Antifungal Activity of 1,4-Dialkoxynaphthalen-2-Acyl Imidazolium Salts by Inducing Apoptosis of Pathogenic Candida spp.
Abstract
:1. Introduction
2. Materials and Methods
2.1. General Remarks
2.2. Synthetic Procedures and Analytical Data
2.2.1. Synthesis of 3-acetyl-4-hydroxynaphthalen-1-yl acetate (2a)
2.2.2. Synthesis of 3-acetyl-4-hydroxy-5-methoxynaphthalen-1-yl acetate (2b)
2.2.3. Synthesis of 3-acetyl-4-alkyloxynaphthalen-1-yl acetate (3a–3d)
3-Aetyl-4-methoxynaphthalen-1-yl acetate (3a)
3-Aetyl-4-(isoamyloxy)naphthalen-1-yl acetate (3b)
3-Acetyl-4-isopropoxynaphthalen-1-yl acetate (3c)
3-Acetyl-4-(isoamyloxy)-5-methoxynaphthalen-1-yl acetate (3d)
2.2.4. General Synthesis of 2-acetyl-1,4-dialkoxynaphthalene (4)
2-Acetyl-1,4-dimethoxynaphthalene (4a; CAS Registry Number 65131-13-7)
2-Acetyl-1,4-diisoamyloxynaphthalene (4b)
2-Acetyl-1,4-diisopropoxynaphthalene (4c)
2-Acetyl-1,4-diisoamyloxy-8-methoxynaphthalene (4d)
2.2.5. General Synthesis of naphthalenacyl bromide (5a–5e)
2-Bromoacetyl-1,4-dimethoxynaphthalne (5a)
2-Bromoacetyl-1,4-diisoamyloxynaphthalene (5b)
2-Bromoacetyl-1,4-diisopropoxynaphthalene (5c)
2-Bromoacetyl-1,4-diisoamyloxy-8-methoxynaphthalene (5d)
2-Bromoacetyl-1-methoxynaphthalene (5e)
2.2.6. General Synthesis of 1-substituted benzylimidazoles (6c and 6d)
1-(4-Methoxybenzyl)-1H-imidazole (6c)
1-(4-Nitrobenzyl)-1H-imidazole (6d)
2.2.7. General Synthesis of NAIMSs (7a–7i, 10, 11)
3-(2-(1,4-Dimethoxynaphthalen-2-yl)-2-oxoethyl)-1-methyl-1H-imidazol-3-ium bromide (NAIMS 7a)
3-(2-(1,4-Bis(isoamyloxy)naphthalen-2-yl)-2-oxoethyl)-1-methyl-1H-imiazol-3-ium bromide (NAIMS 7b)
1-Benzyl-3-(2-(1,4-bis(isoamyloxy)naphthalen-2-yl)-2-oxoethyl)-1H-imiazol-3-ium bromide (NAIMS 7c)
3-(2-(1,4-Bis(isoamyloxy)naphthalen-2-yl)-2-oxoethyl)-1-(4-methoxybenzyl)-1H-imidazol-3-ium bromide (NAIMS 7d)
3-(2-(1,4-Bis(isoamyloxy)naphthalen-2-yl)-2-oxoethyl)-1-(4-nitrobenzyl)-1H-imidazol-3-ium bromide (NAIMS 7e)
1-Benzyl-3-(2-(1,4-diisopropoxynaphthalen-2-yl)-2-oxoethyl)-1H-imidazol-3-ium bromide (NAIMS 7f)
3-(2-(1,4-Bis(isoamyloxy)-8-methoxynaphthalen-2-yl)-2-oxoethyl)-1-methyl-1H-imidazol-3-ium bromide (NAIMS 7g)
1-Benzyl-3-(2-(1,4-bis(isoamyloxy)-8-methoxynaphthalen-2-yl)-2-oxoethyl)-1H-imidazol-3-ium bromide (NAIMS 7h)
3-(2-(1,4-Bis(isoamyloxy)-8-methoxynaphthalen-2-yl)-2-oxoethyl)-1-(4-nitrobenzyl)-1H-imidazol-3-ium bromide (NAIMS 7i)
1-Benzyl-3-(2-(naphthalen-2-yl)-2-oxoethyl)-1H-imidazol-3-ium bromide (NAIMS 10)
1-Benzyl-3-(2-(1-methoxynaphthalen-2-yl)-2-oxoethyl)-1H-imidazol-3-ium bromide (NAIMS 11)
