Synthesis and Antimicrobial Evaluation of Amino Acid Naphthoquinone Derivatives as Potential Antibacterial Agents.

BACKGROUND: The synthesis and biological evaluation of 1,4-naphthoquinone derivatives are of great interest since these compounds exhibit strong antibacterial, antifungal, antimalarial, and anticancer activities. The electronic properties of naphthoquinones are usually modulated by attaching functional groups containing nitrogen, oxygen, and sulfur atoms, which tune their biological potency and selectivity. METHODS: A series of 13 amino acid 1,4-naphthoquinone derivatives was synthesized under assisted microwave and ultrasound conditions. The antibacterial activity of compounds was tested against American Type Culture Collection (ATCC): Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis, as well as 2 multidrug resistant pathogens: E. coli and S. aureus from clinical isolated. Minimal inhibitory concentration (MIC) was determined using the broth microdilution method. RESULTS: MIC of derivatives 4-11, 14, and 16 showed antimicrobial activity against Gram-positive and Gram-negative bacteria. Antimicrobial activities of the compounds 4-8 and 14 were ≤MIC 24.7 µg mL-1 against all the reference strains; even more, compound 6 showed the most potent activity with an MIC of 3.9 µg mL-1 on S. aureus. On the clinical isolated, the compounds 7, 8, and 14 showed an MIC of 49.7 and 24.7 µg mL-1 against S. aureus and E. coli, respectively. About ADME properties and Osiris analysis, the compounds 4-16 presented high gastrointestinal absorption and good characteristics for oral bioavailability, and compound 14 was the less toxic. CONCLUSION: Amino acid 1,4-naphthoquinone derivatives showed good in vitro antibacterial activity against clinical strains, and modifications on C-3 with a chloride atom enhanced the efficiency against the same pathogens.

Bromatological Analysis and Characterization of Phenolics in Snow Mountain Garlic.

The remarkable properties of garlic A. sativum L. have been described, but little is known about Snow mountain garlic. Understanding general aspects of this garlic composition, including the presence of phenolics, will establish its possible use for health or infer which compounds can contribute to improving it. This study aimed to determine the ash content, lipid profile, and characterization of phenolics in Snow mountain garlic. The organic content was obtained by common techniques (oven drying, calcination, Kjeldahl method, etc.). The quantitative analysis of the ashes was made by Inductively Coupled Plasma Emission Spectrometry. The fatty acid profile was determined by Gas Chromatography. The presence of phenolics was determined by foam, Libermann-Burchard, Dragendorff, Salkowski, ferric chloride, vanillin, catechin, Constantinescu, and Shinoda reactions. The total phenolic content was determined via the Folin-Ciocalteu method, and antioxidant activity was determined using the DPPH radical method. The bromatological analysis showed a 51.1% humidity, and the main organic compounds were carbohydrates (46.7%). Ash analysis showed 287.46 g/kg of potassium. The fatty acid profile showed 75.61% of polyunsaturated fatty acid. Phenolics like saponins, alkaloids, triterpenes, tannins, and flavonoids were present. Antioxidant activity was found by radical DPPH of 25.64 (±0.78) µmol TE/1 g dw. Snow mountain garlic shares a composition similar to those found in other garlic.

Differential Proliferation Effect of the Newly Synthesized Valine, Tyrosine and Tryptophan-Naphthoquinones in Immortal and Tumorigenic Cervical Cell Lines.

We previously showed that microwave assisted synthesis is the best method for the synthesis of naphthoquinone amino acid and chloride-naphthoquinone amino acid derivatives by a complete evaluation of reaction conditions such as stoichiometry, bases, and pH influence. Following the same strategy, we synthesized chloride and non-chloride tyrosine, valine, and tryptophan-naphthoquinones achieving 85-95%, 80-92%, and 91-95% yields, respectively. The cyclic voltammetry profiles showed that both series of naphthoquinone amino acid derivatives mainly display one redox reaction process. Overall, chloride naphthoquinone amino acid derivatives exhibited redox potential values (E1/2) more positive than non-chloride compounds. The six newly synthesized compounds were tested in HPV positive and negative as well as in immortal and tumorigenic cell lines to observe the effects in different cellular context simulating precancerous and cancerous status. A dose-response was achieved to determine the IC50 of six newly synthesized compounds in SiHa (Tumorigenic and HPV16 positive), CaLo (Tumorigenic and HPV18 positive), C33-A (Tumorigenic and HPV negative) and HaCaT (Keratinocytes immortal HPV negative) cell lines. Non-chloride tryptophan-naphthoquinone (3c) and chloride tyrosine-naphthoquine (4a) effects were more potent in tumorigenic SiHa, CaLo, and C33-A cells with respect to non-tumorigenic HaCaT cells. Interestingly, there seems to be a differential effect in non-chloride and chloride naphthoquinone amino acid derivatives in tumorigenic versus non tumorigenic cells. Considering all naphthoquinone amino acid derivatives that our group synthesized, it seems that hydrophobic and aromatic amino acids have the greatest effect on cell proliferation inhibition. These results show promising compounds for cervical cancer treatment.

