Exploring the Synthesis, Anti-Inflammatory and Anti-Tumor Potential of 4-Maleimidylphenyl-Hydrazide Derivatives

The design of innovative compounds displaying anti-inflammatory activity in oncological context is a subject of great interest in drug development. It has been proved that a pro-inflammatory microenvironment which accelerates cancer growth and cellular differentiation is often present in malignant bladder tumor. In earlier work, we reported the synthesis of <i>p</i>-aminobenzoic acid derivatives that act as anti-inflammatory compounds able to inhibit the pro-inflammatory markers present in bladder cancer microenvironment. <b>DAB-1</b> rapidly emerged as an effective lead candidate in this investigation, with its ability to shrink by 90% in 25 days the size of human bladder cancer tumors in an ectopic mouse model. This manuscript discloses the synthesis of 23 new hydrazide derivatives of <b>DAB-1</b> and reports their in vitro and in vivo biological evaluation. It was discovered that most of the new compounds are essentially nontoxic against RAW 264.7 cells, as evaluated by an MTT assay. Anti-inflammatory activity of the new derivatives was investigated by evaluation of their impact on cellular nitric oxide production, measured by a Griess assay. Some compounds did significatively inhibit nitric oxide production much more effectively than the original <b>DAB-1</b>. Striking activity of <b>14</b>, which is around four times more potent than <b>DAB-1</b>, promotes this derivative as new lead compound in this study. The study of these analogs reveals that a phenolic/anisole core is a key component to achieve high biological activity. Furthermore, mice models of acute inflammation and invasive BCa tumors were used to assess the in vivo impact of derivative <b>14</b>, and it was found that this compound does reduce inflammation in these mice, possess similar anti-inflammatory activity but higher anti-tumoral activity compared to <b>DAB-1</b> with no apparent signs of toxicity.