Cheng-He Zhou

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

Imidazole ring is an important five‐membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron‐rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole‐based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole‐based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole‐based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti‐inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole‐based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.

Recent developments in azole compounds as antibacterial and antifungal agents

Azole compounds are an important class of nitrogen heterocycles with electron-rich property. This special structure endows azole-based derivatives easily bind with the enzymes and receptors in organisms through noncovalent interactions such as hydrogen bonds, coordination bonds, ion-dipole, cation-π,π-π stacking and hydrophobic effect as well as van der Waals force etc., thereby possessing various applications in medicinal chemistry, especially their protrudent effects such as imidazoles and triazoles against fungal strains. The design, synthesis and antimicrobial activity of azole derivatives have been extensively investigated and have become one of the highly active highlights in recent years, and the progress is quite rapid. In particular, a large number of azole-based antibacterial and antifungal agents have been penetratingly studied as candidates and even some of them have been used in clinic, which have shown the great potential and development value of azole compounds. Based on our researches on azole compounds and referring to other literature, this work scientifically reviewed the researches and developments of azole-based compounds as antibacterial and antifungal agents, including oxazole, imidazole, benzimidazole, triazole, benzotriazole, pyrazole, thiazole, carbazole as well as tetrazole in recent three years. It is hopeful that azole compounds may continue to serve as an important direction for the exploitation of azole-based antibacterial and antifungal drugs with better curative effect, lower toxicity, less side effects, especially fewer resistances and so on.

Synthesis and biological evaluation of α-triazolyl chalcones as a new type of potential antimicrobial agents and their interaction with calf thymus DNA and human serum albumin

A series of α-triazolyl chalcones were efficiently synthesized. Most of the prepared compounds showed effective antibacterial and antifungal activities. Noticeably, α-triazolyl derivative 9a exhibited low MIC value of 4 μg/mL against MRSA and Micrococcus luteus, which was comparable or even superior to reference drugs. The further research revealed that compound 9a could effectively intercalate into Calf Thymus DNA to form 9a-DNA complex which might block DNA replication to exert their powerful antimicrobial activities. Competitive interactions between 9a and metal ions to Human Serum Albumin (HSA) suggested the participation of Fe(3+), K(+) and Mg(2+) ions in 9a-HSA system could increase the concentration of free 9a, shorten its storage time and half-life in the blood, thus improving its antimicrobial efficacy.

Design, synthesis and evaluation of clinafloxacin triazole hybrids as a new type of antibacterial and antifungal agents

A series of clinafloxacin triazole hybrids as a new type of antibacterial and antifungal agents were synthesized for the first time and screened for their antimicrobial efficacy against four Gram-positive bacteria, four Gram-negative bacteria and two fungi by two fold serial dilution technique. The bioactive assay indicated that most of the target compounds displayed broad antimicrobial spectrum and good antibacterial and antifungal activities with low MIC values ranging from 0.25 to 2 μg/mL against all the tested strains which exhibited comparable or even better efficiency in comparison with the reference drugs Chloramphenicol, Clinafloxacin and Fluconazole, respectively. Notably, some synthesized clinafloxacin triazoles showed stronger efficacy against methicillin-resistant Staphylococcus aureus than their parent Clinafloxacin.

Synthesis and biological evaluation of a class of quinolone triazoles as potential antimicrobial agents and their interactions with calf thymus DNA

A novel series of quinolone triazoles were synthesized and characterized by IR, NMR, MS and HRMS spectra. All the newly prepared compounds were screened for their antimicrobial activities against seven bacteria and four fungi. Bioactive assay manifested that most of new compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains including multi-drug resistant MRSA in comparison with reference drugs Norfloxacin, Chloromycin and Fluconazole. The preliminary interactive investigations of compound 6b with calf thymus DNA by fluorescence and UV-vis spectroscopic methods revealed that compound 6b could effectively intercalate DNA to form compound 6b-DNA complex which might block DNA replication and thus exert its antimicrobial activities.

