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Phenothiazine‐based chalcones as potential dual‐target inhibitors toward cholinesterases (AChE, BuChE) and monoamine oxidases (MAO‐A, MAO‐B)
Journal of Heterocyclic Chemistry ( IF 2.0 ) Pub Date : 2020-09-25 , DOI: 10.1002/jhet.4156 Cem Yamali 1, 2 , Feyza Sena Engin 1 , Sinan Bilginer 1 , Mehtap Tugrak 1 , Dilan Ozmen Ozgun 3 , Gulsen Ozli 4 , Serkan Levent 5 , Begum Nurpelin Saglik 5 , Yusuf Ozkay 5 , Halise Inci Gul 1
Journal of Heterocyclic Chemistry ( IF 2.0 ) Pub Date : 2020-09-25 , DOI: 10.1002/jhet.4156 Cem Yamali 1, 2 , Feyza Sena Engin 1 , Sinan Bilginer 1 , Mehtap Tugrak 1 , Dilan Ozmen Ozgun 3 , Gulsen Ozli 4 , Serkan Levent 5 , Begum Nurpelin Saglik 5 , Yusuf Ozkay 5 , Halise Inci Gul 1
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Chalcones targeting neurodegenerative diseases have been known as attractive structures in drug design and discovery. In this study, phenothiazine‐based chalcones as ChEs and MAOs inhibitors were designed and synthesized via base‐catalyzed Claisen‐Schmidt condensation, and chemical structures of the compounds were elucidated by NMRs and HRMS. Compounds 3 and 9 showed promising inhibition potency against AChE enzyme with IC50 values of 0.221 μM and 0.053 μM while compound 9 displayed remarkable inhibition potency toward MAO‐B enzyme with IC50 value of 0.048 μM. Compound 9, as a dual‐target inhibitor, selectively inhibited AChE and MAO‐B enzymes. This promising behavior is an advantage for the compound since MAO‐B and AChE inhibition have a role in Alzheimer's disease. Fused tricyclic ring systems such as phenothiazine incorporated with chalcone moiety being multitargeting ligands may help scientists for the rational design of novel lead compounds targeting neurodegenerative illnesses.
中文翻译：
基于吩噻嗪的查耳酮对胆碱酯酶（AChE，BuChE）和单胺氧化酶（MAO-A，MAO-B）可能是双重靶标抑制剂
靶向神经退行性疾病的查耳酮在药物设计和发现中被认为是有吸引力的结构。在这项研究中，通过碱催化的Claisen-Schmidt缩合反应设计并合成了吩噻嗪基Chalcones作为ChEs和MAOs抑制剂，并通过NMR和HRMS阐明了化合物的化学结构。化合物3和9对AChE酶显示出有希望的抑制潜能，IC 50值为0.221μM和0.053μM，而化合物9对MAO-B酶显示出显着的抑制潜能，IC 50值为0.048μM。化合物9作为双重靶标抑制剂，可选择性抑制AChE和MAO-B酶。这种有希望的行为是该化合物的优势，因为MAO-B和AChE抑制作用在阿尔茨海默氏病中起作用。融合的三环系统，例如吩噻嗪与查耳酮部分结合在一起，可作为多靶点配体，可能有助于科学家合理设计针对神经退行性疾病的新型先导化合物。
更新日期：2020-09-25
中文翻译：
基于吩噻嗪的查耳酮对胆碱酯酶（AChE，BuChE）和单胺氧化酶（MAO-A，MAO-B）可能是双重靶标抑制剂
靶向神经退行性疾病的查耳酮在药物设计和发现中被认为是有吸引力的结构。在这项研究中，通过碱催化的Claisen-Schmidt缩合反应设计并合成了吩噻嗪基Chalcones作为ChEs和MAOs抑制剂，并通过NMR和HRMS阐明了化合物的化学结构。化合物3和9对AChE酶显示出有希望的抑制潜能，IC 50值为0.221μM和0.053μM，而化合物9对MAO-B酶显示出显着的抑制潜能，IC 50值为0.048μM。化合物9作为双重靶标抑制剂，可选择性抑制AChE和MAO-B酶。这种有希望的行为是该化合物的优势，因为MAO-B和AChE抑制作用在阿尔茨海默氏病中起作用。融合的三环系统，例如吩噻嗪与查耳酮部分结合在一起，可作为多靶点配体，可能有助于科学家合理设计针对神经退行性疾病的新型先导化合物。
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