Design, Synthesis And Structure-activity Relationship Study For Small Molecular Peptidomimetics As Novel Peptide Deformylase Inhibitors

People’s life was severely threaten by pathogenic bacteria, and antibiotics were efficient therapeutic agents. Many infectious diseases such as smallpox, tuberculosis, meningitis, typhoid were cured by antibiotics. However, antibiotic-resistant bacteria was generated because the abuse of antibiotics and the situation of antibiotic-resistant bacteria was seriously worrisome until now. By contrast, there is no new antibiotics with novel mechanism in market during the last decade. This crisis has resulted in an intensive research effort to develop a new class of compounds that exhibit novel mechanisms of antibacterial activity.Peptide deformylase (PDF) inhibitor was a kind of antibacterial drug with novel mechanism. PDF is iron(11) ion containing metalloprotease, which play critical role in bacterial protein synthesis while it does not share close homology with any mammalian cell equivalent. PDF inhibitor prevent PDF from catalyzing the deformyl process during bacterial protein synthesis.Therefore, PDF inhibitor with novel mechanism might become a new therapeutic agent against bacterial infections.Thus far, two PDF inhibitors that underwent human clinical trials are BB83698(discovered by British Biotech, in collaboration with Genesoft) and LBM415(discovered by Vicuron pharmaceuticals, in collaboration with Novartis). In this dissertation, we designed two novel PDF inhibitors bearing3,4-dehydroproline or4-methyleneproline structure, and promoted a new route for PDF inhibitor synthesis. Screening antibacterial activities of serials of compounds to study structure-activity relationship(SAR) at different position. Preclinical study including broad-spectrum antibacterial activities, pharmacokinetics,50%effective dose(ED50), stability, solubility, lethal median dose(LD50) were evaluated in this dissertation. At last, we do the research on developing new method for synthesis of important fragment of PDF inhibitor.Chapter1is the short review of the research background including the development of antibiotics, the situation of drug-resistant bacteria, the importance of developing antibiotic with new mechanism, mechanism of PDF inhibitor and the current situation of PDF inhibitor, and the important role of peptidomimetics in the research of development of drugs.Chapter2is about the design and synthesis of novel PDF inhibitor containing3,4-dehydroproline motif. Because we can not get the novel compounds by the route which was used for synthesis of positive control LBM415, we promoted a new method based on the one used for synthesis LBM415, and obtain the final products successfully. Good to excellent antibacterial activities of these compounds were observed, minimum inhibit concentration(MIC) of the best one is0.125μg/ml against methicillin-resistant staphylococcus aureus ATCC43300, and it is better than most existing drugs such as Penicillin, Ciprofloxacin, Linezolid, Vancomycin. And we replaced motif at P1’ and P3’position to discovery the SAR of these compounds.In chapter3, we designed a serial of compounds bearing3-methylene pyrrolidine motif as novel PDF inhibitors, and synthesized these compounds by using the new route promoted by us. They also show good in vitro antibacterial activity against Gram-positive test strains. The SAR at P1’, P2’ and P3’position were explored by contrasting LBM415and novel PDF inhibitors we developed, and different SAR of antibacterial activity at P3’ position was observed between PDF inhibitors containing3,4-dehydroproline motif and the ones bearing3-methylene pyrrolidine motif.In chapter4, we test the good ones of the two novel PDF inhibitors for broad-spectrum antibacterial activities against the clinical isolated susceptive and resistant strains including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Haemophilus influenzae, Enterococcus faecalis, Enterococcus faecium, Moraxella catarrhalis, Escherichia coli, Streptococcus pyogenes, and they show good to excellent antibacterial activities against Gram-positive strains and moderate activities against Gram-negative strains. And we test ED50of the representative compound SW1210using the murine models of MRSA, and ED50of SW1210is6.253mg/kg (95%confidence limit is4.307-9.077mg/kg). To find the relation between the groups in R1, R2and R3position and pharmacokinetic parameters, we have six representative compounds to be tested, and find the absolute bioavailability of SW1201up to88.76%. Although SW2201shows (15.86±1.27)%inhibition against hERG potassium channel in10μM concentration, the rest of these six compounds show less to no inhibition. We do research on study of actue toxicity of SW2201, and find the LD50>250mg/kg.We study on developing new method for synthesis of important fragment of PDF inhibitor in chapter5. The method for construction of chiral center has been reported was inducing by Evans’auxiliary, even high ee value was obtained with this method, it has some disadvantages such as too much steps, low overall yield. We get the racemic product with5steps and about73%yield, and we are doing further study on chemical resolution. We also attempt to synthesis the fragment by catalytic asymmetric reaction such as asymmetric Mannich addition reaction between imine and silyl enol ether, Michael reaction, the first reaction obtain28%ee value catalyzed by (S)-BINOL/Zr. Further studies on the asymmetric synthesis are currently in progress.