Synthesis and Evaluation of Anti-Inflammatory and Antitumor Activities of Carboxyflavanone Derivatives

Synthetic analogues of natural flavonoids have attracted attention by enhancing the bioactivity of flavonoids for the prevention and treatment of several human pathologies. In this study, carboxyflavanone derivatives were synthesized and ADMET predictions were used to assess the pharmacological profile and toxicity risks of these derivatives. The in silico evaluations are described as favourable for all compounds, in terms of biological efficacy. Carboxyflavanones have thus been evaluated for their anti-inflammatory activities on NO production in LPS-induced RAW 264.7 macrophages, and their antitumor activities against K562 chronic myeloid leukemia and HCT116 colon carcinoma cell lines. The structure-activity relationship of these derivatives was investigated by the presence of carboxyl groups at the 2, 3, and 4 positions of the flavanone B ring and by the introduction of different substituents (methyl, methoxy, bromine and aromatic cycle) in different positions on the A ring. The strongest anti-inflammatory activities were observed for compounds 4F (2′-carboxy-6-methylflavanone), 4G (2′-carboxy-7-methylflavanone), and 4H (2′-carboxy-7-methoxyflavanone), respectively. Interestingly, compounds 4F and 4G also showed the highest cytotoxicity against K562 and HCT116 cancer cell lines, along with compounds 4A (flavanone) and 4B (2’-carboxyflavanone). Since relocating the carboxyl group to positions 3’ and 4’ abrogated the bioactivity, these results indicate that the presence of the carboxyl group specifically at the ortho position of the B ring, alone or in combination with a methyl group at positions 6 or 7 of the A ring, significantly enhance bioactivity. This new SAR study thus identified favorable improvement for the development of novel anti-inflammatory and antitumor agents.