of compounds, especially in mixtures.

Structural confirmation of synthetic cannabinoids in seized electronic cigarette oil: A combined mass spectrometric and computational study.

RATIONALE: Synthetic cannabinoids are some of the most used and abused new psychoactive substances, because they can produce a stronger intense pleasure than natural cannabis. Most of the new synthetic cannabinoids are structurally similar to existing synthetic cannabinoids and can be obtained by modifying partial structures of the latter without changing their effects. Therefore, the derivatization rules and common fragmentation patterns of synthetic cannabinoids could be used for rapid screening and structural identification of them. METHODS: The derivatization rules of synthetic cannabinoids are summarized, and the common fragmentation pattern of synthetic cannabinoids including three typical cleavage pathways was explored and extended in this work based on combined mass spectrometry (MS) and density functional theory studies. Five synthetic cannabinoids in electronic cigarette oil from a drug case were separated and characterized using gas chromatography with MS and liquid chromatography coupled to high-resolution quadrupole Orbitrap MS. RESULTS: The structures of five synthetic cannabinoids in seized electronic cigarette oil were deduced from electron impact ion source (EI) MS and high-resolution electrospray ionization (ESI) MSn data, along with the derivatization rules and common fragmentation pattern of synthetic cannabinoids. The proposed structures of these synthetic cannabinoids were further verified via reference substances. Computational study showed that selective cleavage of these compounds was mainly controlled by spin population in EI-MS, but a tunneling effect arose from proton transfer in ESI-MSn detection, which has been rarely reported in previous works. CONCLUSIONS: Our results showed that EI-MS was suitable for identifying synthetic cannabinoids with aromatic ketone structure, which could also be extended to adamantane linked group. Nevertheless, synthetic cannabinoids with carbamoyl linked group were better characterized by high-resolution ESI-MSn compared to EI-MS. This study demonstrated a method with promising potential for rapid and reliable screening of synthetic cannabinoids in mixtures with enhanced detection throughput and operation simplicity.

Quinolone derivatives and their activities against methicillin-resistant Staphylococcus aureus (MRSA).

Methicillin-resistant Staphylococcus aureus (MRSA) is the most common pathogen both in hospital and community settings, and is capable of causing serious and even fatal infections. Several antibiotics have been approved for the treatment of infections caused by MRSA, but MRSA has already developed resistance to them. More than ever, it's imperative to develop novel, high effective and fast acting anti-MRSA agents. Quinolones are one of the most common antibiotics in clinical practice used to treat various bacterial infections, and some of them displayed excellent in vitro and in vivo anti-MRSA activities, so quinolone derivatives are one of the most promising candidates. This review summarizes the recent developments of quinolone derivatives with potential activity against MRSA, and the structure-activity relationship is also discussed.

Design, synthesis and evaluation of oxime-functionalized nitrofuranylamides as novel antitubercular agents.

A series of oxime-functionalized nitrofuranylamides were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against MTB H37Rv and drug-resistant clinical isolates. Among them, two compounds 7a and 7b exhibited excellent activity against the three tested strains. Both of them were comparable to the first-line anti-TB agents INH and RIF against MTB H37Rv, and were far more potent than INH and RIF against MDR-TB 16833 and 16995 strains. Thus, both of them could act as leads for further optimization.

Recent advances of imidazole-containing derivatives as anti-tubercular agents.

Tuberculosis still remains one of the most common, communicable, and leading deadliest diseases known to mankind throughout the world. Drug-resistance in Mycobacterium tuberculosis which threatens to worsen the global tuberculosis epidemic has caused great concern in recent years. To overcome the resistance, the development of new drugs with novel mechanisms of actions is of great importance. Imidazole-containing derivatives endow with various biological properties, and some of them demonstrated excellent anti-tubercular activity. As the most emblematic example, 4-nitroimidazole delamanid has already received approval for treatment of multidrug-resistant tuberculosis infected patients. Thus, imidazole-containing derivatives have caused great interests in discovery of new anti-tubercular agents. Numerous of imidazole-containing derivatives were synthesized and screened for their in vitro and in vivo anti-mycobacterial activities against both drug-sensitive and drug-resistant Mycobacterium tuberculosis pathogens. This review aims to outline the recent advances of imidazole-containing derivatives as anti-tubercular agents, and summarize the structure-activity relationship of these derivatives. The enriched structure-activity relationship may pave the way for the further rational development of imidazole-containing derivatives as anti-tubercular agents.

Fluoroquinolone derivatives and their anti-tubercular activities.

Tuberculosis (TB) remains one of the most widespread and leading deadliest diseases, around one-third of the world's population harbor a latent infection by Mycobacterium tuberculosis (MTB), and 5-10% eventually develop an active TB. The emergency of MTB new virulent forms as well as the co-infection between MTB and HIV alarming the serious problem in TB control and demanding the need for new drugs more potent than earlier with safe ADME profile. Fluoroquinolones are emerged as a large family of synthetic broad spectrum antibiotics, and some of them were recommended as the second-line agents for the treatment of TB mainly in cases involving resistance or intolerance to first-line anti-TB therapy by WHO. Numerous of FQs derivatives have been synthesized for seeking for new anti-TB agents, and some of them exhibited promising potency. This review aims to summarize the recent advances made towards the discovery of FQs derivatives as anti-TB agents and the structure-activity relationship of these derivatives.

Antiplasmodial and antimalarial activities of quinolone derivatives: An overview.

Malaria remains one of the most deadly infectious diseases globally. Considering the growing spread of resistance, development of new and effective antimalarials remains an urgent priority. Quinolones, which are emerged as one of the most important class of antibiotics in the treatment of various bacterial infections, showed potential in vitro antiplasmodial and in vivo antimalarial activities, making them promising candidates for the chemoprophylaxis and treatment of malaria. This review presents the current progresses and applications of quinolone-based derivatives as potential antimalarials to pave the way for the development of new antimalarials.

Network analysis reveals crosstalk between autophagy genes and disease genes.

Autophagy is a protective and life-sustaining process in which cytoplasmic components are packaged into double-membrane vesicles and targeted to lysosomes for degradation. Accumulating evidence supports that autophagy is associated with several pathological conditions. However, research on the functional cross-links between autophagy and disease genes remains in its early stages. In this study, we constructed a disease-autophagy network (DAN) by integrating known disease genes, known autophagy genes and protein-protein interactions (PPI). Dissecting the topological properties of the DAN suggested that nodes that both autophagy and disease genes (inter-genes), are topologically important in the DAN structure. Next, a core network from the DAN was extracted to analyze the functional links between disease and autophagy genes. The genes in the core network were significantly enriched in multiple disease-related pathways, suggesting that autophagy genes may function in various disease processes. Of 17 disease classes, 11 significantly overlapped with autophagy genes, including cancer diseases, metabolic diseases and hematological diseases, a finding that is supported by the literatures. We also found that autophagy genes have a bridging role in the connections between pairs of disease classes. Altogether, our study provides a better understanding of the molecular mechanisms underlying human diseases and the autophagy process.