Synthesis And Antibacterial Evaluation Of Novel3-MBA Derivatives Targeting PC-site Of FtsZ

The development of antimicrobial resistance among human bacterial pathogens has emerged as a major global public health concern. One of the most significant threats is the emergence and spread of multidrug-resistant (MDR) bacteria strains. Filamentary temperature-sensitive mutant Z (FtsZ) is considered to be one of the most important proteins of the bacterial cell division. FtsZ is structurally and functionally homologous to mammalian β-tubulin, which has been successfully exploited for cancer drug discovery. This suggests that FtsZ may also be amenable to antimicrobial inhibitor discovery. To date, a number of compounds have already been shown to block bacterial cell division through inhibition of FtsZ. However, few FtsZ inhibitors have potent antibacterial activity in vivo and none of them get into clinical research. PC190723, one of the alkyoxybenzamide (3-MB A) derivatives, was the first reported FtsZ inhibitor with in vivo efficacy.3-MBA has proven to be an attractive fragment-like starting point for FtsZ inhibitor discovery.In this thesis,3-MBA was selected as the starting point for new FtsZ inhibitor discovery. Based on the structure-activity relationship of3-MBA derivatives, combining the computer-aided drug design with the full consideration of the crystal structure of the SaFtsZ-PC190723complex (3VOB) and principle of bioisosteres, two kinds of3-MBA analogues with new skeleton were designed and synthesized. Our objective was mainly to explore its influence on their biological activity when we introduce benzene ring or heterocyclic ring in the4and5site of3-MBA.In this thesis, compounds of series1were synthesized from benzaldehyde, followed by6steps, such as Stobbe condensation, cyclization reaction, acetylation of naphthol, Williams ether synthesis et al. Compounds of series2were synthesized from gallic acid, followed by8steps, such as esterification reaction, protection of phenolic hydroxyl group, annulation, Williams ether synthesis et al.Oxacillin Sodium, linezolid and ciprofloxacin were selected as the positive control in this thesis. The biological activity of3key intermediates and17novel3-MBA derivatives were determined against four gram-positive bacteria and two gram-negative bacteria by MIC assay. Meanwhile, the on-target activity was determined by morphometric analysis. The results showed that most of the compounds showed little improvement in biological activity compared with3-MBA. However, the key intermediate ZE-A exhibit more than4-16fold higher activity than3-MBA in both biological activitiy and on-target activity against all the six bacteria. In addition, B1exhibit more than32fold higher activity than3-MBA in both biological activity and on-target activity against B. subtilis ATCC9372and A13exhibit more than4fold higher activity than DHBA in both biological activity and on-target activity against B. subtilis ATCC9372.Above all, the thesis mainly explored the biological activity and on-target activity of new3-MBA derivatives. The result showed when we introduce benzene ring or heterocyclic ring in the4and5site of3-MBA, the new compounds can bind more closely to the PC-site of FtsZ.It brought new thought to the discovery of new FtsZ inhibitors starting from3-MBA. Meanwhile, FtsZ was found to be an attractive target for the research and development of antibacterial drugs.