Isoindolines and Isoindoline-1,3-diones as Nonpeptide ACE Inhibitors: An In Silico and In Vitro Modeling Approach

Hypertension, a major cardiovascular risk factor, is often treated with peptide-derived angiotensin-converting enzyme inhibitors (ACEi), which can have several side effects. This study examined a new alternative: isoindoline and isoindoline-1,3-dione derivatives as nonpeptide ACE inhibitors. The synthesis and testing of these compounds involved both in silico molecular docking studies and optimized in vitro inhibitory kinetic assays, along with acute toxicity tests in mice. isoindoline-1,3-dione, D-05, demonstrated the strongest ACE inhibition in vitro (IC₅₀ = 416.4 μM) and effectively bound to the enzyme's catalytic active site in silico. Additionally, isoindoline-1,3-diones showed lower toxicity in mice (LD₅₀ > 1600 mg/kg) compared to isoindolines (LD₅₀ < 1000 mg/kg). This reduced toxicity is attributed to the presence of fewer reactive secondary metabolites. These promising results highlight the potential of isoindoline-1,3-diones as innovative nonpeptide ACE inhibitors and support further in vivo studies to verify their antihypertensive effects.