Design And Synthesis Of Novel Quinazolone Vinylazoles And Their Antimicrobial Study

The increasing bacterial resistance seriously threatens human health and deteriorates the efficacy of existing antibiotics,so it is urgent to develop new broad-spectrum antibacterial agents with high efficacy and low toxicity to combat drug-resistant bacterial infections.With a similar structure to the antibacterial quinolones,quinazolones are expected to exert similar antibacterial effects as well as to avoid toxic side effects caused by carboxylic acid at C-3 position of quinolones.The diverse biological activities of quinazolones in the field of medicinal chemistry and successful applications in clinical practice provide hope for their use as antibacterial drugs.Moreover,the widespread clinical application of azoles demonstrates the antibacterial potential of azoles and their significant status in antibacterial medicine.Hence,based on the research trends of quinazolones in antibacterial field and the research foundation of our subject group about azole antimicrobials,three series of new antibacterial quinazolone vinylazoles were designed and synthesized including: novel quinazolone vinyl imidazoles,quinazolone vinyl thiazoles and quinazolone vinylcyano azoles.The structures of the new compounds were confirmed by NMR and HRMS spectra,the antibacterial activities were tested and structural optimization was carried out.The highly active compounds were further investigated for preliminary druggability and antibacterial mechanism,which provided a foundation for the development of quinazolone vinylazoles as antibacterial drug candidates.The main research work is summarized as follows:First,thirty novel quinazolone vinyl imidazoles were synthesized by multistep reactions including cyclization,substitution and condensation starting from anthranilic acid or anthranilamide.The antibacterial activity evaluation found that some target compounds showed good antibacterial activity against the tested bacteria,especially7-fluoroquinazolone cyclohexyl imidazole II-17 a could effectively inhibit the growth of Escherichia coli ATCC 25922(MIC = 0.002 m M),which was 12 times more active than norfloxacin.The highly active II-17 a possessed low hemolytic activity,low drug resistance and rapid bactericidal capacity.Further antibacterial mechanism exploration found that II-17 a could increase the permeability of bacterial membrane and depolarization,leading to membrane damage and intracellular protein leakage.Highly active target molecule II-17 a might insert into bacterial DNA or bind to bacterial DNA gyrase and topoisomerase IV,which also inhibit the expression of bacteria associated genes,thereby hindering DNA replication.Furthermore,II-17 a could promote antibacterial potency by inducing bacterial oxidative stress and metabolic inactivation.The above results suggested that the novel highly active quinazolone vinyl imidazoles were expected to further develop a novel class of multi-target antibacterial drugs to cope with multi-drug resistant bacterial infections.In view of the good antibacterial activity of the new quinazolone vinyl imidazoles,sixteen novel antibacterial quinazolone vinyl thiazoles analogues were further synthesized by substituting imidazoles with thiazoles,furans and thiophenes.Bioactivity tests showed that the target compounds mostly exhibited moderate to good broad-spectrum antibacterial activity against the tested bacteria,especially the quinazolone vinyl thiazole III-1 showed a good inhibition against MRSA(MIC = 0.5μg/m L),which was 8 times higher than that of norfloxacin.The druggability exploration indicated that the highly active III-1 exhibited low erythrotoxicity,good pharmacokinetic properties,low tendency to induce bacterial resistance and high ability to inhibit biofilm growth.Although III-1 was unable to induce oxidative stress effects in bacteria,III-1 might block replication of DNA by inserting into DNA.Moreover,the synergistic antibacterial effect of the quinazolone vinyl thiazole III-1 with cefdinir could be attributed to the reason that III-1 could induce PBP2 a allosteric regulation of MRSA and trigger the opening of active site to promote the binding of cefdinir to the active site,thus inhibiting the expression of PBP2 a,thereby overcoming MRSA resistance and significantly enhancing the anti-MRSA activity of cefdinir.Given that the introduction of vinylazoles fragment at C-2 position was beneficial for the antibacterial activity of quinazolones and quaternary ammonium salts possessed the ability to target bacterial cell membranes.Thirty-three novel quinazolone vinylcyano azoles and quaternized derivatives were designed and synthesized by introducing various aromatic heterocycles at C-2 position of quinazolones through the cyanoethylene.Antibacterial test results indicated that the pyridine quaternized quinazolone IV-16 b possessed excellent broad-spectrum antibacterial ability against the tested strains,especially IV-16 b could effectively inhibit the growth of MRSA(MIC =0.5 μg/m L)and E.coli(MIC = 0.25 μg/m L).The highly active IV-16 b exhibited rapid killing effect,biofilm growth inhibition ability and low drug resistance against MRSA and E.coli,which exhibited low toxicity to mammalian cells even at a high concentration.Moreover,antibacterial mechanism study proved that highly active IV-16 b could indeed target and destroy the bacterial cell membrane,which in turn caused the leakage of cellular contents.Highly active IV-16 b might also further target bacterial DNA to block its replication.A total of one hundred and thirty-one compounds were synthesized by multistep reactions using anthranilic acid or anthranilamide as the starting materials,in which ninety-six compounds were new,including seventy-seven new target compounds and nineteen new intermediates.Antibacterial activity evaluation found that some of the target compounds exhibited comparable or stronger antibacterial activity than the reference drug norfloxacin,and the novel highly active quinazolone vinylazoles exhibited good biocompatibility,rapid bactericidal ability and low tendency to induce bacterial resistance,which could also effectively block the formation of bacterial biofilm.The preliminary antibacterial mechanism exploration indicated that the highly active target compounds could destroy the integrity of bacterial cell membrane,induce oxidative stress effect in bacteria,and reduce the metabolic activity of bacteria or target macromolecules such as bacterial DNA and enzymes.The above research work indicated that these novel quinazolone vinylazoles possessed the potential as candidates for clinical antibacterial drugs,which was worth further research.