Antihyperlipidemic morpholine derivatives with antioxidant activity: An investigation of the aromatic substitution

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• 作者：Eleni M. Ladopoulou ; Alexios N. Matralis ; Anastasios Nikitakis ; Angeliki P. Kourounakis ; ^{angeliki@pharm.uoa.gr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：IVIZMNTXSFEUDG-UHFFFAOYSA-N ; YBDSSTRDSOBBJG-UHFFFAOYSA-N ; ASKGIKIBLKGDPF-UHFFFAOYSA-N ; ZQIQFGKIFFQDMD-UHFFFAOYSA-N ; OWVQSFQSZMLKCS-UHFFFAOYSA-N ; HQYSPNZMRLTJSN-UHFFFAOYSA-N ; MUZVAXHPAQSRDX-UHFFFAOYSA-N ; NKWWSUVTIYHFHK-UHFFFAOYSA-N ; RBNURSLEXXNDCQ-UHFFFAOYSA-N ; CMJYCIHZKRQNTI-UHFFFAOYSA-N ; IHSDEPWTHHOZHG-UHFFFAOYSA-N ; UNMOGZOCKIEYAK-UHFFFAOYSA-N ; ABXBWSCARYLGMW-UHFFFAOYSA-N ; KDPCCIRKCQEHOI-UHFFFAOYSA-N ; HASWQCLMGPQFQG-UHFFFAOYSA-N ; WWFNMPJZMWZKDY-UHFFFAOYSA-N ; LMKBZJWIOPGNSG-UHFFFAOYSA-N
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2015
• 出版时间：1 November 2015
• 年：2015
• 卷：23
• 期：21
• 页码：7015-7023
• 全文大小：819 K

文摘

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.