Characterization of the fragmentation mechanisms in electrospray ionization tandem mass spectrometry of chloroquinoline derivatives with larvicidal activity against Aedes aegypti.

RATIONALE: 4,7-Dichloroquinoline (DCQ) represents a group of synthetic molecules inspired by natural products with important roles in biological and biomedical areas. This work aimed to characterize DCQ and its derivatives by high-resolution electrospray ionization (ESI) mass spectrometry and tandem mass spectrometry (ESI-MS/MS), supported by theoretical calculations. Biological assays were carried out with DCQ and its derivatives to determine LC50 values against Aedes aegypti larvae. METHODS: Five DCQ derivatives were synthesized by using previously described protocols. ESI-MS/MS analyses were carried out with a quadrupole/time-of-flight and ion-trap instrument. The proposed gas-phase protonation sites and fragmentation were supported by density functional theory calculations. The larvicidal tests were performed with the Ae. aegypti Rockefeller strain, and the LC50 values were determined by employing five test concentrations. Larval mortality was determined after treatment for 48 h. RESULTS: DCQ bromides or aldehydes (C-3 or C-8 positions), as well as the trimethylsilyl derivative (C-3 position), were prepared. Detailed ESI-MS/MS data revealed heteroatom elimination through an exception to the even-electron rule, to originate open-shell species. Computational studies were used to define the protonation sites and fragmentation pathways. High activity of DCQ and its derivatives against Ae. aegypti larvae was demonstrated. CONCLUSION: Our results provided a well-founded characterization of the fragmentation reactions of DCQ and its derivatives, which can be useful for complementary studies of the development of a larvicidal product against Ae. aegypti.

Naphthoquinone derivatives as potential immunomodulators: prospective for COVID-19 treatment.

Inflammation plays a crucial role in COVID-19, and when it becomes dysregulated, it can lead to severe outcomes, including death. Naphthoquinones, a class of cyclic organic compounds widely distributed in nature, have attracted significant interest due to their potential biological benefits. One such naphthoquinone is 3,5,8-trihydroxy-6-methoxy-2-(5-oxohexa-1,3-dienyl)-naphthanthene-1,4-dione (3,5,8-TMON), a compound produced by fungi. Despite its structural similarity to shikonin, limited research has been conducted to investigate its biological properties. Therefore, the objective of this study was to evaluate the effects of 3,5,8-TMON and its synthetic derivatives in the context of inflammation induced by lipopolysaccharide (LPS) and SARS-CoV-2 infection in vitro using cell cultures. 3,5,8-TMON was obtained by acid treatment of crude extracts of fermentation medium from Cordyceps sp., and two derivatives were accessed by reaction with phenylhydrazine under different conditions. The results revealed that the crude extract of the fungi (C. Ex) inhibited the activity of transcription factor NF-kB, as well as the production of nitric oxide (NO) and interleukin-6 (IL-6) when LPS induced it in RAW 264.7 cells. This inhibitory effect was observed at effective concentrations of 12.5 and 3.12 µg mL-1. In parallel, 3,5,8-TMON and the new derivatives 3 and 4 demonstrated the ability to decrease IL-6 production while increasing TNF, with a specific effect depending on the concentration. These concentration-dependent agonist and antagonist effects were observed in THP-1 cells. Furthermore, 3,5,8-TMON inhibited IL-6 production at concentrations of 12.5 and 3.12 µg mL-1 in Calu-3 cells during SARS-CoV-2 viral infection. These findings present promising opportunities for further research into the therapeutic potential of this class of naphthoquinone in the management of inflammation and viral infections.

Are benzoylium and nitrilium ions produced from substituted 2-arene-2-oxazolines during mass spectrometry? A study based on density functional theory calculations, quantum theory of atoms in molecules, and electrospray ionization tandem mass spectrometry.

