Synthesis and Biological Evaluation of <i>O</i><sup>6</sup>-Aminoalkyl-Hispidol Analogs as Multifunctional Monoamine Oxidase-B Inhibitors towards Management of Neurodegenerative Diseases
Ahmed H. E. Hassan,
Hyeon Jeong Kim,
Keontae Park,
Yeonwoo Choi,
Suyeon Moon,
Chae Hyeon Lee,
Yeon Ju Kim,
Soo Bin Cho,
Min Sung Gee,
Danbi Lee,
Jong-Hyun Park,
Jong Kil Lee,
Jong Hoon Ryu,
Ki Duk Park,
Yong Sup Lee
Affiliations
Ahmed H. E. Hassan
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
Hyeon Jeong Kim
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
Keontae Park
Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea
Yeonwoo Choi
Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea
Suyeon Moon
Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea
Chae Hyeon Lee
Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea
Yeon Ju Kim
Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea
Soo Bin Cho
Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea
Min Sung Gee
Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea
Danbi Lee
Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea
Jong-Hyun Park
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
Jong Kil Lee
Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea
Jong Hoon Ryu
Department of Oriental Pharmaceutical Science College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
Ki Duk Park
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
Yong Sup Lee
Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
Oxidative catabolism of monoamine neurotransmitters by monoamine oxidases (MAOs) produces reactive oxygen species (ROS), which contributes to neuronal cells’ death and also lowers monoamine neurotransmitter levels. In addition, acetylcholinesterase activity and neuroinflammation are involved in neurodegenerative diseases. Herein, we aim to achieve a multifunctional agent that inhibits the oxidative catabolism of monoamine neurotransmitters and, hence, the detrimental production of ROS while enhancing neurotransmitter levels. Such a multifunctional agent might also inhibit acetylcholinesterase and neuroinflammation. To meet this end goal, a series of aminoalkyl derivatives of analogs of the natural product hispidol were designed, synthesized, and evaluated against both monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B). Promising MAO inhibitors were further checked for the inhibition of acetylcholinesterase and neuroinflammation. Among them, compounds 3aa and 3bc were identified as potential multifunctional molecules eliciting submicromolar selective MAO-B inhibition, low-micromolar AChE inhibition, and the inhibition of microglial PGE2 production. An evaluation of their effects on memory and cognitive impairments using a passive avoidance test confirmed the in vivo activity of compound 3bc, which showed comparable activity to donepezil. In silico molecular docking provided insights into the MAO and acetylcholinesterase inhibitory activities of compounds 3aa and 3bc. These findings suggest compound 3bc as a potential lead for the further development of agents against neurodegenerative diseases.