Browsing by Author "Zacconi, Flavia C."

Now showing 1 - 6 of 6
  • No Thumbnail Available
    Item
    Experimental measurement and modeling of the solubility of fluorinated compounds derived from dichlone in supercritical carbon dioxide
    (2024) Arevalo, Vicente D.; Cabrera, Adolfo L.; Zacconi, Flavia C.; Morales-Guerrero, Sebastian; del Valle, Jose M.; Taborga, Lautaro; de la Fuente, Juan C.
    Dichlone, also known as 2,3-dichloronaphthalene-1,4-dione, is a solid organic substance employed in the field of agriculture for its fungicidal properties and as a retardant for vegetable decomposition. The bioactive properties of dichlone can be enhanced by modifying its structure, specifically through the synthesis of new derivatives achieved by replacing the functional groups within its molecular structure. Two new solid dichlone derivatives were synthesized in this work, namely 2-chloro-3-((4-fluorobenzyl)amino)naphthalene-1,4-dione (dCl-2B-F) and 2-chloro-3-((4-fluorophenethyl)amino)naphthalene-1,4-dione (dCl-3 P -F) and measured their solubility in supercritical carbon dioxide at (313, 323, and 333) K and pressures between (9. to 32) MPa. The results indicated that solubility ranged between 30.5 and 47.9 mu mol of solute/mol of CO 2 for dCl-2B-F, and from 2.2 to 243.5 mu mol of solute/mol of CO 2 for dCl-3 P -F. The solubility data of dichlone and its synthesized derivatives (dCl-2B-F, dCl3 P -F, 2-chloro-3-((4-chlorobenzyl)amino)naphthalene-1,4-dione (dCl-2B-Cl), 2-chloro-3-((4-chlorophenethyl) amino)naphthalene-1,4-dione (dCl-3 P -Cl), 2-(benzylamino)-3-chloronaphthalene-1,4-dione (dCl-2B) and 2chloro-3-(phenethylamino)naphthalene-1,4-dione (dCl-3 P)) was compared using the density-based correlation of Chrastil and the Statistical Associating Fluid Theory of Variable Range Mie-potential (SAFT-VR Mie) equation of state (EoS), to better comprehend the effects of the structural differences on the solubility. As a result, for the Chrastil model, a root mean square deviation ( rmsd ) of 3% was obtained for dCl-2B-F and 16% for dCl-3 P -F, whereas for the SAFT-VR Mie equation, it averaged 24% for dCl-2B-F and 28% for dCl-3 P -F. It was found that the solubility of the homologous compounds, differing only in one methylene group, increased with solute size (-2B derivatives were less soluble in CO 2 than the -3 P ones), contrary to the expected trend, which could be attributed to the increased probability of ring -to -ring interactions as the chain length connecting the rings decreases. This demonstrates that geometric factors, along with the pressure and temperature, affect the behavior of the solubility and these should be accurately represented in the predictive models.
  • No Thumbnail Available
    Item
    Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation
    (2020) Santana-Romo, Fabian; Lagos, Carlos F.; Duarte, Yorley; Castillo, Francisco; Moglie, Yanina; Maestro, Miguel A.; Charbe, Nitin; Zacconi, Flavia C.
