Compounds with Medicinal Value (2nd Volume)

Sesquiterpene lactones (STLs) are a large group of terpenoids most commonly found in plants of the Asteraceae family, e.g., in chicory plants, displaying a wide range of interesting biological activities. However, further studies on the biological potential of chicory-derived STLs and analogues are challenging as only four of these molecules are commercially available (as analytical standards), and to date, there are no published or patented simple extraction–purification processes capable of large-scale STLs isolation. In this work, we describe a novel three-step large-scale extraction and purification method for the simultaneous purification of 11,13-dihydrolactucin (DHLc) and lactucin (Lc) starting from a chicory genotype rich in these STLs and the corresponding glucosyl and oxalyl conjugated forms. After a small-scale screening on 100 mg of freeze-dried chicory root powder, the best results were achieved with a 17 h water maceration at 30 °C. With these conditions, we managed to increase the content of DHLc and Lc, at the same time favoring the hydrolysis of their conjugated forms. On a larger scale, the extraction of 750 g of freeze-dried chicory root powder, followed by a liquid–liquid extraction step and a reversed-phase chromatography, allowed the recovery of 642.3 ± 76.3 mg of DHLc and 175.3 ± 32.9 mg of Lc. The two pure STLs were subsequently used in the context of semisynthesis to generate analogues for biological evaluation as antibacterial agents. In addition, other described chicory STLs that are not commercially available were also synthesized or extracted to serve as analytical standards for the study. In particular, lactucin-oxalate and 11,13-dihydrolactucin-oxalate were synthesized in two steps starting from Lc and DHLc, respectively. On the other hand, 11β,13-dihydrolactucin-glucoside was obtained after a MeOH/H₂O (70/30) extraction, followed by a liquid–liquid extraction step and a reversed-phase chromatography. Together, this work will help facilitate the evaluation of the biological potential of chicory-derived STLs and their semisynthetic analogues. Full article

Purine scaffolds constitute a starting point for the synthesis of numerous chemotherapeutics used in treating cancer, viruses, parasites, as well as bacterial and fungal infections. In this work, we synthesized a group of guanosine analogues containing an additional five-membered ring and a sulfur atom at the C-9 position. The spectral, photophysical, and biological properties of the synthesized compounds were investigated. The spectroscopic studies revealed that a combination of the thiocarbonyl chromophore and the tricyclic structure of guanine analogues shifts the absorption region above 350 nm, allowing for selective excitation when present in biological systems. Unfortunately, due to the low fluorescence quantum yield, this process cannot be used to monitor the presence of these compounds in cells. The synthesized compounds were evaluated for their effect on the viability of human cervical carcinoma (HeLa) and mouse fibroblast (NIH/3T3) cells. It was found that all of them display anticancer activity. In vitro studies were preceded by in silico ADME and PASS analyses, which confirmed that the designed compounds are promising candidates for anticancer agents. Full article

Some radiological contrast agents have been shown to have effects on bacterial growth. In this study, the antibacterial effect and mechanism of action of iodinated X-ray contrast agents (Ultravist 370, Iopamiro 300, Telebrix Gastro 300 and Visipaque) and complexed lanthanide MRI contrast solutions (MultiHance and Dotarem) were tested against six different microorganisms. Bacteria with high and low concentrations were exposed to media containing different contrast media for various lengths of time and at pH 7.0 and 5.5. The antibacterial effect of the media was examined in further tests using agar disk diffusion analysis and the microdilution inhibition method. Bactericidal effects were found for microorganisms at low concentrations and low pH. Reductions were confirmed for Staphylococcus aureus and Escherichia coli. Full article

Staphylococcus aureus (S. aureus) is a worldwide leading versatile pathogen that causes a wide range of serious infections. The emergence of antimicrobial resistance against S. aureus resulted in an urgent need to develop new antimicrobials in the new era. The methicillin-resistant S. aureus (MRSA) prevalence in hospital and community settings necessitates the discovery of novel anti-pathogenic agents. Staphyloxanthin (STX) is a key virulence factor for the survival of MRSA against host innate immunity. The current work aimed to demonstrate the anti-virulence properties of meloxicam (MXM) as compared to diclofenac (DC), which was previously reported to mitigate the virulence of multidrug-resistant Staphylococcus aureus and test their activities in STX production. A total of 80 S. aureus clinical isolates were included, wherein a qualitative and quantitative assessment of STX inhibition by diclofenac and meloxicam was performed. The quantitative gene expression of STX biosynthetic genes (crtM, crtN and sigB) and hla (coded for α-hemolysin) as a virulence gene with and without DC and MXM was conducted, followed by molecular docking analysis for further confirmation. DC and MXM potently inhibited the synthesis of STX at 47 and 59 µg/mL to reach 79.3–98% and 80.6–96.7% inhibition, respectively. Treated cells also revealed a significant downregulation of virulence genes responsible for STX synthesis, such as crtM, crtN and global transcriptional regulator sigB along with the hla gene. Furthermore, computational studies unveiled strong interactions between the CrtM binding site and DC/MXM. In conclusion, this study highlights the potential role and repurposing of DC and MXM as adjuvants to conventional antimicrobials and as an anti-virulent to combat MRSA infections. Full article

