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Design, Synthesis, and In Vitro and In Vivo Antifungal Activity of Novel Triazoles Containing Phenylethynyl Pyrazole Side Chains - PubMed

️Sat Jan 01 2022

Design, Synthesis, and In Vitro and In Vivo Antifungal Activity of Novel Triazoles Containing Phenylethynyl Pyrazole Side Chains

Tingjunhong Ni et al. Molecules. 2022.

Abstract

A series of triazole derivatives containing phenylethynyl pyrazole moiety as side chain were designed, synthesized, and most of them exhibited good in vitro antifungal activities. Especially, compounds 5k and 6c showed excellent in vitro activities against C. albicans (MIC = 0.125, 0.0625 μg/mL), C. neoformans (MIC = 0.125, 0.0625 μg/mL), and A. fumigatus (MIC = 8.0, 4.0 μg/mL). Compound 6c also exerted superior activity to compound 5k and fluconazole in inhibiting hyphae growth of C. albicans and inhibiting drug-resistant strains of C. albicans, and it could reduce fungal burdens in mice kidney at a dosage of 1.0 mg/kg. An in vivo efficacy evaluation indicated that 6c could effectively protect mice models from C. albicans infection at doses of 0.5, 1.0, and 2.0 mg/kg. These results suggested that compound 6c deserves further investigation.

Keywords: CYP51; antifungal; molecular docking; synthesis; triazole.

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Conflict of interest statement

These authors declare no conflict of interest.

Figures

**Figure 1**
Several triazole drugs for IFIs in clinic and the structures of our lead compounds.

**Figure 2**
Design strategy of target compounds.

**Scheme 1**
Synthesis of the target compounds. (i) 4-Iodo-1H-pyrazole, K₂CO₃, DMF, 80 °C, 4 h; (ii) Methyl 4-ethynylbenzoate, PdCl₂(PPh₃)₂, CuI, DIEA, NMP, 60 °C, 6 h; (iii) LiOH, THF/H₂O (V/V= 1:1), 50 °C, 6 h; (iv) Alkyl amines or aromatic amines, DIEA, PyBOP, 50 °C, 4~8 h; (v) substituted (4-ethynylphenoxy)methyls, PdCl₂(PPh₃)₂, CuI, DIEA, NMP, 60 °C, 6 h.

**Figure 3**
The evaluation chart of Alog P and PSA of target compounds. The 95% and 99% confidence limit ellipses of blood–brain barrier (BBB) and human intestinal absorption (Absorption) models.

**Figure 4**
Anti-hyphal effects of different concentrations of compounds 5k and 6c with FCZ (fluconazole) as a positive agent. Exponentially growing *C. albicans* SC5314 cells were transferred to hypha-inducing Spider liquid medium. The cellular morphology was photographed after incubation at 37 °C for 3 h. Scale bar = 20 μm.

**Figure 5**
Effects of the antifungal treatments on the tissue burden. Each mouse was intravenously infected with *C. albicans* SC5314 5 × 10⁶. Saline, FCZ (fluconazole, 0.3 mg/kg), compound 6c (0.3 mg/kg and 1.0 mg/kg) were administered orally once daily for 3 days after infection. Kidneys of mice were harvested on day 4 and colony-forming units were measured. * p < 0.05, ** p < 0.01, *** p < 0.001, determined by ANOVA.

**Figure 6**
In vivo efficacy of compound 6c (0.5, 1.0 and 2.0 mg/kg) and FCZ (fluconazole, 0.5 mg/kg) in a systemic infection of an ICR mouse model (n = 10) with *C. albicans* SC5314. ** p < 0.01, *** p < 0.001, determined by ANOVA.

**Figure 7**
The binding mode of compound 6c in the active site of CYP51. Compound 6c, heme group, residues are shown in brown, yellow or green sticks, respectively. Hydrogen-bonding interaction was shown in red and π–π stacking interaction was shown in forest green. Image depicting the proposed binding mode was generated using PyMOL.

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References

1. Perfect J.R. The antifungal pipeline: A reality check. Nat. Rev. Drug Discov. 2017;16:603–616. doi: 10.1038/nrd.2017.46. - DOI - PMC - PubMed
1. Fang W., Chen M., Liu J., Hagen F., Zhang P., Guo Y., Boekhout T., Deng D. Cryptococcal meningitis in systemic lupus erythematosus patients: Pooled analysis and systematic review. Emerg. Microbes Infect. 2016;5:95. doi: 10.1038/emi.2016.93. - DOI - PMC - PubMed
1. Garbee D.D., Pierce S.S., Manning J. Opportunistic Fungal Infections in Critical Care Units. Crit. Care Nurs. Clin. N. Am. 2017;29:67–79. doi: 10.1016/j.cnc.2016.09.011. - DOI - PubMed
1. Brown G.D., Denning D.W., Gow N.A.R., Levitz S.M., Netea M.G., White T.C. Hidden Killers: Human Fungal Infections. Sci. Transl. Med. 2012;4:165rv13. doi: 10.1126/scitranslmed.3004404. - DOI - PubMed
1. Stop neglecting fungi. Nat. Microbiol. 2017;2:17120. doi: 10.1038/nmicrobiol.2017.120. - DOI - PubMed

Design, Synthesis, and In Vitro and In Vivo Antifungal Activity of Novel Triazoles Containing Phenylethynyl Pyrazole Side Chains - PubMed