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  • Open access
  • 40 Reads
The value of food waste: Citrus reticulata (mandarin) peel as potent biological agent
Published: 26 September 2022 by MDPI in 8th International Electronic Conference on Medicinal Chemistry session General

Citrus reticulata (mandarin) is used in the food industry mainly for juice production, while its peel represents a byproduct with high content of miscellaneous biologically active compounds. This research aimed to assess the antioxidant and enzyme-inhibitory activities of different peel extracts of mandarin cultivated under natural conditions in the Montenegrin coastal region (Lastva Grbaljska). Mandarin fruits were collected in November 2017, and their extracts were prepared using acetone, methanol, and boiling distilled water as solvents. Total phenolic (TPC) and flavonoid (TFC) contents were determined at the concentration of 0.5 mg/mL, as well as the extracts’ antioxidant (using DPPH and total reducing power assays) and enzyme-inhibitory activities (using acetylcholinesterase (AChE) and α-glucosidase inhibition assays). The results indicated that the acetonic extract exhibited the highest radical scavenging activity (12.70%), while also showing the highest TPC (52.40 mg GAE/g) and TFC (13.05 mg QE/g), which is not surprising since acetone is known to extract biologically highly active flavonoid aglycones from plants. Although the aqueous extract had the lowest TPC and TFC, it exerted the highest reducing power (199.06 µmol AAE/g), as well as AChE inhibition activity (22.44%), indicating that other groups of phytochemicals besides phenolics, such as various classes of glycosides, are responsible for the displayed bioactivity. Moreover, none of the extracts inhibited the activity of α-glucosidase. Finally, this study suggests that mandarin peel should not be dismissed in food processing since it possesses a valuable medicinal potential that remains to be further investigated.

  • Open access
  • 22 Reads
Novel Homo Disubstituted Triphenylethylenes with Potential Proteasomal Inhibition and Anti-Cancer Activity

The 26S proteasome regulates several biological activities, including cell cycle progression, cell growth, differentiation and proliferation. The proteasome's abnormal degradation of essential regulatory proteins disrupts these processes which results in uncontrolled cell cycle progression and reduced cell death. Ridaifen analogues were reported as non-peptide non-covalent inhibitors of human 20S proteasome catalytic subunits (T-L, CT-L, PGPH), they are effective against both multiple myeloma and solid tumors. Herein we report novel non-covalent non-peptide proteasome inhibitors bearing a triphenylethylene (TPE) backbone. Compounds were tested for their ability to inhibit the three different catalytic subunits of the 20S proteasome core in vitro. Two series were adopted in this work, with rigid and flexible skeletons. We examined the structural activity relationship of the novel analogues to optimize their proteasomal inhibition activity. Compounds were tested for their anti-proliferative effects in the National Cancer Institute (NCI) -60 cell lines. Compound I, a rigid analogue bearing a bis-dimethlyamino propoxy side chain on ring B and C and a para methoxy substituent on ring A, showed mean GI50 = 1.65 µM on all 60 NCI cell lines, IC50 CT-L activity = 0.36 µM and PGPH activity IC50 = 0.48 µM. TPE based SERMs like Toremifene and Clomiphene were reported to inhibit viral entry of Ebola Virus (EBOV) and its replication. Compound VI showed ability to inhibit EBOV replication with EC50 = 0.11 µM, SI = 33.

  • Open access
  • 31 Reads
A grape (Vitis vinifera L.) pomace water extract: phenolic composition and protective effects in the colon.

Grape (Vitis vinifera L.) pomace is a residue derived from the winemaking process, which contains bioactive compounds displaying noteworthy health-promoting properties. A characterization of the water extract from grape pomace from Montepulciano d’Abruzzo variety (Villamagna doc) was conducted, and the bioactive phenolic compounds were quantified through HPLC-DAD-MS analysis. The aim of the present study was to investigate the phenolic composition and protective effects of a water extract of grape pomace (WEGP) in colorectal cancer cell line SW480 and in isolated mouse colon exposed to Escherichia coli lipopolysaccharide (LPS). The extract decreased SW-480 cell viability, as well as vascular endothelial factor A (VEGFA), hypoxia-induced factor 1α (HIF1α), and transient receptor potential M8 (TRPM8) LPS-induced gene expression. Moreover, the extract inhibited mRNA levels of nuclear factor kB (NFkB), cyclooxygenase (COX)-2, tumor necrosis factor (TNF)α, interleukin (IL)-6, IL-1β, IL-10, inducible nitric oxide synthase (iNOS), and interferon (IFN)γ, in isolated colon. Conversely, WEGP increased the gene expression of antioxidant catalase (CAT) and superoxide dismutase (SOD), in the same model. The modulatory effects exerted by WEGP could be related, at least in part, to the phenolic composition, with particular regards to the catechin level. Grape pomace could be considered as a valuable source of bioactive extracts and phytochemicals with protective effects in the colon.

