Isoindolines and Isoindoline-1,3-diones as Nonpeptide ACE Inhibitors: An <i>In Silico</i> and <i>In Vitro</i> 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 <i>in silico</i> molecular docking studies and optimized <i>in vitro</i> inhibitory kinetic assays, along with acute toxicity tests in mice. isoindoline-1,3-dione, D-05, demonstrated the strongest ACE inhibition <i>in vitro</i> (IC₅₀ = 416.4 μM) and effectively bound to the enzyme's catalytic active site <i>in silico</i>. 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 <i>in vivo</i> studies to verify their antihypertensive effects.