Novel berberine triazoles: Synthesis, antimicrobial evaluation and competitive interactions with metal ions to Human Serum Albumin

A series of novel berberine triazoles were synthesized and characterized by IR, NMR, MS and HRMS spectra. All target compounds and their precursors were screened for antimicrobial activities in vitro against four Gram-positive bacteria, four Gram-negative bacteria and two fungal strains. Bioactive assay indicated that most of the prepared compounds exhibited good antibacterial and antifungal activities with low MIC values ranging from 2 to 64 μg/mL, which were comparable to or even better than the reference drugs Berberine, Chloromycin, Norfloxacin and Fluconazole. The competitive interactions between compound 5a and metal ions to Human Serum Albumin (HSA) revealed that the participation of Mg(2+) and Fe(3+) ions in compound 5a-HSA association could result in the concentration increase of free compound 5a, shorten the storage time and half-life of compound 5a in the blood, thus improving its antimicrobial efficacy.

1,2,3-Triazole-derived naphthalimides as a novel type of potential antimicrobial agents: synthesis, antimicrobial activity, interaction with calf thymus DNA and human serum albumin.

A series of 1,2,3-triazole-derived naphthalimides as a novel type of potential antimicrobial agents were synthesized and characterized by IR, NMR and HRMS spectra. All the new compounds were screened for their antimicrobial activity against four Gram-positive bacteria, four Gram-negative bacteria and three fungi. Bioactive assay manifested that 3,4-dichlorobenzyl compound 9e and its corresponding hydrochloride 11e showed better anti-Escherichia coli activity than Norfloxacin and Chloromycin. Preliminary research revealed that compound 9e could effectively intercalate into calf thymus DNA to form compound 9e-DNA complex which might block DNA replication and thus exert antimicrobial activities. Human serum albumin could effectively store and carry compound 9e by electrostatic interaction.

Synthesis and bioactive evaluation of novel hybrids of metronidazole and berberine as new type of antimicrobial agents and their transportation behavior by human serum albumin

A series of novel hybrids of metronidazole and berberine as new type of antimicrobial agents were synthesized and characterized by (1)H NMR, (13)C NMR, IR, MS and HRMS spectra. Bioactive assay manifested that most of the prepared compounds exhibited effective antibacterial and antifungal activities and some showed comparable or superior potency against Methicillin-resistant Staphylococcus aureus to reference drugs Norfloxacin, Chloromycin and Berberine. The transportation behavior of human serum albumin (HSA) to the highly active compound 5g was evaluated and revealed that the association of imidazole derivative 5g with HSA was spontaneous and the electrostatic interactions played important roles in the transportation of HSA to 5g. The calculated parameters indicated that compound 5g could be effectively stored and carried by HSA.

Design and biological evaluation of novel quinolone-based metronidazole derivatives as potent Cu2+ mediated DNA-targeting antibacterial agents

A series of novel quinolone-based metronidazole derivatives as new type of antimicrobial agents were developed and characterized. Most of them gave good antibacterial activity towards the Gram-positive and negative bacteria. Noticeably, quinolone derivative 3i exhibited low MIC value of 0.25 μg/mL against Pseudomonas aeruginosa, which was even superior to reference drugs Norfloxacin, Ciprofloxacin and Clinafloxacin. The further research revealed that compound 3i could intercalate into P. aeruginosa DNA through copper ion bridge to form a steady 3i-Cu(2+)-DNA ternary complex which might further block DNA replication to exert the powerful bioactivities.

Discovery of novel berberine imidazoles as safe antimicrobial agents by down regulating ROS generation

A series of novel berberine-based imidazole derivatives as new type of antimicrobial agents were developed and characterized. Most of them gave good antibacterial activity toward the Gram-positive and negative bacteria. Noticeably, imidazolyl berberine 3a exhibited low MIC value of 1μg/mL against Eberthella typhosa, which was even superior to reference drugs berberine, chloromycin and norfloxacin. The cell toxicity and ROS generation assay indicated that compound 3a showed low cell toxicity. The interactive investigation by UV-vis spectroscopic method revealed that compound 3a could effectively intercalate into calf thymus DNA to form 3a-DNA complex which might further block DNA replication to exert the powerful antimicrobial activities. The binding behavior of compound 3a to DNA topoisomerase IB revealed that hydrogen bonds and electrostatic interactions played important roles in the association of compound 3a with DNA topoisomerase IB.