    The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production. Thrombosis is a common causal pathology for three widespread cardiovascular syndromes: acute coronary syndrome (ACS), venous thromboembolism (VTE), and strokes. In this research a series of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitor were designed, synthesized, and evaluated for their FXa inhibitor activity, cytotoxicity activity and coagulation parameters. Rational design for the desired novel molecules was performed through protein-ligand complexes selection and ligand clustering. The microwave-assisted synthetic strategy of selected compounds was carried out by using Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions under microwave irradiation. The microwave methodology proved to be an efficient way to obtain all novel compounds in high yields (73-93%). Furthermore, a thermochemical analysis, optimization and reactivity indexes such as electronic chemical potential (mu), chemical hardness (eta), and electrophilicity (omega) were performed to understand the relationship between the structure and the energetic behavior of all the series. Then, in vitro analysis showed that compounds 27, 29-31, and 34 exhibited inhibitory activity against FXa and the corresponding half maximal inhibitory concentration (IC50) values were calculated. Next, a cell viability assay in HEK293 and HepG2 cell lines, and coagulation parameters (anti FXa, Prothrombin time (PT), activated Partial Thromboplastin Time (aPTT)) of the most active novel molecules were performed to determine the corresponding cytotoxicity and possible action on clotting pathways. The obtained results suggest that compounds 27 and 29 inhibited FXa targeting through coagulation factors in the intrinsic and extrinsic pathways. However, compound 34 may target coagulation FXa mainly by the extrinsic and common pathway. Interestingly, the most active compounds in relation to the inhibition activity against FXa and coagulation parameters did not show toxicity at the performed coagulation assay concentrations. Finally, docking studies confirmed the preferential binding mode of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives inside the active site of FXa.
  • No Thumbnail Available
    Item
    Probing 3CL protease: Rationally designed chemical moieties for COVID-19
    (2020) Sharma, Mousmee; Prasher, Parteek; Mehta, Meenu; Zacconi, Flavia C.; Singh, Yogendra; Kapoor, Deepak N.; Dureja, Harish; Pardhi, Dinesh M.; Tambuwala, Murtaza M.; Gupta, Gaurav; Chellappan, Dinesh K.; Dua, Kamal; Satija, Saurabh
  • No Thumbnail Available
    Item
    Solubility in supercritical carbon dioxide of two novel amine derivatives of 2,3-dichloronaphthalene-1,4-dione (dichlone)
    (2023) Schulz, Alex C.; Zacconi, Flavia C.; Cabrera, Adolfo L.; del Valle, Jose M.; Espinoza, Luis; de la Fuente, Juan C.
    Dichlone (2,3-dichloronaphthalene-1,4-dione) is an important antimicrobial agent for agriculture, which effectiveness could be improved by modifying its structure, while the recovery of high-purity synthesized derivatives from a reaction mixture could be accomplished by extracting them with supercritical carbon dioxide. Two new amine derivatives, 2-chloro-3-((4-chlorobenzyl)amino)naphthalene-1,4-dione (dCl-2B-Cl) and 2-chloro-3-((4-chlorophenethyl)amino)naphthalene-1,4-dione (dCl-3P-Cl), were synthesized from dichlone, and their solubility in supercritical carbon dioxide was measured afterwards at (313, 323 and 333) K and a pressure range from (8-33) MPa. Experimental solubilities spanned from (10.3 center dot 10(-6) to 22.1 center dot 10(-6)) mol center dot mol(-1) for dCl-2B-Cl, and from (32.7 center dot 10(-6) to 131 center dot 10(-6)) mol center dot mol(-1) for dCl-3P-Cl. The solubility data of the dichlone family (dichlone, dCl-2B-Cl, dCl-3P-Cl, 2-(benzylamino)-3-chloronaphthalene-1,4-dione (dCl-2B) and 2-chloro-3-(phenethylamino)naphthalene-1,4-dione (dCl-3P)) was compared using three models, i.e., the Chrastil equation, the Molecular Connectivity Indices model, and the Statistical Associating Fluid Theory of Variable Range and Mie Potential equation of state, to identify the quantitative structure-property relationship between them. Solubility had an inverse relation with solute size and polarity, but there were some exceptions that could be explained by performing a stereochemical analysis, which showed that steric effects involved in the folding of dCl-3P and dCl-3P-Cl provided them a better geometry for solvation than dCl-2B and dCl-2B-Cl, respectively, making them more soluble. This demonstrates that the solute geometry is an important factor in the solvation process, and it must be represented accurately to develop better predictive models.
