A Unique Hybridization Route to Access Hydrazylnaphthalimidols as Novel Structural Scaffolds of Multitargeting Broad-Spectrum Antifungal Candidates.

This study developed a class of novel structural antifungal hydrazylnaphthalimidols (HNs) with multitargeting broad-spectrum potential via multicomponent hybridization to confront increasingly severe fungal invasion. Some prepared HNs exhibited considerable antifungal potency; especially nitrofuryl HN 4a (MIC = 0.001 mM) exhibited a potent antifungal activity against Candida albicans, which is 13-fold higher than that of fluconazole. Furthermore, nitrofuryl HN 4a displayed low cytotoxicity, hemolysis and resistance, as well as a rapid fungicidal efficacy. Preliminary mechanistic investigations revealed that nitrofuryl HN 4a could inhibit lactate dehydrogenase to decrease metabolic activity and promote the accumulation of reactive oxygen species, leading to oxidative stress. Moreover, nitrofuryl HN 4a did not exhibit membrane-targeting ability; it could embed into DNA to block DNA replication but could not cleave DNA. These findings implied that HNs are promising as novel structural scaffolds of potential multitargeting broad-spectrum antifungal candidates for treating fungal infection.

Ethylenic conjugated coumarin thiazolidinediones as new efficient antimicrobial modulators against clinical methicillin-resistant Staphylococcus aureus.

In an effort for the development of novel antimicrobial agents, ethylenic conjugated coumarin thiazolidinediones as potential multi-targeting new antimicrobial compounds were synthesized through convenient procedures from commercially available resorcinol and were evaluated for their antimicrobial potency. Bioactive evaluation revealed that some of the prepared compounds showed strong antimicrobial activities towards the tested microorganisms including clinically drug-resistant strains. Especially, propargyl derivative 12b exhibited effective anti-MRSA potency with MIC value of 0.006 µmol/mL, which was highly advantageous over clinical antibacterial drug norfloxacin. Compound 12b showed rapid killing effect, low toxicity against hepatocyte LO2 cell line, and no obvious drug resistance development against MRSA. Preliminary exploration of action mechanism manifested that molecule 12b acted upon MRSA through forming stable supramolecular complex with bacterial DNA which might impede DNA replication. Molecular docking showed that compound 12b could bind with DNA-gyrase through hydrogen bonds.

Heterocyclic Naphthalimides as New Skeleton Structure of Compounds with Increasingly Expanding Relational Medicinal Applications.

Naphthalimide compounds are an important type of nitrogen-containing aromatic heterocycles with cyclic double imides and the naphthalene framework. This π-deficient large conjugated planar structure enables naphthalimide derivatives to readily interact with various biological cations, anions, small molecules and macromolecules such as DNAs, enzymes and recetors in living organism via noncovalent bonds, therefore exhibiting extensive potentiality in relatively medicinal applications. Currently, some naphthalimides as anticancer agents have entered into clinical trials and other naphthalimide-based medicinal developments as potential drugs for treatment of various diseases are actively and unprecedentedly expanding. Naphthalimide-derived artificial ion receptors, fluorescent probes and cell imaging agents are being overwhelmingly investigated and have a diversity of potential applications in real-time detecting ions and biomolecules, understanding biological processes and determining pharmacological and pharmacokinetic properties. All the above mentions have strongly implied that naphthalimide-based derivatives as new skeleton structure of compounds possess increasingly expanding relational medicinal applications, and the related research is becoming a quite attractive active topic and newly rising highlight. Combining with our research and referring other works from literature, this work systematically reviews the current research and development of heterocyclic naphthalimides as anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antidepressant agents as well as artificial cation and anion receptors, diagnostic agents and pathologic probes, and cell imaging agents for biologically important species. Some rational design strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of naphthalimide-based medicinal chemistry are also presented.

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.

N-[4-(Azetidin-1-ylsulfon-yl)phen-yl]-N-(2,4-difluoro-benz-yl)acetamide.

In the title mol-ecule, C(18)H(18)F(2)N(2)O(3)S, the dihedral angle between the benzene rings is 79.40 (11)°. The 2,4-difluoro-benzyl and azetidine fragments adopt a trans arrangement relative to the central benzene ring. In the crystal, weak C-H⋯O hydrogen bonds connect mol-ecules into a two-dimensional network parallel to (001).

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.

6-Bromo-2-(diprop-2-ynyl-amino)-1H-benzo[de]isoquinoline-1,3(2H)-dione.

The asymmetric unit of the title compound, C(18)H(11)BrN(2)O(2), contains two independent mol-ecules in which the prop-2-ynyl-amino groups have different mutual orientations. In one mol-ecule, the Br atom is disordered over two positions, with refined occupancies of 0.742 (2) and 0.258 (2).

9-(4-Bromo-but-yl)-9H-carbazole.

In the title compound, C(16)H(16)BrN, the bromo-butyl group lies on one side of the carbazole ring plane and has a zigzag shape. The dihedral angle between the two benzene rings is 0.55°. In the crystal, mol-ecules are connected by van der Waals inter-actions.

(Z)-1,3-Bis(4-chloro-phen-yl)-2-(1H-1,2,4-triazol-1-yl)prop-2-en-1-one.

In the title mol-ecule, C(17)H(11)Cl(2)N(3)O, the C=C bond connecting the triazole and 4-chloro-phenyl groups adopts a Z geometry. The dihedral angles formed by the triazole ring and the 4-chloro substituted benzene rings are 67.3 (1) and 59.1 (1)°. The dihedral angle between the two benzene rings is 73.5 (1)°.

(Z)-1-(2,4-Difluoro-phen-yl)-3-(4-fluoro-phen-yl)-2-(1H-1,2,4-triazol-1-yl)prop-2-en-1-one.

In the title mol-ecule, C(17)H(10)F(3)N(3)O, the C=C bond connecting the triazole ring and 4-fluoro-phenyl groups adopts a Z conformation. The triazole ring forms dihedral angles of 15.3 (1) and 63.5 (1)°, with the 2,4-difluoro-substituted and 4-fluoro-substituted benzene rings, respectively. The dihedral angle between the two benzene rings is 51.8 (1)°.

1H-1,2,4-Triazol-4-ium (3,4-dichloro-phen-yl)methane-sulfonate.

In the title molecular salt, C(2)H(4)N(3) (+)·C(7)H(5)Cl(2)O(3)S(-), C-C-S angle [112.25 (18)°] deviates slightly from that expected for ideal sp(3)-hybridization geometry. In the crystal, the components are linked by N-H⋯O and bifurcated N-H⋯(O,O) hydrogen bonds into chains parallel to [110].

2-Chloro-1-[4-(2,4-difluoro-benz-yl)piperazin-1-yl]ethanone.

In the title mol-ecule, C(13)H(15)ClF(2)N(2)O, the piperazine ring is in a chair conformation with the 2,4-difluoro-benzyl and chloro-acetyl substituents in equatorial positions.