Synthesis And Bioactive Evaluation Of N-phenylnicotinamides Derivatives And Urea Derivatives From O-hydroxybenzylamines And Phenylisocyanate

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain and inflammatory diseases. The clinical efficacy of most NSAIDs is closely related to their inhibition of cyclooxygenases (COXs), which exists in two distinct isoforms, a constitutive form (COX-1) and an inducible form (COX-2). It is reported that inhibition of COX-1alone is not sufficient to induce gastric damage. Therefore, COX-1-selective inhibitors are anticipated to be candidates as novel analgesic agents with reduced gastroenteric disturbance.Herein, we designed a series of N-phenylnicotinamides (1-40) and evaluated in vitro for their COX inhibitory activities. Most of the synthesized compounds were proved to be potent and selective inhibitors of COX-1. Compound28showed the most potent COX-1inhibitory activity (COX-1IC50=0.68±0.07μM) and good selectivity (COX-2IC50>100μM). This compound may be useful as a lead compound for superior COX-1inhibitors. On the basis of the biological results, structure-activity relationships for the COX-1-inhibitory activities of the synthesized N-phenylnicotinamides were discussed concisely.The multi-drug resistance to most of all antibiotics has become a serious medical problem. An attractive target is β-ketoacyl-acyl carrier protein synthase III (FabH), which is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and Gram-negative bacteria.O-Hydroxy diphenyl ethers is widely used as effective broad-spectrum antibiotic, and its molecular fragment "o-hydroxyphenyl" shows favorable biological activity.Herein, a series of o-hydroxybenzylamines1-16and its corresponding new urea derivatives17-32were synthesized and fully characterized by spectroscopic methods and elemental analysis. This new urea derivatives class demonstrates strong antibacterial activity. Compounds18and20displayed most potent activity with MIC values of both1.56μg/mL against E. coli ATCC35218, which were superior to the positive control kanamycin B. The E. coli FabH inhibitory potency was examined and compounds18and20showed potent inhibitory activity with IC50of6.6μM and4.7μM, respectively. Preliminary structure activity relationships and molecular modeling study provided further insight into interactions between the enzyme and its ligand. The results provided valuable information for the design of E. coli FabH inhibitors as antibiotics.