Design, Synthesis, and In Vitro and In Vivo Antifungal Activity of Novel Triazoles Containing Phenylethynyl Pyrazole Side Chains
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. In Vitro Antifungal Activity
2.3. Theoretical Evaluation of ADME/T Properties
2.4. Anti-Hyphal Activity
2.5. Fungal Burden Evaluation
2.6. In Vivo Potency
2.7. Molecular Docking
3. Materials and Methods
3.1. Chemistry
3.1.1. Procedure for the Synthesis of 2-(2,4-Difluorophenyl)-1-(4-iodo-1H-pyrazol-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (2)
3.1.2. Procedure for the Synthesis of Methyl 4-((1-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-1H-pyrazol-4-yl)ethynyl)benzoate (3)
3.1.3. Procedure for the Synthesis of 4-((1-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-1H-pyrazol-4-yl)ethynyl)benzoic acid (4)
3.1.4. General Procedure for the Synthesis of Target Compound (5a–5v)
3.1.5. General Procedure for the Synthesis of Target Compound (6a–6e)
3.2. In Vitro Antifungal Activities Assay
3.3. Hyphal Formation Assay
3.4. Fungal Burden Evaluation
3.5. In Vivo Antifungal Potency
3.6. Statistics
3.7. Computational Methodology
3.7.1. ADME/T Prediction
3.7.2. Molecular Docking
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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Compd. | R1 | R2 | MIC (μg/mL) | ||
---|---|---|---|---|---|
C. alb SC5314 | C. neo 32609 | A. fum 7544 | |||
3 | - | - | 0.5 | 8.0 | >64.0 |
4 | - | - | 0.5 | 1.0 | >64.0 |
5a | - | 0.0625 | 0.125 | >64.0 | |
5b | - | 0.0625 | 0.125 | >64.0 | |
5c | - | 0.5 | 0.5 | 64.0 | |
5d | - | 0.25 | 0.5 | >64.0 | |
5e | - | 0.5 | 0.5 | >64.0 | |
5f | - | 0.5 | 1.0 | >64.0 | |
5g | - | 0.5 | 0.5 | >64.0 | |
5h | - | 0.5 | 2.0 | >64.0 | |
5i | - | 0.25 | 0.5 | 64.0 | |
5j | - | 0.0625 | 0.125 | >64.0 | |
5k | - | 0.125 | 0.125 | 8.0 | |
5l | - | 0.5 | 0.5 | >64.0 | |
5m | - | 0.5 | 0.5 | >64.0 | |
5n | - | 1.0 | 0.5 | 16.0 | |
5o | - | 0.0625 | 0.25 | >64.0 | |
5p | - | 0.25 | 0.5 | >64.0 | |
5q | - | 0.25 | 0.25 | >64.0 | |
5r | - | 0.5 | 0.25 | >64.0 | |
5s | - | 0.25 | 0.25 | >64.0 | |
5t | - | 0.125 | 0.125 | 8.0 | |
5u | - | 0.25 | 0.125 | 8.0 | |
5v | - | 0.25 | 0.25 | 8.0 | |
6a | F | - | 0.0625 | 0.0625 | 16.0 |
6b | Cl | - | 0.125 | 0.25 | >64.0 |
6c | CN | - | 0.0625 | 0.0625 | 4.0 |
6d | CF3 | - | 0.125 | 0.25 | 16.0 |
6e | OCF3 | - | 0.125 | 0.125 | 64.0 |
FCZ | - | - | 0.5 | 0.25 | >64.0 |
POS | - | - | 0.5 | 1.0 | 1.0 |
Compd. | C. alb. | |
---|---|---|
Strain 100 | Strain 103 | |
5a | 16.0 | 2.0 |
5b | 8.0 | 8.0 |
5j | 8.0 | 8.0 |
5k | 16.0 | 4.0 |
6a | 8.0 | 2.0 |
6c | 4.0 | 4.0 |
FCZ | >64.0 | >64.0 |
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Ni, T.; Ding, Z.; Xie, F.; Hao, Y.; Bao, J.; Zhang, J.; Yu, S.; Jiang, Y.; Zhang, D. Design, Synthesis, and In Vitro and In Vivo Antifungal Activity of Novel Triazoles Containing Phenylethynyl Pyrazole Side Chains. Molecules 2022, 27, 3370. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27113370
Ni T, Ding Z, Xie F, Hao Y, Bao J, Zhang J, Yu S, Jiang Y, Zhang D. Design, Synthesis, and In Vitro and In Vivo Antifungal Activity of Novel Triazoles Containing Phenylethynyl Pyrazole Side Chains. Molecules. 2022; 27(11):3370. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27113370
Chicago/Turabian StyleNi, Tingjunhong, Zichao Ding, Fei Xie, Yumeng Hao, Junhe Bao, Jingxiang Zhang, Shichong Yu, Yuanying Jiang, and Dazhi Zhang. 2022. "Design, Synthesis, and In Vitro and In Vivo Antifungal Activity of Novel Triazoles Containing Phenylethynyl Pyrazole Side Chains" Molecules 27, no. 11: 3370. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27113370