Drugs affecting more than one target could result in a more efficient treatment of multifactorial diseases as well as fewer safety concerns, compared to a one-drug one-target approach. Within our continued efforts towards the design of multifunctional molecules against atherosclerosis, we hereby report the synthesis of 17 new morpholine derivatives which structurally vary in terms of the aromatic substitution on the morpholine ring. These derivatives simultaneously suppress cholesterol biosynthesis through SQS inhibition (IC50 values of the most active compounds are between 0.7 and 5.5 μM) while exhibiting a significant protection of hepatic microsomal membranes against lipid peroxidation (with IC50 values for the most active compounds being between 73 and 200 μM). Further evaluation of these compounds was accomplished in vivo in an animal model of acute experimental hyperlipidemia, where it was observed that compounds reduced the examined lipidemic parameters (TC, TG and LDL) by 15-80%. In order to examine the mode of binding of these molecules in the active catalytic site of SQS, we also performed docking simulation studies. Our results indicate that some of the new compounds can be considered interesting structures in the search for new multifunctional agents of potential application in atherosclerosis.
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http://dx.doi.org/10.1016/j.bmc.2015.09.034 | DOI Listing |
J Inorg Biochem
December 2024
Department of Molecular and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7-8, H-6720 Szeged, Hungary. Electronic address:
Schiff bases derived from aminoguanidine are extensively investigated for their structural versatility. The tridentate 2-formylpyridine guanylhydrazones act as analogues of 2-formyl or 2-acetylpyridine thiosemicarbazones, where the thioamide unit is replaced by the guanidyl group. Six derivatives of 2-formylpyridine guanylhydrazone were synthesized and their proton dissociation and complex formation processes with Cu(II), Fe(II) and Fe(III) ions were studied using pH-potentiometry, UV-visible, NMR and electron paramagnetic resonance spectroscopic methods.
View Article and Find Full Text PDFJ Hematol Oncol
December 2024
Department of Onco-Haematology and Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, San Paolo N°15 Street, 00146, Rome, Italy.
Sarcomas are rare, mesenchymal tumors, representing about 10-15% of all childhood cancers. GD2 is a suitable target for chimeric antigen receptor (CAR) T-cell therapy due to its overexpression in several solid tumors. In this preclinical study, we investigated the potential use of iCasp9.
View Article and Find Full Text PDFRSC Adv
December 2024
Zhejiang Provincial Key Laboratory of Chemical Utilization of Forestry Biomass, Zhejiang A&F University Zhejiang Hangzhou 311300 China.
Pyrazinamide derivatives have been extensively studied for their biological activities, such as anti-tuberculosis activity and antiviral activities. In this work, a continuous-flow system was developed for the synthesis of pyrazinamide derivatives from pyrazine esters and amines (aliphatic amine, benzylamines and morpholine) catalyzed by Lipozyme® TL IM from , which was used for the first time. The reaction parameters including solvent, substrate ratio, reaction temperature and reaction time/flow rate were also studied in detail.
View Article and Find Full Text PDFRSC Adv
December 2024
Department of Chemistry, Faculty of Science, Suez Canal University Ismailia 41522 Egypt
A novel series of nicotinonitrile and pyrazolyl nicotinonitrile were synthesized, and their PIM-1 kinase inhibitors and caspase activators were investigated. New Manich bases 6-8 were synthesized reaction of pyridine 4 with piperidine, dimethyl amine, and morpholine in the presence of formalin. On the other hand, the pyrazolyl analogues 10-12 were synthesized heterocyclization of acetohydrazide derivative 9 with acetylacetone, malononitrile, and ethyl cyanoacetate, respectively, in ethanol.
View Article and Find Full Text PDFCurr Med Sci
December 2024
Department of Cardiovasology, Affiliated Renhe Hospital of China Three Gorges University, Yichang, 443002, China.
Objective: To investigate whether cardiac mast cells (MCs) participate in pressure overload-induced myocardial hypertrophy through the regulation of transient receptor potential vanilloid 4 (TRPV4).
Methods: Pressure overload-induced myocardial hypertrophy was induced via abdominal aortic constriction (AAC). Myocardial hypertrophy was evaluated by measuring the heart weight index (HW/BW), lung weight index (LW/BW), ratio of heart weight to tibia length (HW/TL), ratio of lung weight to tibia length (LW/TL), and cross-sectional area of myocardial cells.
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