Background: Phenolic Mannich bases have been reported as acetylcholinesterase (AChE) inhibitors for the medication of Alzheimer's disease. Carbonic Anhydrases (CAs) are molecular targets for anticonvulsant, diuretic and antiglaucoma drugs in the clinic. Phenolic compounds have also been mentioned as CA inhibitors. The importance of Mannich bases in drug design inspired our research group to design novel phenolic Mannic bases as potent enzyme inhibitors.

Objective: In this study, novel Mannich bases, 1-(3,5-bis-aminomethyl-4-hydroxyphenyl)-3-(4- substitutedphenyl)-2-propen-1-ones (1-9), were designed to discover new and potent AChE inhibitors for the treatment of Alzheimer's disease and also to report their carbonic anhydrase inhibitory potency against the most studied hCA I and hCA II isoenzymes with the hope to find out promising enzyme inhibitors.

Methods: Mannich bases were synthesized by the Mannich reaction. The structures of the compounds were elucidated by 1H NMR, 13C NMR, and HRMS. Enzyme inhibitory potency of the compounds was evaluated spectrophotometrically towards AChE, hCA I and hCA II enzymes.

Results and Discussion: The compounds showed inhibition potency in nanomolar concentrations against AChE with Ki values ranging from 20.44±3.17 nM to 43.25±6.28 nM. They also showed CAs inhibition potency with Ki values in the range of 11.76±1.29-31.09±2.7 nM (hCA I) and 6.08 ± 1.18-23.12±4.26 nM (hCA II). Compounds 1 (hCA I), 5 (hCA II), and 4 (AChE) showed significant inhibitory potency against the enzymes targeted.

Conclusion: Enzyme assays showed that Mannich derivatives might be considered as lead enzyme inhibitors to design more selective and potent compounds targeting enzyme-based diseases.

背景：据报道，酚类曼尼希碱是用于治疗阿尔茨海默氏病的乙酰胆碱酯酶（AChE）抑制剂。碳酸酐酶（CAs）是临床上抗惊厥药，利尿药和抗青光眼药物的分子靶标。酚类化合物也被提及作为CA抑制剂。曼尼希碱在药物设计中的重要性激发了我们的研究小组设计新颖的酚类曼尼尼碱作为有效的酶抑制剂。

目的：在本研究中，设计了新型曼尼希碱1-（3,5-双-氨基甲基-4-羟基苯基）-3-（4-取代苯基）-2-丙烯-1-酮（1-9）发现了用于治疗阿尔茨海默氏病的新型有效AChE抑制剂，并报告了它们对大多数研究过的hCA I和hCA II同工酶的碳酸酐酶抑制能力，以期找到有希望的酶抑制剂。

方法：通过曼尼希反应合成曼尼希碱。通过1 H NMR，13 C NMR和HRMS阐明了化合物的结构。用分光光度法评估了化合物对AChE，hCA I和hCA II酶的酶抑制能力。

结果与讨论：该化合物在纳摩尔浓度下对AChE表现出抑制作用，Ki值为20.44±3.17 nM至43.25±6.28 nM。他们还显示了CA抑制效力，Ki值在11.76±1.29-31.09±2.7 nM（hCA I）和6.08±1.18-23.12±4.26 nM（hCA II）范围内。化合物1（hCA I），5（hCA II）和4（AChE）对目标酶表现出显着的抑制作用。

结论：酶分析表明，曼尼希衍生物可被视为主要的酶抑制剂，以设计针对酶类疾病的更具选择性和更强效的化合物。