  • Open access
  • 81 Reads
In silico drug discovery of new anti-breast cancer inhibitors based on 3D-QSAR, molecular docking and ADMET investigation
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Breast cancer is a common kind of cancer affecting women with a fatal outcome. Due to extensive treatment cycles, breast cancer resistance has now become a worldwide issue. Therefore, the only realistic treatment is the rapid development anti-breast cancer medications. To improve and propose new anti-breast cancer drugs, three-dimensional quantitative structure-activity relationships (3D-QSAR) and molecular docking studies on thioquinazolinone derivatives with aromatase enzyme (PDB: 3S7S) were attempted. Comparative Molecular Similarity Indices Analysis (CoMSIA) was utilized to develop the 3D-QSAR model in this study. The best CoMSIA model (with considerable values of Q2, R2 and R2pred) was also utilized in an effort to get the high predictability. External validation that uses a test set has been utilized to validate the predictive ability of the fitted model. According to the findings, the Electrostatic, Hydrophobic, Hydrogen Bond Donor and Acceptor fields had a serious influence on anti-breast cancer activities. Thus, we designed a variety of novel effective aromatase inhibitors based on prior findings and predicted their inhibitory activities using the best model. Moreover, ADMET investigations were employed to analyze the pharmacokinetic properties of drug-candidates.

  • Open access
  • 38 Reads
A novel and promising NLRP3 inflammasome inhibitor: Dehydroisohispanolone

The NLRP3 inflammasome is a complex present in cells of the innate immune system and involved in numerous inflammatory diseases, being a potential target for their treatment. NLRP3 inflammasome regulates caspase-1 activation and subsequent interleukin (IL)-1β and IL-18 release, and a type of cell death named pyroptosis. However, no specific NLRP3 inhibitors are clinically available to date. Dehydroisohispanolone (DIH) is a natural compound derived from the diterpene hispanolone with anti-inflammatory activity via inhibition of NF-κB activation. In this study, we evaluated whether DIH modulates NLRP3 inflammasome activation in macrophages. Our findings revealed that DIH inhibited NLRP3 activation in J774A.1 macrophages triggered by diverse stimuli (LPS plus nigericin/ adenosine triphosphate/ monosodium urate crystals), as it reduced IL-1β release and caspase-1 activation. DIH treatment also diminished cleaved IL-1β and caspase-1 p10 expression, although expression of NLRP3, ASC, pro-IL-1β and pro-caspase-1 was not affected. Pyroptosis mediated by NLRP3 activation was also attenuated by DIH. In addition, we found that DIH acts as a dual NLRP3 inhibitor by inhibition of LPS-induced priming step in NLRP3 inflammasome activation. Similar results on IL-1β release were observed in nigericin-activated bone marrow-derived macrophages. Covalent molecular docking study of DIH onto the ATP-binding site revealed that DIH binds to NLRP3, forming a covalent bond with Cys415. In conclusion, our experiments show that DIH is an effective NLRP3 inflammasome inhibitor, by inhibiting both the priming and the activation steps, making DIH a promising therapeutic agent for the treatment of inflammatory-related diseases.

  • Open access
  • 22 Reads
Identification of Potential Allosteric Site Binders of Indoleamine 2,3-Dioxygenase 1 from Plants: A Virtual and Molecular Dynamics Investigation

Ligand and structure-based computational screenings were carried out to identify flavonoids with potential anticancer activity. Kushenol E, a flavonoid with proven anticancer activity and, at the same time, an allosteric site binder of the enzyme indoleamine 2,3-dioxygenase-1 (IDO1), was used as the reference compound. Molecular docking and molecular dynamics simulations were performed for the screened flavonoids with known anticancer activity. The following two of these flavonoids were identified as potential inhibitors of IDO1: dichamanetin and isochamanetin. Molecular dynamics simulations were used to assess the conformational profile of IDO1-flavonoids complexes, as well as for calculating the bind-free energies.

  • Open access
  • 26 Reads
Computational studies indicated the effectiveness of human metabolites against SARS-CoV-2 main protease.

To fight against the devastating COVID-19 pandemic, identifying robust anti-SARS-CoV-2 therapeutics from all possible directions is demanding. To contribute to this effort, we selected a human metabolites database containing thousands of water and lipid-soluble metabolites to screen against 3-chymotrypsin-like proteases (3CL pro ) protein of SARS-CoV-2. This protease has a critical role in the virus life cycle, making it a potential drug target against COVID-19. The top 8 hits, obtained from virtual screening, displayed a docking score varying between ~ -11 to ~ -14 kcal/mol. The virtual screening study is complemented by molecular dynamics simulations in conjunction with the molecular mechanics generalized Born surface area (MM/GBSA) scheme. Molecular docking and molecular dynamics studies revealed that (HMDB0132640) has the best glide docking score, -14.06 kcal/mol, and MM-GBSA binding free energy, -18.08 kcal/mol. The other three lead molecules are also selected along with the top lead through a critical inspection of their pharmacokinetics properties. HMDB0132640 displayed a better binding affinity compared to the other three compounds (HMDB0127868, HMDB0134119, and HMDB0125821) due to increased favorable contributions from the intermolecular electrostatic and van der Waals interactions. Critical residues involved in the protein-ligand interactions were identified via per-residue decomposition of the binding free energy. Further, we have investigated the ligand-induced structural dynamics of the main protease. Overall, we have identified new compounds that can serve as potential leads for developing novel antiviral drugs against SARS-CoV-2 and elucidated molecular mechanisms of their binding to the main protease.

