Pharmacochemical Study of Multitarget Amino Acids' Hybrids. Design, Synthesis, In vitro, and In silico Studies.

Neuro-inflammation is a complex phenomenon resulting in several disorders. ALOX-5, COX-2, pro-inflammatory enzymes, and amino acid neurotransmitters are tightly correlated to neuro- inflammatory pathologies. Developing drugs that interfere with these targets will offer treatment for various diseases. Herein, we extend our previous research by synthesizing a series of multitarget hybrids of cinnamic acids with amino acids recognized as neurotransmitters. The synthesis was based on an in silico study of a library of cinnamic amide hybrids with glycine, γ- aminobutyric, and L - glutamic acids. Drug-likeness and ADMET properties were subjected to in silico analysis. Cinnamic acids were derived from the corresponding aldehydes by Knoevenagel condensation. The synthesis of the amides followed a two-step reaction with 1-hydroxybenzotriazole monohydrate and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in dry dichloromethane and the corresponding amino acid ester hydrochloride salt in the presence of N,N,-diisopropyl-Nethylamine. The new compounds, such as lipoxygenase, cyclooxygenase-2, lipid peroxidation inhibitors, and anti-inflammatories, were tested in vitro. The compounds exhibited LOX inhibition with IC50 values in the low μM region. Compounds 18a, 23b, and 11c are strong lipid peroxidation inhibitors (99%, 78%, and 92%). Compound 28c inhibits SLOX-1 with IC50 =8.5 μM whereas 11a and 22a highly inhibit COX-2 (IC50 6 and 5 μM). Hybrids 14c and 17c inhibit both enzymes. Compound 29c showed the highest anti-inflammatory activity (75%). The in silico ADMET properties of 14c and 11a support their drug-likeness.