Synthesis of Amino Acid-Naphthoquinones and In Vitro Studies on Cervical and Breast Cell Lines.

We performed an extensive analysis about the reaction conditions of the 1,4-Michael addition of amino acids to 1,4-naphthoquinone and substitution to 2,3-dichloronaphthoquinone, and a complete evaluation of stoichiometry, use of different bases, and the pH influence was performed. We were able to show that microwave-assisted synthesis is the best method for the synthesis of naphthoquinone-amino acid and chloride-naphthoquinone-amino acid derivatives with 79-91% and 78-91% yields, respectively. The cyclic voltammetry profiles showed that both series of naphthoquinone-amino acid derivatives mainly display one quasi-reversible redox reaction process. Interestingly, it was shown that naphthoquinone derivatives possess a selective antitumorigenic activity against cervix cancer cell lines and chloride-naphthoquinone-amino acid derivatives against breast cancer cell lines. Furthermore, the newly synthetized compounds with asparagine-naphthoquinones (3e and 4e) inhibited ~85% of SiHa cell proliferation. These results show promising compounds for specific cervical and breast cancer treatment.

In vitro Antibacterial Activity of 7-Substituted-6-Fluoroquinolone and 7-Substituted-6,8-Difluoroquinolone Derivatives.

BACKGROUND: Fluoroquinolones are widely prescribed synthetic antimicrobial agents. Quinolones act by converting their targets, gyrase and topoisomerase IV, into toxic enzymes that fragment the bacterial chromosome; the irreversible DNA damage eventually causes the killing of bacteria. Thorough knowledge of the structure-activity relationship of quinolones is essential for the development of new drugs with improved activity against resistant strains. METHODS: The compounds were screened for their antibacterial activity against 4 representing strains using the Kirby-Bauer disk diffusion method. Minimal inhibitory concentration (MIC) was determined by measuring the diameter of the inhibition zone using concentrations between 250 and 0.004 µg/mL. RESULTS: MIC of derivatives 2, 3, and 4 showed potent antimicrobial activity against gram-positive and gram-negative bacteria. The effective concentrations were 0.860 µg/mL or lower. MIC for compounds 5-11 were between 120 and 515 µg/mL against Escherichia coli and Staphylococcus aureus, and substituted hydrazinoquinolones 7-10 showed poor antibacterial activity against gram-positive and gram-negative bacteria compared with other quinolones. CONCLUSION: Compounds obtained by modifications on C-7 of norfloxacin with the acetylated piperazinyl, halogen atoms, and substituted hydrazinyl showed good in vitro activity - some even better than the original compound.

Photoinduced and thermal denitrogenation of bulky triazoline crystals: insights into solid-to-solid transformation.

The photoinduced and thermal denitrogenation of crystalline triazolines with bulky substituents leads to the quantitative formation of aziridines in clean solid-to-solid reactions despite very large structural changes in the transition from reactant to product. Analysis of the reaction progress by powder X-ray diffraction, solid-state (13)C CPMAS NMR, solid-state FTIR spectroscopy, and thermal analysis has revealed that solid-to-solid reactions proceed either through metastable phases susceptible to amorphization or by mechanisms that involve a reconstructive phase transition that culminates in the formation of the stable phase of the product. While the key for a solid-to-solid transformation is that the reaction occurs below the eutectic temperature of the reactant and product two-component system, experimental evidence suggests that those reactions will undergo a reconstructive phase transition when they take place above the glass transition temperature.

Aziridine nitrogen inversion by dynamic NMR: activation parameters in a fused bicyclic structure.

The nitrogen inversion of a N-phenyl aziridine fused to a succinimide ring is influenced by the presence of a phenyl ring in the succinimide moiety. The endo invertomer is favored, showing an unsymmetrical equilibrium in variable (1)H NMR studies.

