Design, Synthesis And Evaluation Of New Monobactams Containing Siderophore Moieties As Antibacterial Agents Against Gram-negative Bacteria

In recent years, with the overuse and even abuse of antibiotics, an increasingly number of pathogenic bacteria became resistant to many commonly prescribed antibiotics. Infections caused by drug-resistant Gram-negative bacteria, have become global threats to public health. Even though a lot of efforts were made for the development of new antibiotics to treat drug-resistant Gram-negative bacteria infections, not much inspiring progress was gained. Therefore, there is an urgent need to develop new antibiotics and strategy to deal with the serious global antibiotic crisis.Aztreonam (Figure 1), which is the first and representative β-monobactam, has been used as a second-line antibiotic in the treatment of infections caused by Gram-negative bacteria. Recent years, highlighted by clinicians, Aztreonam plays an increasingly important role in the treatment of multidrug resistance (MDR) Gram-negative bacterial infections.BAL30072 (Figure 1), displayed potent activities against MDR Gram-negative organisms, which was developed by the Swiss Basilea Pharmaceuticals applying the Trojan Strategy, has entered the second Phase I clinic trials. The so called Trojan Strategy is that combining siderophores with antibiotics through appropriate linker to form Trojan conjugates. As siderophores could be selectively and specifically recognized and transported via bacterial iron acquisition system, the antibiotic part of conjugates will be positively transported into the bacteria by linking to siderophore, which could cause the death of bacteria. The success of BAL30072 makes monobactam back to research highlights again.Firstly, we applied the Trojan Strategy in this thesis. Aztreonam, Ampicillin and Cefadroxil were chosen as the antibiotic part to link with different sidrophores via linker to form Trojan conjugates.(1) Pyridoxal isonicotinoyl hydrazone (PIH) was a popular siderophore characterized by its simple structure, it could selectively and specifically tricoordinate with iron (Fe3+) and formed a PIH-Fe complex of high stability and low toxicity. Therefore, simplified PIH-like chelators which retained the core coordinate sites were designed and constructed as the new siderophores, which were then conjugated with AZN to form the corresponding novel AZN-PIH Trojan conjugates SA-48, SA-49, SA-54, SA-58, SA-52, SA-50.(2) Connecting the comformational mimic of Enterobactin with Ampicillin or Cefadroxil via succinamide as linker to offer Trojan conjugates H-12 and H-13.All of the 6 AZN-PIH conjugates displayed good antibacterial activities against most susceptible Gram-negative strains, especially for P. rettgeri with MICs value of ≤0.03-0.06 μg/mL. The 6 conjugates showed certain activities against drug-resistance Gram-negative strains. Compound SA-48 exhibited a reasonable potency against β-lactamase producing P.aeruginosa at MICs of 4-8 μg/mL.Secondly. Aztreonam was taken as the lead compound while retaining its aminothiazole fragment as a necessary pharmacophore for the activities against Gram-negative strains. A series of novel analogues were designed, synthesized by introducing the a new 4,4-dimethyl-β-lactam core and structural modification on the oxime side chain.(1) Introducing benzyl, pyridin-2-yl, and pyridin-3-yl on the side chain via substitution reaction offered target compounds SA-73, SA-82, SA-83.(2) Click Chemistry was firstly used in structural optimization of monobactam and efficiently produced target compounds SA-74A, SA-108, SA-101 which containning 1-substituted (methyl,1-cyclopropylmethyl and carbonylmethyl) 1,2,3-triazole group.According to the in vivo anti-bacterial essay, most generated target compounds except SA-73 displayed good potencies against susceptible Gram-negative strains. Analogs with lower ClogP value showed good activities against drug-resistance Gram-negative strains. Compounds SA-82, SA-83, SA-74A, SA-101 exhibited high potencies against ESBLs-produced E.coli MICs ranging from 2 μg/mL to 8 μg/mL.In summary, these results show that target compounds which introduced appropriate groups on the side chain while retaining the aminothiazole fragment and β-lactam core displayed good activities against susceptible Gram-negative strains. Introduction of hydrophilic groups on the side chain to lower the ClopP value might be beneficial to increase potency against drug-resistance Gram-negative bacteria. These results offered powerful information for further strategic optimization in search of the antibacterial candidates against MDR Gram-negative bacteria.In this thesis,34 new compounds (including 14 target compounds) were synthesized, and all of them were confirmed and characterized by MS, 1H NMR,13C NMR and HRMS. AZN-PIH conjugates and SA-74A/108/101 were prepared via a six-step convergent route with good yield. Parts of the work were submitted on ACS Med. Chem. Lett.