Design and Synthesis of Novel Bioactive Squamolone Derivatives Targeting Carbonic Anhydrase and Acetylcholinesterase Enzymes.

A new series of squamolone-based γ-lactam derivatives (SQ1a-SQ1l) was rationally designed, synthesized, and structurally confirmed via FT-IR, NMR, and HRMS analyses. The synthesized compounds were evaluated for their inhibitory potential against human carbonic anhydrase isoforms I and II (hCA I and hCA II) and acetylcholinesterase (AChE), enzymes implicated in a range of pathological conditions including glaucoma, epilepsy, cancer, and Alzheimer's disease. Several derivatives demonstrated potent nanomolar inhibition, notably SQ1g against hCA I (K i = 17.99 ± 8.31 nM), SQ1c against hCA II (K i = 31.41 ± 10.26 nM), and SQ1b against AChE (K i = 0.35 ± 0.16 nM). Molecular docking studies corroborated the experimental findings, revealing key hydrogen bonding and hydrophobic interactions within the active sites of each enzyme. Furthermore, DFT-based HOMO-LUMO and molecular electrostatic potential (MEP) analyses provided insight into the compounds' electronic and reactive properties. In silico pharmacokinetic profiling using SwissADME tools showed that several compounds possessed favorable oral bioavailability, lipophilicity, and metabolic stability. Among them, SQ1g emerged as the most promising multitarget candidate due to its superior enzymatic activity, drug-like properties, and favorable docking profile. Collectively, these results highlight Squamolone as a versatile pharmacophore for the development of multifunctional enzyme inhibitors with therapeutic potential in neurodegenerative, oncological, and ophthalmological disorders, thereby supporting United Nations Sustainable Development Goal 3 (UN SDG3, Good Health and Well-being) through the advancement of innovative therapeutic agents for major human diseases.