Design, Synthesis And SAR Studies Of Novel Gram-negative Agents

With the extensive use of antimicrobial agents, the emergence of multidrug-resistant strains is becoming a serious threat to public health. Especially, infections caused by Gram-negative bacteria pathogens are more difficult to control. Therefore, the need for new and safe antibacterials active against Gram-negative bacteria is very critical. However, only a few novel Gram-negative agents are at early stages of clinical research;Lipid A is an important component of the Gram negative bacterial outer membrane, which can prevent the bacterium from obstruction of antibiotics, and LpxC which catalyzes an committed step in the biosynthesis pathway of lipid A is highly conserved among many kinds of Gram-negative bacteria. It was reported that inhibition of LpxC may lead to death of bacteria. Thus, research on LpxC inhibitors has been an appealing area in the study of novel Gram-negative agents. In the search for new Gram-negative agents with the advantage of broad-spectrum and low toxicity, we designed and synthesized 20 compounds on the basis of CHIR-090.Firstly, we studied novel inhibitors of LpxC with five different "teminus", and compound 1 which exhibited the best antibacterial activity deserved to research. We then looked to optimize the activity of compound 1 through modification of phenyl groups and amino acid groups. Finally, compound 9 which exhibited antibacterial activities to CHIR-090 was prepared.Many LpxC inhibitors have problems in metabolism.Thus, the balance of antibacterial activity and metabolic properties is a big challenge to develop novel LpxC inhibitors. The terminal methylsulfone which is a steady group for metabolism was introduced into the LpxC inhibitors, then hydrophobic tails with different length were synthesized to match the hydrophobic tunnel. Systematic optimization of two locales on the scaffold provided compounds 12,14 and 15 with better Gram-negative activity. Finally, I sought to improve the Gram-negative activity further by modifying the amino acid groups. The metabolic stability of compounds 14 and 15 which showed the best antibacterial activities was evaluated. In addition, compounds 14 and 15 with comparable antibacterial activities to CHIR-090 and better metabolic stability than CHIR-090 were acquired, indicating that the terminal methylsulfone may be an excellent structure in the design of novel LpxC inhibitors.