Broad‐Spectrum Antifungal Agents: Fluorinated Aryl‐ and Heteroaryl‐Substituted Hydrazones

Chandrika, Nishad Thamban; Dennis, Emily K.; Brubaker, Katelyn R.; Kwiatkowski, Stefan; Watt, David S.

doi:10.1002/cmdc.202000626

Cited by 8 publications

(10 citation statements)

References 54 publications

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“…Finally, target compounds 4−35 were synthesized by condensation reaction between various substituted benzaldehydes and key intermediate 3 in the catalysis of glacial acetic acid. All the target compounds were obtained in good yields and characterized by 1 H NMR, 13 C NMR, and LC−MS (Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

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From Synergy to Monotherapy: Discovery of Novel 2,4,6-Trisubstituted Triazine Hydrazone Derivatives with Potent Antifungal Potency In Vitro and In Vivo

Xie,

Hao,

Liu

et al. 2024

J. Med. Chem.

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Invasive fungal infections pose a serious threat to public health and are associated with high mortality and incidence rates. The development of novel antifungal agents is urgently needed. Based on hit-to-lead optimization, a series of 2,4,6trisubstituted triazine hydrazone compounds were designed, synthesized, and biological evaluation was performed, leading to the identification of compound 28 with excellent in vitro synergy (FICI range: 0.094−0.38) and improved monotherapy potency against fluconazole-resistant Candida albicans and Candida auris (MIC range: 1.0−16.0 μg/mL). Moreover, 28 exhibited broad-spectrum antifungal activity against multiple pathogenic strains. Furthermore, 28 could inhibit hyphal and biofilm formation, which may be related to its ability to disrupt the fungal cell wall. Additionally, 28 significantly reduced the CFU in a mouse model of disseminated infection with candidiasis at a dose of 10 mg/kg. Overall, the triazine-based hydrazone compound 28 with low cytotoxicity, hemolysis, and favorable ADME/T characteristics represents a promising lead to further investigation.

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Section: Resultsmentioning

confidence: 99%

“…Chemistry. 1 H and 13 C NMR spectra were recorded in DMSO-d 6 with a Bruker AC-600P and 400P spectrometer ( 1 H NMR, 600 MHz, 400 MHz; 13 C NMR, 151 MHz, 100 MHz), using tetramethylsilane (TMS) as internal standard. Chemical shifts (δ values) and coupling constants (J values) are given in ppm and Hz, respectively.…”

Section: Methodsmentioning

confidence: 99%

From Synergy to Monotherapy: Discovery of Novel 2,4,6-Trisubstituted Triazine Hydrazone Derivatives with Potent Antifungal Potency In Vitro and In Vivo

Xie,

Hao,

Liu

et al. 2024

J. Med. Chem.

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“…51,52 Next, we explored the efficacy of monohydrazones over bishydrazones. 53 With the promising results we observed for monohydrazones, we now decided to explore novel substituted monohydrazides as potential antifungals. Herein, we report the synthesis and antifungal activity of 64 novel substituted monohydrazides by in vitro studies as well as by time-kill studies.…”

Section: Introductionmentioning

confidence: 99%

Discovery and development of novel substituted monohydrazides as potent antifungal agents

et al. 2023

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“…Fluorine changes the electronic distribution and reactivity, which increases drug–receptor interactions and lipophilicity. Fluorinated motifs have a variety of therapeutic effects, including antimycotic, antimalarial, antituberculosis, antiviral, antibiotic, antidiabetic, antidopaminergic, anti-hyperlipidemia, anti-inflammatory, antihistamine, antidepressant, anti-cancer, and anticonvulsant properties. − In materials science, fluorinated aryls and polyaryls, due to the outstanding stability of the F–C bond, low polarizability, and small size of fluorine, display very weak intermolecular dispersion interactions and are used as liquid crystal displays, organic solar cells, dye-sensitized solar cells, molecular wires in diodes, and in photoluminescence substances. − The fluorinated biphenyl and polyphenyl compounds were synthesized by different coupling reactions, among which one can name the Heck reaction, Glaser coupling, Hiyama coupling, and Suzuki reaction. Among these coupling reactions, the Suzuki reaction is the best procedure for C–C bond formation because boronic acid, the main ingredient in the Suzuki reaction, reacts easily and is not dangerous by nature. − …”

Section: Introductionmentioning

confidence: 99%

Novel Fluorinated Biphenyl Compounds Synthesized via Pd(0)-Catalyzed Reactions: Experimental and Computational Studies

et al. 2023

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Five new difluorinated biphenyl compounds, 4′-(tert-butyl)-3,4-difluoro-1,1′-biphenyl (TBDFBP), 1-(3′,4′-difluoro-[1,1′-biphenyl]-4-yl)ethanone (DFBPE), 3′,4′-difluoro-2,5-dimethoxy-1,1′-biphenyl (DFDMBP), 3,4-difluoro-3′-nitro-1,1′-biphenyl (DFNBP), and (3′,4′-difluoro-[1,1′-biphenyl]-3-yl)(methyl)sulfane (DFBPMS), have been successfully synthesized by the well-known Suzuki–Miyaura coupling with excellent yields averaging 78%. UV–visible, Fourier transform infrared ,and 13C NMR and 1H NMR spectroscopies along with single-crystal X-ray diffraction (SC-XRD) analysis (for TBDFBP and DFBPE) were used for the structure elucidation of the synthesized compounds. The SC-XRD results demonstrated the crystal systems of the studied compounds, TBDFBP and DFBPE, to be monoclinic, and their space groups were found to be P21/c. Also, a detailed density functional theory study was performed. The calculated structures for TBDFBP and DFBPE were found to agree quite well with the experimental results. The natural bonding orbital charge analysis suggested that molecules of these compounds should interact quite noticeably with each other in the solid phase and with polar solvent molecules. Molecular electrostatic potential analysis suggests that accumulation of positive and negative potential implies possibility of quite significant dipole–dipole intermolecular interactions in crystals of these compounds, as well as quite strong interactions with polar solvent molecules. The global reactivity parameters analysis suggests all compounds to be quite stable in redox reactions, with the compound DFNBP being relatively more reactive and the compounds TBDFBP and DFDMBP being relatively more stable.

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Broad‐Spectrum Antifungal Agents: Fluorinated Aryl‐ and Heteroaryl‐Substituted Hydrazones

Cited by 8 publications

References 54 publications

From Synergy to Monotherapy: Discovery of Novel 2,4,6-Trisubstituted Triazine Hydrazone Derivatives with Potent Antifungal Potency In Vitro and In Vivo

From Synergy to Monotherapy: Discovery of Novel 2,4,6-Trisubstituted Triazine Hydrazone Derivatives with Potent Antifungal Potency In Vitro and In Vivo

Discovery and development of novel substituted monohydrazides as potent antifungal agents

Novel Fluorinated Biphenyl Compounds Synthesized via Pd(0)-Catalyzed Reactions: Experimental and Computational Studies

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