Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Thiocarbohydrazone and Chalcone-Derived 3,4-Dihydropyrimidinethione as Lipid Peroxidation and Soybean Lipoxygenase Inhibitors
Δημιουργός/Συγγραφέας:	Georgiou, Nikitas Chontzopoulou, Eleni Cheilari, Antigoni Katsogiannou, Aikaterini Karta, Danai Vavougyiou, Kyriaki Hadjipavlou-Litina, Dimitra Javornik, Uroš Plavec, Janez [EL] Τζέλη, Δήμητρα[EN] Tzeli, Demeter Vassiliou, Stamatia [EL] Μαυρομούστακος, Θωμάς[EN] Mavromoustakos, Thomas
Ημερομηνία:	2023-04-04
Γλώσσα:	Αγγλικά
ISSN:	2470-1343 2470-1343
DOI:	10.1021/acsomega.2c07625
Άλλο:	37033811
Περίληψη:	The potential of the 4,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione (abbreviated as KKII5) and (E)-N'-benzylidenehydrazinecarbothiohydrazide (abbreviated as DKI5) compounds as possible drug leads is investigated. KKII5 and DKI5 are synthesized in high yield of up to 97%. Their structure, binding in the active site of the LOX-1 enzyme, and their toxicity are studied via joint experimental and computational methodologies. Specifically, the structure assignment and conformational analysis were achieved by applying homonuclear and heteronuclear 2D nuclear magnetic resonance (NMR) spectroscopy (2D-COSY, 2D-NOESY, 2D-HSQC, and 2D-HMBC) and density functional theory (DFT). The obtained DFT lowest energy conformers were in agreement with the NOE correlations observed in the 2D-NOESY spectra. Additionally, docking and molecular dynamics simulations were performed to discover their ability to bind and remain stabile in the active site of the LOX-1 enzyme. These in silico experiments and DFT calculations indicated favorable binding for the enzyme under study. The strongest binding energy, -9.60 kcal/mol, was observed for dihydropyrimidinethione KKII5 in the active site of LOX-1. ADMET calculations showed that the two molecules lack major toxicities and could serve as possible drug leads. The redox potential of the active center of LOX-1 with the binding molecules was calculated via DFT methodology. The results showed a significantly smaller energy attachment of 2.8 eV with KKII5 binding in comparison to DKI5. Thus, KKII5 enhanced the ability of the active center to receive electrons compared to DKI5. This is related to the stronger binding interaction of KKII5 relative to that of DK15 to LOX-1. The two very potent LOX-1 inhibitors exerted IC50 19 μΜ (KKII5) and 22.5 μΜ (DKI5). Furthermore, they both strongly inhibit lipid peroxidation, namely, 98% for KKII5 and 94% for DKI5.
Τίτλος πηγής δημοσίευσης:	ACS omega
Τόμος/Κεφάλαιο:	8
Τεύχος:	13
Σελίδες:	11966 - 11977
Θεματική Κατηγορία:	[EL] Χημική μηχανική[EN] Chemical engineering [EL] Χημεία[EN] Chemistry
EU Grant identifier:	P1-242
Κάτοχος πνευματικών δικαιωμάτων:	© 2023 The Authors. Published by American Chemical Society
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://doi.org/10.1021/acsomega.2c07625
Σημειώσεις:	The authors acknowledge the CERIC–ERIC consortium for the access to experimental facilities and financial support. Materials were supported by Special Account for Research Grants (SARG), National Kapodistrian University of Athens (NKUA). U.J. and J.P. acknowledge financial support of Slovenian Research Agency (ARRS, Grant P1-242).
Εμφανίζεται στις συλλογές:	Ινστιτούτο Θεωρητικής και Φυσικής Χημείας (ΙΘΦΧ) - Επιστημονικό έργο