Synthesis, biological evaluation, and pharmacokinetic profiling of benzophenone derivatives as tumor necrosis factor-alpha and interleukin-6 inhibitors

A new series of benzophenone derivatives are reported with comparative less toxicity with qualifying pharmacokinetic profiles. They were synthesized by Fridel-Craft acylation and evaluated for their anti-inflammatory activity (against Tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6)) by LPS-induced cytokine production assay (phorbol myristate acetate stimulated human THP-1 cells in vitro). The screened compounds exhibited promising activity against IL-6 in a range of 63-82% at 10 mu M concentration. Cytotoxicity was also determined by using CCK-8 cells at 10 mu M. The synthesized benzophenone derivative 1c was not cytotoxic in CCK-8 cells up to the concentration of 100 mu M and showed potent IL-6 inhibitory activity with IC50 of 0.19 mu M. With few exceptions, all other compounds were found to be moderate inhibitors of TNF-alpha. In silico, pre-lead prioritization of the leads was performed using QikProp 3.2, qualifying them for further study.