Design And Synthesis Of Novel Clinically Useful3-Hydroxypridine-4-One Derivatives

Since the birth of antibiotics, their excellent antibacterial effect brings the gospel to human being. However, with the emergence of drug resistant bacterial strains, the use of antibiotics has been increasingly restricted, which has become a global problem. Therefore, the development of novel antimicrobial agents not only has important social value, but also has broad market demand.Iron is an essential element to the growth of bacteria. The mechanism of the uptake of iron involves the secretion of a kind iron chelators, namely siderophores. It can compete with host cell to scavenge iron(Ⅲ). Therefore, we have designed and synthesized a series of3-hydroxypyridine-4-one iron chelators. These compounds can compete with siderophores to bind iron from the environment, thereby rendering the bacteria not to absorb sufficient iron, which leads to the bacterial inhibition or death.As a second generation of photodynamic therapeutic (PDT) agent, 5-ALA has been used to treat many kinds of cancer and condyloma acuminatum, which obtained satisfactory therapeutic effect since1996. The main drawback of ALA is the poor absorption by cells due to its high hydrophilicity, causing a low bioavailability. ALA is metabolized to produce the Protoporphyrin IX (PpIX) in the cytoplasm, the latter generated singlet oxygen under illumination and killed tumor cells. Ferrochelatase can catalyze protoporphyrin IX to form optical inactive haem. Inhibiting the enzyme activity can increase the cellular PpIX level, which can improve the therapeutic effect of drugs. Therefore, this thesis first innovative design and synthesize a range of ALA-HPO conjugates, which not only can solve the problem of absorption by cells, but also further enhance the efficacy of drug via the inhibition of ferrochelatase.The main results of this thesis are summarized as follows:1). A novel hexadentate3-hydroxylpyridine-4-one with high iron(Ⅲ) affinity was designed and synthesized. The pKa and pFe3+values are determined by spectrophotometric titration. In the presence of chloramphenicol, we found that this chelator had an appreciable inhibitory effect against Providencia stuartii and Staphylococcus aureus, with the bactericidal rates of85.4%and61%respectively ([7]=60μg/mL,[chloramphenicol]=0.8μg/mL).2). We designed and synthesized two groups of hexadentate3-hydroxyl-pyridine-4-ones using maltol as a starting material. The inhibition zone test was employed to evaluate the antibacterial activity. The result indicated that the compounds exhibited variable antibacterial activity, while all compounds were found to show stronger inhibition against Bacillus subtilis and Pseudomonas aeruginosa than DTPA3). Using5-aminolevulinic acid methyl ester hydrochloride as a starting material, through amidation and esterification, we synthesized2series of and totally153-hydroxypyridine-4-one-ALA conjugates, providing the foundation for further investigation of their anti-tumor activity...