Design, Synthesis And Antibacterial Evaluation Of 4-Bromo-1H-Indazole Derivatives Targeting FtsZ

Bacterial infections pose a constant and serious threat to human health, and the emergence and prevalence of bacterial resistance around the world have aggravated this kind of threat. Therefore, there is a top priority for the reserch and development antimicrobial agents with a new mechanism against resistant bacterial infections. Filamentary temperature-sensitive mutant Z (FtsZ), an essential bacterial cell division protein, is highly conserved and plays an important role in bacterial cell division, so it is considered to be a very promising target for antibacterial agents with new mechanism of action.5-Substituted 1-phenylnaphthalene has been found to be the pharmacophore fragment of sanguinarine, chelerythrine and deirivatives. In addition, several 5-substituted 1-phenylnaphthalene derivatives have exerted marked antibacterial activity against methicillin-resistant S. aureus with minimum inhibitory concentration (MIC) values from 0.5 to 4.0 μg/mL. Moreover, FtsZ polymerization results have suggested that the antibacterial activity of the phenylnaphthalenes is associated with their stimulatory impact on the dynamics of FtsZ polymerization. Hydrophobic functionality at the 1-position is beneficial to antibacterial activity. Therefore, we designed and synthesized a novel of 4-bromo-1H-Indazole derivatives including 30 derivatives of three series through replacing the naphthalene and phenyl group of 5-substituted 1-phenylnaphthalene with the indazole and bromine group, respectively, on the basis of the principle of biososterism.All the target compounds and 3-MBA, curcumin (CUR), oxacillin sodium, linezolid, ciprofloxacin were evaluated for their in vitro antibacterial activity and on-target activity through the broth microdilution method. The results were summarized as below.(1) The derivatives of series A exhibited better antibacterial activity against S. epidermidis and S. pyogenes PS than the other tested strains. A majority of A-B series showed superior or comparable antibacterial activity against B. subtilis ATCC9372 compared to 3-MBA, oxacillin sodium and linezolid. Half of A-B series demonstrated imporved antibacterial activity against S. aureus ATCC25923 compared with 3-MBA and CUR, but weaker activity than oxacillin sodium, ciprofloxacin and linezolid. Some of A-B series exhibited more important antibacterial activity against S. aureus ATCC29213, S. aureus PR and S. epidermidis than references. Most of A series displayed enhanced or comparable antibacterial activity against E.coli ATCC25922 compared to CUR, oxacillin sodium and linezolid. Compounds of A series displayed generally highly antibacterial activity compared with B and C series of compounds.(2) Among all the target compounds, compound A1l displayed the best antibacterial activity with an MIC value of 4 μg/mL against S. pyogenes PS, showing over 32-fold,1024-fold and 2-fold better activity than 3-MBA, curcumin and ciprofloxacin, respectively, but it was 4 times less active than oxacillin sodium and linezolid. Compounds A14 and B14 exhibited the most potent activity against S. aureus PR (MIC=16μg/mL), which was 256-fold,256-fold,8-fold and 8-fold better than 3-MBA, CUR, oxacillin sodium and ciprofloxacin, respectively. Compound B14 also showed the strongest activity against S. aureus ATCC29213, being 64-fold, 128-fold,4-fold and 4-fold more potent than 3-MBA, CUR, oxacillin sodium and linezolid. A25 displayed the best antibacterial activity against B. subtilis ATCC9372 and S. pyogenes PR, showing 128-fold better than CUR against S. pyogenes PR.(3) Half of A-B series demonstrated improved cell division inhibitory activity against E.coli ATCC25922 compared to CUR. Compounds A11, B12, B23 and B33 showed more potent cell division inhibitory activity against S. aureus ATCC25923 than 3-MBA and CUR. Compounds B12, B14, B23 and B24 displayed better cell division inhibitory activity against B. subtilis ATCC9372 than 3-MBA.Structure-activity relationships (SARs) of 4-bromo-1H-Indazole derivatives were conclusively analysised as below.(1) Core structure of target compounds was 4-bromo-1H-indazole, which was obviously different from references and showed moderate activity against mang bacteria. It generally displayed significantly improved activity compared to CUR and 3-MBA, and displayed slightly improved activity against certain bacteria compared to other references.(2) The introduction of amino side chains at the 1-position of 4-bromo-1H-indazole enhanced the polarity of componds, which were beneficial to the antibacterial activity against Gram-positve and Gram-negative bacteria, and the length of the linkages had almost no effect on the antibacterial activity. Their antibacterial activity against Gram-positve bacteria was better than antibacterial activity against Gram-negative bacteria. Minority compounds demonstrated improved cell division inhibitory activity against the tested strains, the length of the linkages affected on-target activity. These demonstrated that amino side chains at the 1-position of the indazole were beneficial to the antibacterial activity, the length of the linkage had almost no effect on the antibacterial activity and amino side chains were unobvious for on-target activity, the length of the linkage impacted on-target activity.(3) The introduction of carbonyl groups at the 1-position of 4-bromo-1H-indazole, many compounds displayed differently improved on-target activity,but were slightly improved on antibacterial activity. Compounds bearing hydroxycarbamoyl groups exhibited better antibacterial activity against Gram-positve and Gram-negative bacteria than other comounds.(4) The introduction of lipid solubility benzyl group at the 1-position of 4-bromo-1H-indazole did not increase the antibacterial activitiy and on-target activitiy. The change of groups at different position of benzyl also had no effect on antimicrobial activitiy and on-target activitiy.In conclusion,4-bromo-1H-Indazole derivatives targeting FtsZ were designed and synthesized, their structures were confirmed by MS and NMR spectrum analysis method, their in vitro antibacterial activity and on-target activity were evaluated by the broth microdilution method, and their SARs were analyzed. Antibacterial activity of compounds was consistent with their on-target activity. The research of this paper provides a new train of thought and a lead compound for the research and development of FtsZ inhibitors.