Design,Synthesis And Antibacterial Evaluation Of 5-Methyl Phenanthridium Derivatives Targeting FtsZ

Bacterial infection has been being a serious threat to human health,and with the emergence and spread of bacterial resistance,this threat is becoming more and more harmful.Consequently,antibacterial agents with novel mechanisms and targeting novel targets should be quickly developed to effectively control the spread of multi-drug resistant bacteria.Filamentary temperature-sensitive protein Z(FtsZ),an essential bacterial cell division protein that is highly conserved,plays an important role in bacterial cell division.Therefore,it is considered to be a very promising target for novel antibacterial agents,which has been widely concerned.Phenzophenanthridine is structural truncated form of sanguinarine and chelerythrine.Many phenzophenanthridine derivatives have been synthesized based on the structural truncated form,showing good antibacterial activity as FtsZ inhibitors.Therefore,it is possible to develop more effective FtsZ inhibitors by simplifying the structure of benzophenanthridine.5-Methylphenanthridine was found through simplification and docking of the structure of phenzophenanthridine by using computer aided drug design software.The quaternary ammonium salt in the structure of 5-methylphenanthridine could bind to the tail of the GTP binding pocket of FtsZ and the aromatic ring could interact with Gly46,Gly47 and Ala48 amino acids mainly through hydrophobic effects.Therefore,5-methylphenanthridine was selected as a lead structure for structural modificatoin.On the basis of the GTP binding pocket of FtsZ,3 series of 5-methylphenanthridine derivatives,a total of 22 new compunds,were designed and synthesized.The new compounds were evaluated for their in vitro antibacterial activity and cell division inhibitory activity by using sanguinarine,curcumin,ciprofloxacin and oxacillin sodium as positive control drugs.The results were summarized as below:(1)5-Methylphenanthridine derivatives showed good antibacterial activity against B.subtilis ATCC9372,S.aureus PR,S.pyogenes PS and S.pyogenes PR,some of them being better than sanguinarine.In contrast,they exihibited poor antibacterial activity against S.aureus ATCC25923,S.aureus ATCC29213 and S.epidermidis and had even no activity against E.coli ATCC25922 and P.aeruginosa ATCC27853 under the experimental conditions.The 5-methyl phenanthridine derivatives showed similar trends in in vitro antibacterial activity and cell division inhibitory activity.(2)Compounds 5A5,5A6,5A8,5B1,5B3,5B6,5C1 and 5C2 showed the stronggest antibacterial activity against B.subtilis ATCC9372(MIC = 4 μg/mL),2 fold better than sanguinarine,ciprofloxacin and oxacillin sodium while compounds 5A4,5A7,5A11,5B2,5B4,5B7,5C3 and 5C4 displayed the same antibacterial activity against B.subtilis as sanguinarine,ciprofloxacin and oxacillin sodium(MIC =8 μg/mL).(3)Compounds 5A5,5A6,5B1,5B6,5C1 and 5C2 showed the greatest antibacterial activity against S.aureus ATCC29213(MIC = 4 μg/mL),the same as sanguinarine,compound 5B3 had potent antibacterial activity against S.aureus ATCC25923(MIC = 8 μg/mL),similar to sanguinarine and oxacillin sodium,and compound 5B7 showed antibacterial activity against S.aureus ATCC29213(MIC =16 μg/mL).(4)Most of the target compounds exhibited antibacterial activity against S.pyogenes PS and S.pyogenes PR,better than or similar to sanguinarine.In addition,on the basis of the above results,preliminary structure-activity relationships(SARs)of the 5-methylphenanthridine derivatives were summarized as below:(1)Introduction of alkyl side chains to the 2-position of 5-methylphenanthridine generally increased the antibacterial activity and on-target activity,and the straight alkyl side chains were better than the branch ones in the above activity.Introduction of methoxy and methylthio groups to the 2-position retained the antibacterial activity and on-target activity while introduction of halogen,trifluoromethyl and trifluoromethoxy groups to the 2-position decreased the above activity.(2)Introduction of alkyl groups such as methoxy,trifluoromethoxy and methylthio groups to the 4-position of 5-methylphenanthridine retained or slightly enhanced the antibacterial activity and on-target activity while introduction of trifluoromethyl group to the 4-position decreased the above activity.(3)Introduction of alkyl groups to the 2-and 4-positions of 5-methylphenanthridine didn’t increased the antibacterial activity but enhanced slightly the on-target activity.In this thesis,taking FtsZ as antibacterial target,the structures of natural FtsZ inhibitors sanguinarine and chelerythrine were simplified and optimized.Based on the selected 5-methylphenanthridine as the lead structure for structural modification,3 series of 5-methylphenanthridine derivatives were designed,synthesized and evaluated for their in vitro antibacterial activity against 9 kinds of bacteria and on-target activity.Their SARs were analyzed.In view of the above results,5-methylphenanthridine derivatives are considered as lead compounds for further optimization in order to find new FtsZ inhibitors.Therefore,the research results presented in this thesis will provide new ieads and methods for design and synthesis of new FtsZ inhibitors...