Coumarins have wide application in the fields of bromatology,materials and medicinal chemistry.Thiazole in a variety of clinically antibacterial drugs can easily bind with various biomolecules in organisms through noncovalent interactions,thus exhibiting multi-targeting potential.Hydroxyethyl fragment plays a crucial role in the phase of exerting biological effect,which is widely present in many medicinal drugs such as disinfectant ethanol,antibacterial metronidazole,antifungal fluconazole and so on.Here a series of coumarin skeleton-based threc-component hybrids by the combination of thiazole ring and diethanolamine fragment were first designed and synthesized,and their biological behaviour was evaluated with the aim to discover novel type of multi-targeting antimicrobial agents for overcoming drug resistance.

Natural products play an important role for the development of most of the biologically active compounds due to the presence of enormous structure and chemical diversity which cannot be matched by any synthetic libraries of small molecules.From all the approved antibacterial drugs approximately 68% of them are natural products or their derivatives.Berberine is a natural product with unique structure,a quaternary nitrogen and a large desirableπ-conjugated backbone enables berberinc-based derivatives to readily bind with biomolecules like deoxyribonucleic acid（DNA） or an enzyme via noncovalent forces such as π-π stacking and electronic interactions,thus exerting potent biological activities.Herein,we are interested to synthesize a series of hybrids of berberine and metronidazole as a novel class of antibacterial agents.

A series of new potentially multi-targeting antimicrobial naphthalimidc-derived fluconazole analogs were designed and conveniently synthesized from 4-bromonaphthalic anhydride.Their structures were characterized by ~1H NMR,^13 C NMR and HRMS spectra.Bioactivity assays revealed that some prepared compounds exhibited significantly inhibitory efficiencies towards bacteria and fungi.Remarkably,the derivative 11 e could effectively inhibit the growth of Acinetobacter baumannii with MIC value of 0.013 μmol/L.

A series of Ofloxacin imidazole hybrids as potentially antimicrobial agents have been successfully synthesized via multistep reactions starting from commercial ethyl acetoacetate and triethylorthoformate.This synthetic route mainly involved cyclization and nucleophile substitution reactions,which has several advantages including commercially available starting materials,easy operation and moderate to good yield.The antibacterial evaluation revealed that most of the synthesized compounds exhibited good antibacterial efficiencies.Especially,compound 3 a displayed superior anti-bacterial activity against Escherichia coli ATCC 25922 with MIC value of 0.023 μmol/mL.

Structural characteristics of Aloe emodin endow natural superior resources with good interactions on DNA via multiple modes,thus Aloe emodin derivatives exhibit extensive potential in medicinal chemistry.On the basis of our previous work in carbazoles with a library of potent candidate probes for biomolecular processes,herein our interest is to combine aloe emodin scaffold with carbazole via isopropanol bridge to develop a series of new potential hybrid candidates of artificial probes for sensitive bacterial DNA in clinic.

A series of novel coumarin azoles including imidazoles,triazoles,tetrazoles,thiazoles and so on were designed and synthesized as potentially multi-targeting antimicrobial agents.Their structures were characterized by ~1H NMR,^13 C NMR and HRMS spectra.Bioactivity of the prepared compounds and dauggability of the highly active molecules including cytotoxicity,drug resistance,membrane permeabilization etc.were evaluated.

Natural and synthetic congeners of carbazole comprise a large group of therapeutically useful agents in medicinal chemistry.Herein a series of novel isopropanol-bridged sulfonyl carbazoles as novel potential antimicrobial agents were designed and synthesized via multi-step procedure from commercial aniline and carb azole in an effort to overcome drug resistance.Most of the prepared compounds exerted powerful antibacterial activities toward a panel of Gram-positive and Gram-negative organisms,including drug-resistant pathogens.The active molecules could effectively intercalate into methicillin-resistant Staphylococcus aureus DNA via supramolecular interactions,which might block DNA replication to exhibit their powerful antibacterial activity.

A series of novel potentially antimicrobial nitroimidazoles were developed.Compound 4i was found to give stronger anti-P.aeruginosa efficacy, could rapidly kill P.aeruginosa strains and effectively cleave the sensitive P.aeruginosa DNA.The active molecule 4i could also be efficiently stored and carried by human serum albumin via supramolecular interactions.The hydrogen bonds drive to stabilize the compound 4i-topoisomerase Ⅱ supramolecular complex.^[1-4]

With the abuse of anti-infective agents, the resistance problem has become increasingly urgent.In this context, carbazole-derived fluconazole analogs were originally designed and synthesized with the view of broadening antifungal spectrum and overcoming drug resistance^[1-3] .Further active evaluation indicated that compound 5d exhibited superior inhibitory efficacy to standard drug Fluconazole against all the tested fungal strains with low propensity of fungal pathogens to develop resistance.Hybrid 5d could intercalate into DNA through the base pairs of DNA along with a reduced face-to-face base stacking to form 5d-DNA supramolecular complex, thus causing an extension of the DNA.

The natural berberine is an isoquinoline alkaloid, which could effectively interact with various biologically important species including DNAs, enzymes, and receptors to form supermolecules.Therefore, we designed and synthesized a new class of berberine azolyl ethanols and further investigated their antibacterial effects and the non-covalent interaction with bacterial DNA.The results demonstrated that compound 5a exerted superior activity against E.faecalis（MIC = 0.002 mM） and could intercalated into the double helix of DNA.These results suggested that compound 5a was a potential candidate as effective DNA intercalator.^[1-5]