Discovery of potent and reversible MAO-B inhibitors as furanochalcones

被引:44
作者
Suresh, Jerad [1 ]
Baek, Seung Cheol [2 ]
Ramakrishnan, Surya Parakkot [1 ]
Kim, Hoon [2 ]
Mathew, Bijo [3 ,4 ]
机构
[1] Madras Med Coll & Govt Gen Hosp, Dept Pharmaceut Chem, Coll Pharm, Madras 600003, Tamil Nadu, India
[2] Sunchon Natl Univ, Inst Life Pharmaceut Sci, Dept Pharm & Res, Sunchon 57922, South Korea
[3] Ahalia Sch Pharm, Dept Pharmaceut Chem, Div Drug Design, Palakkad 678557, Kerala, India
[4] Ahalia Sch Pharm, Dept Pharmaceut Chem, Med Chem Res Lab, Palakkad 678557, Kerala, India
关键词
Furanochalcone; MAO-B; Reversible and competitive inhibitor; Potent; Molecular docking; MONOAMINE-OXIDASE-B; THIENYL CHALCONES; DERIVATIVES; BIOCHEMISTRY;
D O I
10.1016/j.ijbiomac.2017.11.159
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A series of twelve furanochalcones (F1-F12) was synthesized and investigated for their human monoamine oxidase inhibitory activities. Among the series, compound (2E, 4E)-1-(furan-2-yl)-5-phenylpenta-2, 4-dien-1-one (F1), which was analyzed by single-crystal X-ray diffraction, showed potent and selective MAO-B inhibitory activity with an inhibition constant (K-i) value of 0.0041 mu M and selectivity index of (SI) 172.4, and exhibited competitive inhibition. Introduction of a cinnamyl group to the furanochalcone significantly increased the inhibitory activity. In the dilution-recovery experiments, the residual activities of MAO-A and MAO-B by F1 under the diluted condition fully recovered as compared with the undiluted condition, indicating F1 is a reversible inhibitor. The K-i value of F1 is the lowest among the values of chalcone derivatives and furthermore lower than that (0.0079 mu M) of the reversible MAO-B inhibitor, lazabemide, a marketed drug. Molecular docking study against hMAO-B provided the binding site interactions of the lead compound, including strong pi-pi stacking between the phenyl system and FAD nucleus. (C) 2017 Elsevier B.V. All rights reserved.
引用
收藏
页码:660 / 664
页数:5
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