DESIGN AND SYNTHESIS OF BERBERINE DERIVATIVES AS PCSK9 INHIBITORFOR LIPID REDUCTION

Abstract

Nowadays, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) has become a new target for hypercholesterolemia treatment. PCSK9 is a crucial protein in Low-Density Lipoprotein cholesterol (LDL-C) metabolism by regulating the degradation of hepatic low-density lipoprotein receptors (LDLRs). Recently, two monoclonal antibodies (mAbs) PCSK9 inhibitors were approved by the Food and Drug Administration (FDA). However, no orally administrable small molecule has been approved. In addition, berberine (BBR), an isoquinoline alkaloid, has been reported to reduce total cholesterol levels and decrease PCSK9 expression with no severe side effects. Therefore, a novel series of BBR derivatives was designed based on molecular docking to serve as PCSK9 inhibitors in this work. The binding energy of BBR derivatives was investigated to confirm that all of the designed compounds showed better binding energy and stronger interaction than that of the parent BBR. An in silico study was also confirmed that most of the compounds fulfilled drug-likeness properties. Then, eight desired BBR derivatives were successfully synthesized starting from BBR via manich, demethylation, and alkylation reactions. Additionally, BBR derivatives were evaluated for the PCSK9 inhibition activity and the results showed that all of the compounds could down-regulate the PCSK9 expression. Especially, compounds 21 and 24 displayed a high inhibitory effect on PCSK9 by 20-fold higher activity than BBR. Furthermore, the naphthalene substitution at the C-13 position and alkoxy benzenesulfonamide substitution at the C-9 position of BBR significantly affected the inhibition of target enzyme activity. In summary, novel BBR derivatives could be proposed as potential PCSK9 inhibitors for hypercholesterolemia treatment.

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