Synthesis and In Silico Evaluation of the Ninhydrin Derivatives Interaction with Target Proteins Involved in Cancer Pathogenesis and Progression

Ninhydrins represent a promising chemical space for the search for new biologically active molecules with antimicrobial, antiprotease, and antitumor properties. In the present work, new ninhydrin derivatives were synthesized, and for the first time, a systematic in silico study of ninhydrins as multitarget ligands for five pharmacologically significant targets (HER1/HER4, HER2/HER3, Trk-B, PPAR-α, and LTβR) was conducted, whose amplification or overexpression plays a key role in the pathogenesis and progression of certain aggressive cancer types. Among the studied ninhydrin derivatives, compound 1 (2,2-dihydroxy-5,6-dimethoxy-1H-indene-1,3(2H)-dione) stands out as the most potentially active molecule. It exhibits high affinity for HER1/HER4, Trk-B, and PPAR-α, opening up potential applications in oncology (HER family and Trk-B inhibition during BDNF overexpression), neurodegenerative diseases (Trk-B modulation), and metabolic disorders (PPAR-α activation). Compound 4 (2,2-Dihydroxy-5-trifluoromethylindane-1,3-dione) is a leader in LTβR binding and also holds promise for immuno-oncology and anti-inflammatory strategies.