Kumar Sunil, Oh Jong Min, Abdelgawad Mohamed A, Abourehab Mohammed A S, Tengli Anand Kumar, Singh Ashutosh Kumar, Ahmad Iqrar, Patel Harun, Mathew Bijo, Kim Hoon
Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, India.
Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea.
ACS Omega. 2023 Feb 7;8(7):6908-6917. doi: 10.1021/acsomega.2c07694. eCollection 2023 Feb 21.
Thirteen isopropyl chalcones () were synthesized and evaluated for their inhibitory activity against monoamine oxidase (MAO). All compounds inhibited MAO-B more effectively than MAO-A. Compound most potently inhibited MAO-B with an IC value of 0.032 μM, similar to that of (IC = 0.035 μM) and with high selectivity index (SI) values for MAO-B over MAO-A (SI = 49.75 and 353.23, respectively). The -OH () or -F () group at the para position on the A ring provided higher MAO-B inhibition than that of the other substituents (-OH ≥ -F > -Cl > -Br > -OCHCH > -CF). On the other hand, compound most potently inhibited MAO-A with an IC value of 0.310 μM and effectively MAO-B (IC = 0.074 μM). The Br-containing thiophene substituent () instead of the A ring showed the highest MAO-A inhibition. In a kinetic study, values of compounds and for MAO-B were 0.076 ± 0.001 and 0.027 ± 0.002 μM, respectively, and that of for MAO-A was 0.016 ± 0.005 μM. A reversibility study showed that and were reversible inhibitors of MAO-B and was a reversible inhibitor of MAO-A. In docking and molecular dynamics, the hydroxyl group of and two hydrogen bonds contributed to the stability of the protein-ligand complex. These results suggest that and are potent reversible selective MAO-B inhibitors and can be used for the treatment of Parkinson's disease.
合成了13种异丙基查尔酮，并对其对单胺氧化酶（MAO）的抑制活性进行了评估。所有化合物对MAO-B的抑制作用均比对MAO-A更有效。化合物 对MAO-B的抑制作用最强，IC值为0.032 μM，与 （IC = 0.035 μM）相似，且对MAO-B相对于MAO-A具有高选择性指数（SI）值（分别为SI = 49.75和353.23）。A环对位的-OH（ ）或-F（ ）基团比其他取代基（-OH ≥ -F > -Cl > -Br > -OCHCH > -CF）对MAO-B的抑制作用更高。另一方面，化合物 对MAO-A的抑制作用最强，IC值为0.310 μM，对MAO-B也有有效抑制作用（IC = 0.074 μM）。含Br的噻吩取代基（ ）而非A环对MAO-A的抑制作用最高。在动力学研究中，化合物 和 对MAO-B的 值分别为0.076 ± 0.001和0.027 ± 0.002 μM，而 对MAO-A的 值为0.016 ± 0.005 μM。可逆性研究表明， 和 是MAO-B的可逆抑制剂， 是MAO-A的可逆抑制剂。在对接和分子动力学研究中， 的羟基和两个氢键有助于蛋白质-配体复合物的稳定性。这些结果表明， 和 是有效的可逆性选择性MAO-B抑制剂，可用于治疗帕金森病。
