Design of novel 4-maleimidylphenyl-hydrazide molecules displaying anti-inflammatory properties: Refining the chemical structure

Abstract

The discovery of new drugs possessing multiple biological properties in a single molecular entity is a subject of considerable scrutiny by the scientific community. This strategy can lead to better drug candidates for the treatment of many diseases, including cancer. In our quest for a more efficient bladder cancer treatment, we recently identified a compound readily accessible from para-aminobenzoic acid that showed anti-inflammatory, anti-metastatic as well as anticancer activities. This unique compound called DAB-1 can reduce the size of a tumor in an animal model by 90% within 25 days without apparent side effects. Its structure was modified to provide the molecule 2, a second-generation molecule named DAB-2-28, with enhanced in vitro and in vivo biological properties compared to DAB-1. The prospect of lead optimization is significant. This manuscript describes the synthesis of 2 as well as several higher analogs and reports on their anti-inflammatory activity in addition to their in vitro biological potential against bladder cancer. Amongst the results, it was discovered that the substitution pattern on the hydrazide core significantly affects the anti-inflammatory potential of the molecules. In fact, all the mono-acylated hydrazide derivatives 1, 5, 7, 9 were highly effective inhibiting the production of NO measured by the Griess reagents. By using the MTT assay, the same products displayed slightly lower toxicity (average 90% cell viability) on murine bladder cancer MB49-I cells in comparison to the reference DAB-1 molecule (85%). The best mono-acylated derivative 1 showed about 83% NO production inhibition level in relation to the relative number of viable/proliferating cells, the results are disclosed herein.

Keywords

• Hydrazide derivatives
• Acylation reaction
• SAR study
• Anti-inflammatory
• Nitric oxide
• Bladder cancer