  • Open access
  • 39 Reads
Pro-apoptotic and anti-migration properties of a thiazoline-containing platinum(II) complex in MDA-MB-231 breast cancer cells: role of melatonin as synergistic agent

Triple-negative breast cancer (TNBC) is an aggressive cancer that does not respond to hormonal and HER2-targeted therapies and have poor prognosis. Therefore, there is a need for the development of convenient anticancer strategies that can be effectively used for the treatment of TNBC. Herein, we evaluated the antitumoral potential of a platinum(II) complex coordinated with the ligand 2-(3,5-diphenylpyrazol-1-yl)-2-thiazoline (DPhPzTn), hereafter PtDPhPzTn, against the TNBC cell line MDA-MB-231. The potentiating actions of melatonin on the tumor-killing ability of PtDPhPzTn were also checked in MDA-MB-231 cells. We first examined the cytotoxic effect of both PtDPhPzTn and melatonin in the TNBC cells, which were dose-dependent. We then combined different doses of PtDPhPzTn and melatonin to test their combinatorial effect and found a synergistic effect, especially when combining 1 mM melatonin and 5, 10 and 25 µM PtDPhPzTn. Additionally, PtDPhPzTn induced apoptosis mediated by caspase-3/-9 activation and dependent on reactive oxygen species overproduction. Likewise, PtDPhPzTn almost completely blunted the migration capacity of MDA-MB-231 cells. Combined treatment with PtDPhPzTn and melatonin moderately potentiated the pro-apoptotic and anti-migratory actions of the complex alone. These findings suggest that aromatic groups improve the cytotoxicity of the compound and provide evidence that PtDPhPzTn and melatonin could be potentially applied to TBNC treatment as synergistic agents.

  • Open access
  • 25 Reads
Hepatopathological assessment of rats exposed to alkaloids of Vitex doniana

The study examined how well the alkaloid content of Vitex doniana affected the liver function in albino rats. The liver damage in albino rats was induced using a CCl4 solution in paraffin (1:1). The liver function tests were performed by administering several groups of albino rats oral dosages (200, 400, and 600 mg/kg) of the bulk alkaloid over the course of 14 days, After the rats were sacrificed, the liver was examined hepatopathologically to determine the serum levels of albumin, total protein, cholesterol, triglycerides, low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). When compared to the control, the alkaloid fraction of V. doniana significantly (p ˂ 0.05) enhanced the levels of total protein, serum albumin, and HDLs. The findings also demonstrated that rats administered with alkaloid fraction had significantly (p ˂ 0.05) lower serum levels of CHOL, TAG, LDLs, and BUN as compared to untreated rats. The alkaloids repaired the normal cellular architecture of the liver that had been damaged by the standard hepatotoxin. The use of V. doniana in treating disorders linked to the liver is supported by the fact that its alkaloids repair CCl4-induced hepatocellular damage.

  • Open access
  • 55 Reads
Halotolerant Bacillus spp. strains isolated from the Great Sebkha of Oran (Algeria): a source of antimicrobial secondary metabolites
, , ,
Published: 01 November 2022 by MDPI in 8th International Electronic Conference on Medicinal Chemistry session General

Bacillus species are Gram-positive bacteria found in abundance in nature, they could colonize different habitats even under extreme conditions and their secondary metabolites were found to possess various potential activities, notably antimicrobial. In this study, three-halotolerant Bacillus sp. LMB3051, LMB3073 and LMB3093 were isolated from water of the Great Sebkha of Oran, they exhibited interesting antimicrobial activities against a broad spectrum of reference bacterial and fungal strains. Their metabolites were extracted with chloroform and ethyl acetate solvents. Structural elucidation of actives compounds was carried out using gas chromatography–mass spectrometry (GC-MS). Fifty-six compounds were identified; they include tert-butyl phenol compounds, fatty acid methyl esters due to the methylation procedure, hydrocarbons, aldehydes, benzoquinones, pyrrols, and terpenes. Literature reports such compounds to have wide biological and pharmaceutical applications. Partial 16S rRNA gene sequencing of the three isolates showed very high similarity with many species of Bacillus. The comparison with 16S rRNA EzBioCloud database revealed that the isolates LMB3051 (529 bp) and LMB3073 (429 bp) showed a similarity of 99.81% and 98.60%, respectively, with Bacillus licheniformis ATCC 14,580, B. aureus 24 K, B. paralicheniformis KJ-16, B. glicinifermentans GO-13, B. haynesii NRRL B-41327, and B. piscis16MFT21. The isolate LMB3093 (400 bp) showed 98.75% of similarity with Bacillus paralicheniformis KJ-16 and B. haynesii NRRL B-41327. The findings suggest that the Great Sebkha of Oran is a valuable source of strains exhibiting variety of beneficial attributes that can be utilized in the development of biological antibiotics.