  • Thumbnail Image
    Item
    Zerumbone liquid crystalline nanoparticles protect against oxidative stress, inflammation and senescence induced by cigarette smoke extract in vitro
    (2024) Paudel, Keshav Raj; Clarence, Dvya Delilaa; Panth, Nisha; Manandhar, Bikash; De Rubis, Gabriele; Devkota, Hari Prasad; Gupta, Gaurav; Zacconi, Flavia C.; Williams, Kylie A.; Pont, Lisa G.; Singh, Sachin Kumar; Warkiani, Majid Ebrahimi; Adams, Jon; Macloughlin, Ronan; Oliver, Brian G.; Chellappan, Dinesh Kumar; Hansbro, Philip Michael; Dua, Kamal
    The purpose of this study was to evaluate the potential of zerumbone-loaded liquid crystalline nanoparticles (ZER-LCNs) in the protection of broncho-epithelial cells and alveolar macrophages against oxidative stress, inflammation and senescence induced by cigarette smoke extract in vitro. The effect of the treatment of ZER-LCNs on in vitro cell models of cigarette smoke extract (CSE)-treated mouse RAW264.7 and human BCi-NS1.1 basal epithelial cell lines was evaluated for their anti-inflammatory, antioxidant and anti-senescence activities using colorimetric and fluorescence-based assays, fluorescence imaging, RT-qPCR and proteome profiler kit. The ZER-LCNs successfully reduced the expression of pro-inflammatory markers including Il-6, Il-1 beta and Tnf-alpha, as well as the production of nitric oxide in RAW 264.7 cells. Additionally, ZER-LCNs successfully inhibited oxidative stress through reduction of reactive oxygen species (ROS) levels and regulation of genes, namely GPX2 and GCLC in BCi-NS1.1 cells. Anti-senescence activity of ZER-LCNs was also observed in BCi-NS1.1 cells, with significant reductions in the expression of SIRT1, CDKN1A and CDKN2A. This study demonstrates strong in vitro anti-inflammatory, antioxidative and anti-senescence activities of ZER-LCNs paving the path for this formulation to be translated into a promising therapeutic agent for chronic respiratory inflammatory conditions including COPD and asthma.
  • Thumbnail Image
    Item
    Zerumbone-incorporated liquid crystalline nanoparticles inhibit proliferation and migration of non-small-cell lung cancer in vitro
    (2024) Manandhar, Bikash; Paudel, Keshav Raj; Clarence, Dvya Delilaa; De Rubis, Gabriele; Madheswaran, Thiagarajan; Panneerselvam, Jithendra; Zacconi, Flavia C.; Williams, Kylie A.; Pont, Lisa G.; Warkiani, Majid Ebrahimi; MacLoughlin, Ronan; Oliver, Brian Gregory; Gupta, Gaurav; Singh, Sachin Kumar; Chellappan, Dinesh Kumar; Hansbro, Philip M.; Dua, Kamal
    Lung cancer is the second most prevalent type of cancer and is responsible for the highest number of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) makes up the majority of lung cancer cases. Zerumbone (ZER) is natural compound commonly found in the roots of Zingiber zerumbet which has recently demonstrated anti-cancer activity in both in vitro and in vivo studies. Despite their medical benefits, ZER has low aqueous solubility, poor GI absorption and oral bioavailability that hinders its effectiveness. Liquid crystalline nanoparticles (LCNs) are novel drug delivery carrier that have tuneable characteristics to enhance and ease the delivery of bioactive compounds. This study aimed to formulate ZER-loaded LCNs and investigate their effectiveness against NSCLC in vitro using A549 lung cancer cells. ZER-LCNs, prepared in the study, inhibited the proliferation and migration of A549 cells. These inhibitory effects were superior to the effects of ZER alone at a concentration 10 times lower than that of free ZER, demonstrating a potent anti-cancer activity of ZER-LCNs. The underlying mechanisms of the anti-cancer effects by ZER-LCNs were associated with the transcriptional regulation of tumor suppressor genes P53 and PTEN, and metastasis-associated gene KRT18. The protein array data showed downregulation of several proliferation associated proteins such as AXL, HER1, PGRN, and BIRC5 and metastasis-associated proteins such as DKK1, CAPG, CTSS, CTSB, CTSD, and PLAU. This study provides evidence of potential for increasing the potency and effectiveness of ZER with LCN formulation and developing ZER-LCNs as a treatment strategy for mitigation and treatment of NSCLC.