Computer-Aided Drug Design, Synthesis, and In Vitro Safety Evaluation of Carprofen Analogs for Novel Alzheimer's...

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and indomethacin, have reduced amyloid beta (Aβ) levels and improved cognitive function in mouse models of Alzheimer's disease (AD). The objective of the current research is to evaluate different NSAIDs using computer-aided drug design (CADD) to explore their potential as new treatments for AD. CADD is an advanced technique for designing biologically active molecules and involves two primary approaches: structure-based virtual screening and ligand-based virtual screening. After identifying the NSAID with the highest affinity for amyloid Aβ1-42 fibrils (PDB 2BEG), we designed analogs through bioisosteric modifications. Twenty derivatives were created, and two carprofen analogs with the most promising properties were synthesized, yielding 75% success with compound A-1 and 70% with compound A-2. These analogs exhibited lower predicted IC₅₀ values (1.57 μM) and more negative interaction energies (-6.43 and -6.67 kcal/mol for A-1 and A-2, respectively) compared to carprofen. Safety evaluations in L929 cells indicated that these compounds were safe at concentrations of 40 µM. In conclusion, two carprofen analogs were successfully designed and synthesized, demonstrating higher affinity for the amyloid Aβ1-42 fibrils, better-predicted IC₅₀ values than carprofen, and safety in the L929 in vitro assay.