RATIONALE: Oxazolines are important compounds for drug development, synthesis, and pharmaceutical applications. Interest in analyzing and developing methods to characterize reaction products from these small heterocyclics has led us to study the gas-phase reactivity and fragmentation of seven 2-arene-2-oxazolines compounds using computational chemistry combined with mass spectrometry. METHOD: Protonation sites were investigated using computed proton affinity, gas-phase basicity, and some quantum chemistry descriptors of reactivity; the B3LYP/6-31+G(d,p) computational model was used. Fragmentation mechanisms were suggested by employing data from collision-induced dissociation (CID), energy-resolved plots from MS/MS spectra, multiple-stage experiments, and survival-yield method. RESULTS: Protonation studies based on quantum theory of atoms in molecules (QTAIM) and computational thermochemistry were useful to describe the reactivity of the investigated 2-arene-2-oxazolines, which can be protonated at the nitrogen atom. Three major fragmentation pathways were identified for the protonated molecules: formation of (a) benzoylium or (b) nitrilium ions through elimination of 71 and 72 u from the protonated molecules, respectively, and (c) elimination of 54 u from [M+H]+ . These pathways were exploited by the density functional theory calculations combined with QTAIM studies. CONCLUSIONS: Our results can help in identifying 2-arene-2-oxazoline derivatives using electrospray ionization tandem mass spectrometry (ESI-MS/MS), which can be applied for monitoring reactions through the identified diagnostic ions (product ions). Also, we can suggest that benzoylium and nitrilium ions emerge during fragmentation under CID conditions.

Continuous flow Aza-Michael reaction for preparing the fast-acting synthetic opioid drug Remifentanil

Abstract Remifentanil is a modern fentanyl analogue with ultrashort-action granted by an esterase-labile methyl propanoate chain. Here, we present the development of a continuous flow methodology for the key N-alkylation step of remifentanil preparation in a biphasic, "slug-flow" regime. We screened parameters under microwave-assisted reactions, translated conditions to flow settings, and obtained remifentanil under 15-min residence time in a 1-mL microreactor, with a space-time yield of 89 mg/mL·h and 94% yield.

Dehydration of D-fructose to 5-hydroxymethyl-2-furfural in DMSO using a hydrophilic sulfonated silica catalyst in a process promoted by microwave irradiation.

SiO2-SO3H, with a surface area of 115 m2/g, pore volumes of 0.38 cm3g-1 and 1.32 mmol H+/g, was used as a 10% w/w catalyst for the preparation of 5-hydroxymethyl-2-furfural (HMF) from fructose. A conversion of 100% was achieved in a microwave reactor during 10 min at 150 °C in DMSO, with 100% selectivity for HMF, at a molar ratio of fructose: DMSO equal to 1:56. The catalyst could be re-used three times.

Gas-phase reactivity of protonated 2-oxazoline derivatives: mass spectrometry and computational studies.

RATIONALE: Oxazolines have attracted the attention of researchers worldwide due to their versatility as carboxylic acid protecting groups, chiral auxiliaries, and ligands for asymmetric catalysis. Electrospray ionization tandem mass spectrometric (ESI-MS/MS) analysis of five 2-oxazoline derivatives has been conducted, in order to understand the influence of the side chain on the gas-phase dissociation of these protonated compounds under collision-induced dissociation (CID) conditions. METHODS: Mass spectrometric analyses were conducted in a quadrupole time-of-flight (Q-TOF) spectrometer fitted with electrospray ionization source. Protonation sites have been proposed on the basis of the gas-phase basicity, proton affinity, atomic charges, and a molecular electrostatic potential map obtained on the basis of the quantum chemistry calculations at the B3LYP/6-31 + G(d,p) and G2(MP2) levels. RESULTS: Analysis of the atomic charges, gas-phase basicity and proton affinities values indicates that the nitrogen atom is a possible proton acceptor site. On the basis of these results, two main fragmentation processes have been suggested: one taking place via neutral elimination of the oxazoline moiety (99 u) and another occurring by sequential elimination of neutral fragments with 72 u and 27 u. These processes should lead to formation of R(+). CONCLUSIONS: The ESI-MS/MS experiments have shown that the side chain could affect the dissociation mechanism of protonated 2-oxazoline derivatives. For the compound that exhibits a hydroxyl at the lateral chain, water loss has been suggested to happen through an E2-type elimination, in an exothermic step.