Synthesis of novel amides, characterization by spectrometric methods, cytotoxic activity and theoretical calculations

Photosantonic acid (2), produced by photochemical reaction of α-santonin (1), was converted into eighteen alkyl and aryl amides. These compounds were characterized by the spectrometric methods and evaluated for their cytotoxic activity against a human T-leukemia cell line (Jurkat). Quantum-chemical calculations at B3LYP/6-31G(d) level of theory were performed to explore the structure-cytotoxic activity relationships (SAR) of α-santonin (1) and its derivatives. The most active compound 19 presented the highest energy of HOMO (highest occupied molecular orbital), being the most nucleophilic of all evaluated structures. The calculations showed also that compound 19 is the most reactive, least stable and most polarizable of all amides evaluated. The polar surface area (PSA), which is an important parameter in structure-activity relationship studies, presented a correlation coefficient (r2) of 0.61 with the percentage of reduction of viable Jurkat cells at 30 μM of the most active compounds.