Mathew Bijo, Mathew Githa Elizabeth, Ucar Gulberk, Joy Monu, Nafna E K, Lohidakshan Krishnakumar K, Suresh Jerad
Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, 678557, Kerala, India.
Department of Pharmacology, Grace College of Pharmacy, Palakkad 678004, Kerala, India.
Int J Biol Macromol. 2017 Nov;104(Pt A):1321-1329. doi: 10.1016/j.ijbiomac.2017.05.162. Epub 2017 Jun 1.
The MAO-B inhibitory activity of chalcone (1, 3- diphenyl-2-propen-1-one) based compounds arise from its structural similarity with 1, 4-diphenyl-2-butene, a known MAO-B inhibitor. Based on our previous report, the methoxy-substituted with fluorine containing chalcones are promising reversible MAO-B inhibitors, while in the present study, a series of methoxylated chalcones (C1-C9) bearing substitution on the para position of ring B was synthesized and evaluated for their human monoamine oxidase inhibitory activity. With the exception of (2E)-1-(4-methoxyphenyl)-3-(4-nitrophenyl) prop-2-en-1-one (C7), which is a nonselective inhibitor, the chalcones exhibited competitive, selective, and reversible inhibition of hMAO-B. The most potent compound, (2E)-3-[4-(dimethylamino) phenyl]-1-(4-methoxyphenyl) prop-2-en-1-one (C5), showed the best inhibitory activity towards hMAO-B (IC=0.29±0.011μM;K=0.14±0.001μM). The reversibility of MAO-B inhibition by compound C5 was demonstrated by the recovery of enzyme activity after dialysis of mixtures containing enzyme and inhibitor. The reversiblity of C5 was 25.38±1.40 and 92.00±3.87% before and after dialysis, respectively. PAMPA was carried out to evaluate the blood-brain barrier effects of the designated compounds. Moreover, the most potent MAO-B inhibitor, C5, was found to be nontoxic towards cultured hepatic cells at 5 and 25μM, with 97 and 90% viability. Molecular docking study was performed against hMAO-B to observe the binding site interactions of the lead compound.
基于查尔酮（1,3 - 二苯基 - 2 - 丙烯 - 1 - 酮）的化合物的单胺氧化酶B（MAO - B）抑制活性源于其与已知的MAO - B抑制剂1,4 - 二苯基 - 2 - 丁烯的结构相似性。根据我们之前的报告，含氟甲氧基取代的查尔酮是有前景的可逆MAO - B抑制剂，而在本研究中，合成了一系列在B环对位带有取代基的甲氧基化查尔酮（C1 - C9），并评估了它们对人单胺氧化酶的抑制活性。除了（2E）-1 - （4 - 甲氧基苯基）-3 - （4 - 硝基苯基）丙 - 2 - 烯 - 1 - 酮（C7）是一种非选择性抑制剂外，这些查尔酮对人MAO - B表现出竞争性、选择性和可逆性抑制。最有效的化合物（2E）-3 - [4 - （二甲基氨基）苯基]-1 - （4 - 甲氧基苯基）丙 - 2 - 烯 - 1 - 酮（C5）对人MAO - B表现出最佳抑制活性（IC = 0.29±0.011μM；K = 0.14±0.001μM）。通过对含有酶和抑制剂的混合物进行透析后酶活性的恢复，证明了化合物C5对MAO - B抑制的可逆性。透析前后C5的可逆性分别为25.38±1.40和92.00±3.87%。进行了平行人工膜渗透实验（PAMPA）以评估指定化合物的血脑屏障效应。此外，发现最有效的MAO - B抑制剂C5在5和25μM浓度下对培养的肝细胞无毒，细胞活力分别为97%和90%。针对人MAO - B进行了分子对接研究，以观察先导化合物的结合位点相互作用。
