Affiliation:
1. Institute of Chemical Sciences Bahauddin Zakariya University Multan Pakistan
2. Department of Chemistry Quaid‐i‐Azam University Islamabad Pakistan
3. Centre for Advanced Drug Research COMSATS University Islamabad, Abbottabad Campus Abbottabad Pakistan
4. Department of Pharmacy COMSATS University Islamabad, Lahore Campus Islamabad Punjab Pakistan
5. Department of Botany and Microbiology King Saud University Riyadh Saudi Arabia
6. Department of Chemistry COMSATS University Islamabad, Abbottabad Campus Abbottabad Pakistan
7. Department of Pharmaceutical & Medicinal Chemistry University of Bonn Bonn Germany
Abstract
AbstractAlzheimer's disease (AD) presents a multifactorial neurological disorder with multiple enzyme involvement in its onset. Conventional monotherapies fall short in providing long‐term relief, necessitating the exploration of alternative multitargeting approaches to address the complexity of AD. Therefore, the design, synthesis, and in vitro and in silico evaluation of 2‐oxoquinoline‐based thiosemicarbazones 9a–r as multipotent analogs, able to simultaneously inhibit the cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of AD, are reported. In the in vitro experimental evaluation of MAO and ChE inhibition, all tested compounds demonstrated remarkable potency exhibiting nonselective inhibition of both MAO‐A and MAO‐B, and selective inhibition of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE), with 9d, 9j, and 9m evolving as lead compounds for MAO‐A, MAO‐B, and AChE, displaying IC50 values of 0.35 ± 0.92, 0.50 ± 0.02, and 0.25 ± 0.13 μM, respectively. Moreover, the kinetic studies revealed that all tested compounds inhibited all three enzymes through a competitive mode of inhibition. Furthermore, the molecular docking studies of the most active compounds revealed several crucial interactions, particularly hydrogen bonding interactions. These interactions were observed between the nitrogen and sulfur atoms of thiosemicarbazone and the nitrogen and oxygen atoms of the quinoline ring with various amino acids, suggesting the strong interactions of these compounds with the enzymes.
Subject
Drug Discovery,Pharmaceutical Science