The Relevance and Insights on 1,4-Naphthoquinones as Antimicrobial and Antitumoral Molecules: A Systematic Review.

Natural product derivatives are essential in searching for compounds with important chemical, biological, and medical applications. Naphthoquinones are secondary metabolites found in plants and are used in traditional medicine to treat diverse human diseases. Considering this, the synthesis of naphthoquinone derivatives has been explored to contain compounds with potential biological activity. It has been reported that the chemical modification of naphthoquinones improves their pharmacological properties by introducing amines, amino acids, furan, pyran, pyrazole, triazole, indole, among other chemical groups. In this systematic review, we summarized the preparation of nitrogen naphthoquinones derivatives and discussed their biological effect associated with redox properties and other mechanisms. Preclinical evaluation of antibacterial and/or antitumoral naphthoquinones derivatives is included because cancer is a worldwide health problem, and there is a lack of effective drugs against multidrug-resistant bacteria. The information presented herein indicates that naphthoquinone derivatives could be considered for further studies to provide drugs efficient in treating cancer and multidrug-resistant bacteria.

In Vitro Inhibitory and Proliferative Cellular Effects of Different Extracts of Struthanthus quercicola: A Preliminary Study.

Struthanthus quercicola, a hemiparasitic plant known as "seca palo," is used by Nahuatl traditional healers against diabetes, wounds, and rashes. We aimed to investigate the effects of different S. quercicola extracts, which were selected based on their traditional use in Tamazunchale, San Luis Potosí, on the cell viability and antioxidant activity in HeLa cell cultures. S. quercicola growing on Guazuma ulmifolia and Citrus sp. hosts was collected, and methanolic and ethanolic extracts as well as decoctions, infusions, and microwave-assisted extracts were obtained. The terpenoid, alkaloid, flavonoid, saponin, and tannin contents of each extract were evaluated qualitatively and quantitatively. The effects of different extracts on the viability of cervical adenocarcinoma (HeLa) cells were tested using an MTT assay. The differences in the total flavonoid and phenolic contents and free-radical scavenging activity in relation to the host and the extract were also determined. In assessments of the effects of the extracts on cell viability, eight organic extracts (4 from G. quercicola grown on Host 1 and 4 from G. quercicola grown on Host 2) were shown to decrease cell viability significantly in comparison with the control. However, the extract obtained by percolation (PMeOH) caused a significant increase in cell viability (p < 0.05), especially with the plant grown on Host 1. The microwave aqueous and methanolic extracts of the plants grown on both hosts showed a significant increase in the percentage of apoptosis (p < 005). In conclusion, different extracts of Struthanthus quercicola showed variable effects on cell viability and apoptosis. Isolation of the molecule or molecules with inhibitory and proliferative effects on cells should be conducted to evaluate their possible use as antineoplastic agents.

Interactions of Antibacterial Naphthoquinones with Mesoporous Silica Surfaces: A Physicochemical and Theoretical Approach.

1,4-naftoquinone (NQ) molecules have been extensively evaluated as potent antibacterial compounds; however, their use is limited, since they have low water solubility and exhibit toxicities in healthy eukaryotic cells. A possible path to overcoming these challenges is the use of particulate vehicles, such as SBA-15, which is a biocompatible and biodegradable mesoporous silica material, that may enhance drug delivery and decrease dosages. In this work, an isotherm model-based adsorption of three NQs into SBA-15 microparticles was evaluated. Interactions between NQs and SBA-15 microparticles were modeled at the B3LYP/6-31+G(d,p) level of theory to understand the nature of such interactions. The results demonstrated that the adsorption of NQ, 2NQ, and 5NQ into SBA-15 fit the Freundlich adsorption model. According to theorical studies, physisorption is mediated by hydrogen bonds, while the most stable interactions occur between the carbonyl group of NQ and silica surfaces. Both experimental and theoretical results contribute to a deeper understanding of the use of SBA-15 or similar particles as nanovehicles in such a way that NQs can be modified in carbonyl or C3 to enhance adsorptions. The theoretical and experimental results were in accordance and contribute to a deeper understanding of how interactions between NQ-type molecules and SiO2 materials occur.

Efficient aziridine synthesis in metastable crystalline phases by photoinduced denitrogenation of crystalline triazolines.

The solid-state photodenitrogenation of crystalline triazolines proceeds with high efficiency to form the corresponding aziridines in high chemical yields upon selection of the proper irradiation wavelength. It was shown that the solid-to-solid reactions occur by formation of the product in metastable crystalline phases.