Facial microbiota dysbiosis is an important factor in causing acne vulgaris. The present study aimed to analyze the effect of 2% Supramolecular Salicylic Acid (SSA) on acne-associated facial bacteria. In the current study, 30 acne vulgaris patients (treated with 2% SSA for eight weeks) and ten volunteers with no facial acne were selected. Samples from acne patients (before and after treatment) and volunteers (not treated) were analyzed via high throughput sequencing, Deblur algorithm, and R microbiome package. After treatment with 2% SSA, the total lesion count and global acne grading system (GAGS) score reduced significantly (p < 0.001). Metagenomic sequencing analysis revealed that the pre-treated acne group had low α and deviated β diversity compared to the control and post-treated acne groups. Due to the treatment with 2% SSA, α diversity index was increased and β diversity was stabilized significantly (p < 0.001). The relative abundance of bacterial genera in the pre-treated acne group was uneven and had a high proportion of Staphylococcus, Ralstonia, and Streptococcus. The proportion of these three genera was significantly decreased in the post-treated group, and overall bacteria genera distribution tends toward the healthy individual. It is concluded that 2% SSA normalizes the microbial communities associated with the skin. Full article

Background: Despite the existence of a wide variety of anti-inflammatory drugs, the vast majority are classified as steroidal or non-steroidal. Both classes present a variety of side effects that limit usage. Thus, the search for new molecules with anti-inflammatory potential is still important. Methods: Five phenylbenzohydrazides were synthetized and evaluated in pre-clinical models of acute inflammation in vivo and in vitro. Results: The new substances (INL-06, -07, -10, and -11), as well as AISCT, significantly reduced cell migration induced by carrageenan. It was also observed that all INLs inhibited protein extravasation as well as cytokines (IL-6, IL-1β, and TNF-α) and nitric oxide (NO) production. The INL-11 was demonstrated to be the most potent, since the inhibition observed in several parameters was significant even when compared with dexamethasone. In vitro INLs also reduced cytokines and NO production and inducible nitric oxide (iNOS) enzyme activity. The INL-11 was the most effective in reducing cell migration in vitro. Conclusions: Our data suggest that these substances are suitable for further development into a new series of compounds that could lead to new hits and future drug prototypes for anti-inflammatory conditions. Full article

Cydonia Oblonga Mill. is widely distributed in Turkey, Uzbekistan and China and commonly used by the food industry to produce jam, jelly and candies. The aim of this study was to investigate the in vitro antidiabetic activity and anti-diabetic mechanism of Cydonia Oblonga Mill. fruit (COMF). The chemical compositions were further characterized in COMF by UPLC-Q-Orbitrap/MS and 65 components including 22 flavonoids, 16 organic acids, 11 polyphenols, 5 amino acids, 3 pentacyclic triterpenoids and 8 other compounds were identified. The antioxidant activity by DPPH scavenging method and α-glucosidase inhibitory activity were tested. Furthermore, we detected the effects of COMF extract on the proliferation activity of HUVECs, cell viability of HUVECs under H₂O₂-induced oxidative stress, and NO production. Then, molecular docking activity and α-glucosidase inhibitory activity of seven key flavonoid components selected by bioinformatics analysis and literature in the COMF were studied. Among them, quercetin showed potent inhibitory activity, kaempferol, isorhamnetin, luteolin and apigenin demonstrated moderate inhibitory activity, while rutin and epicatechin exhibited poor inhibitory activity. Subsequently, the effects of quercetin, kaempferol, isorhamnetin, leteolin and apigenin on the gene expression levels of AKT1, IL-6 and VEGFA were verified by real-time fluorescence quantification (RT-qPCR). Molecular biology result showed that different active ingredients can significantly recover the levels of AKT1, IL-6 and VEGFA in HUVECs injured by high glucose. Full article

Prostate cancer (PCa) is a common cancer and a major cause of cancer-related death worldwide in men, necessitating novel targets for cancer therapy. High expression of Bloom’s syndrome protein (BLM) helicase is associated with the occurrence and development of PCa. Therefore, the identification and development of new BLM inhibitors may be a new direction for the treatment of PCa. Here, we identified a novel inhibitor by molecular docking and put it to systematic evaluation via various experiments, AO/854, which acted as a competitive inhibitor that blocked the BLM-DNA interaction. Cellular evaluation indicated that AO/854-suppressed tumor growth and metastasis in PC3 cells by enhancing DNA damage, phosphorylating Chk1/Chk2, and altering the p53 signaling pathway. Collectively, the study highlights the potential of BLM as a therapeutic target in PCa and reveals a distinct mechanism by which AO/854 competitively inhibits the function of BLM. Full article

Bacterial resistance has become one of the main motives in the worldwide race for undescribed antibacterial agents. The difficulties in the treatment of bacterial infections are a public health issue that increasingly highlights the need for antimicrobial agents. Endophytic microorganisms are a promising alternative in the search for drugs, due to the vast number of metabolites produced with unique characteristics and bioactive potential. This review highlights the importance of endophytic microorganisms as a source of secondary metabolites in the search for active molecules against bacteria of medical importance, with a special focus on gram-negative species. This fact is supported by the findings raised in this review, which brings an arsenal of 166 molecules with characterized chemical structures and their antibacterial activities. In addition, the low cost, ease of maintenance, and optimization-controlled fermentation conditions favor reproducibility in commercial scale. Given their importance, it is necessary to intensify the search for new molecules from endophytic microorganisms, and to increasingly invest in this very promising font. Full article