2.3. Fungal Strains and Culture
2.4. Antifungal Susceptibility Microdilution Assay
2.5. Cell Viability Assay
2.6. Fungal Cell Growth Test
2.7. ROS Detection
2.8. Measurement of Mitochondrial Membrane Potential (△Ψm)
2.9. Detection for Release of UV Absorbing Materials at 260 and 280 nm
2.10. Quantitative Reverse Transcriptase PCR (qRT-PCR) analysis
2.11. Statistical Analysis
3. Results
3.1. Chemistry
3.2. Antifungal Activity of NAIMS 7c Against Candida spp.
3.3. Inducing ROS Level and the Loss of Mitochondria Membrane Potential by NAIMS 7c.
3.4. The Cell Lysis and the Apoptosis of C. albicans by NAIMS 7c
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gene | Oligomer | References |
---|---|---|
ACT1 | F: TAGGTTTGGAAGCTGCTGG | [36] |
R: CCTGGGAACATGGTAGTAC | ||
YPK1 | F: CAACACAACACAGTAGCACC | This study |
R: GTTGTGGATAAAGGTGGTTCG | ||
HAC1 | F: TACAACCAACACATCAACCAG | [37] |
R: ATTAGTTGGACCGGAAGATG | ||
MCA1 | F: TATAATAGACCTTCTGGAC | [38] |
R: TTGGTGGACGAGAATAATG |
Compound | C. albicans | C. tropicalis var. tropicalis | C. parapsilosis var. parapsilosis | C. glabrata | C. tropicalis | C. auris |
---|---|---|---|---|---|---|
KCTC7965 | KCTC17762 | KACC45480 | KCTC7219 | KCTC7212 | KCTC17810 | |
Miconazole | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | >100 |
NAIMS 7c | 3.125 | 6.25 | 3.125 | 6.25 | 3.125 | 3.125 |
NAIMS 7g | 12.5 | 25 | 6.25 | 25 | 6.25 | 6.25 |
NAIMS 7h | 50 | 25 | 25 | 25 | 50 | 25 |
8 | >100 | >100 | >100 | >100 | >100 | N/A |
9′ | >100 | >100 | >100 | >100 | >100 | N/A |
9 | >100 | >100 | >100 | >100 | >100 | >100 |
NAIMS 10 | >100 | >100 | >100 | >100 | 25 | >100 |
NAIMS 11 | >100 | >100 | >100 | >100 | 25 | >100 |
NAIMS 7e | 6.25 | 6.25 | 6.25 | 6.25 | 6.25 | 3.125 |
NAIMS 7b | 6.25 | 12.5 | 3.125 | 12.5 | 3.125 | 6.25 |
NAIMS 7i | 12.5 | 12.5 | 6.25 | 12.5 | 6.25 | 12.5 |
NAIMS 7a | >100 | >100 | >100 | >100 | >100 | >100 |
NAIMS 7d | 3.125 | 6.25 | 3.125 | 6.25 | 3.125 | 6.25 |
NAIMS 7f | 100 | 100 | 12.5 | 6.25 | 25 | 100 |
Fungal Strains | Time | Miconazole | NAIMS 7c | NAIMS 7g | NAIMS 7h | 8 | 9′ | 9 | NAIMS 10 | NAIMS 11 | NAIMS 7e | NAIMS 7b | NAIMS 7i | NAIMS 7a | NAIMS 7d | NAIMS 7f |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
C. albicans (KCTC7965) | 48h | 12.5 | 6.25 | 12.5 | 100 | >100 | >100 | >100 | >100 | >100 | 12.5 | 12.5 | 12.5 | >100 | 3.125 | 100 |
72h | 12.5 | 6.25 | 12.5 | 100 | >100 | >100 | >100 | >100 | >100 | 25 | 12.5 | 12.5 | >100 | 6.25 | 100 | |
C. tropicalis var. tropicalis (KCTC17762) | 48h | 12.5 | 6.25 | 25 | 50 | >100 | >100 | >100 | >100 | >100 | 12.5 | 12.5 | 12.5 | >100 | 6.25 | 100 |
72h | 12.5 | 12.5 | 25 | 100 | >100 | >100 | >100 | >100 | >100 | 12.5 | 12.5 | 25 | >100 | 12.5 | 100 | |
C. parapsilosis var. parapsilosis (KACC45480) | 48h | 12.5 | 6.25 | 6.25 | 50 | >100 | >100 | >100 | >100 | >100 | 6.25 | 6.25 | 6.25 | >100 | 6.25 | 12.5 |
72h | 12.5 | 12.5 | 6.25 | 100 | >100 | >100 | >100 | >100 | >100 | 12.5 | 6.25 | 12.5 | >100 | 6.25 | 12.5 | |
C. glabrata (KCTC7219) | 48h | 12.5 | 3.125 | 25 | 50 | >100 | >100 | >100 | >100 | >100 | 12.5 | 12.5 | 12.5 | >100 | 12.5 | 6.25 |
72h | 12.5 | 6.25 | 25 | 50 | >100 | >100 | >100 | >100 | >100 | 12.5 | 12.5 | 25 | >100 | 12.5 | 6.25 | |
C. tropicalis (KCTC7212) | 48h | 12.5 | 6.25 | 6.25 | 50 | >100 | 25 | 50 | 25 | 50 | 12.5 | 6.25 | 6.25 | >100 | 6.25 | N/A |
72h | 12.5 | 6.25 | 6.25 | 100 | >100 | 50 | 50 | 50 | 50 | 25 | 6.25 | 6.25 | >100 | 6.25 | N/A | |
C. auris (KCTC17810) | 48h | >100 | 3.125 | 6.25 | 25 | >100 | >100 | >100 | >100 | >100 | 6.25 | 6.25 | 6.25 | >100 | 6.25 | 100 |
72h | >100 | 3.125 | 6.25 | 25 | N/A | N/A | >100 | >100 | >100 | 6.25 | 6.25 | 12.5 | >100 | 12.5 | 100 |
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Lee, J.; Kim, J.-G.; Lee, H.; Lee, T.H.; Kim, K.-Y.; Kim, H. Antifungal Activity of 1,4-Dialkoxynaphthalen-2-Acyl Imidazolium Salts by Inducing Apoptosis of Pathogenic Candida spp. Pharmaceutics 2021, 13, 312. https://doi.org/10.3390/pharmaceutics13030312
Lee J, Kim J-G, Lee H, Lee TH, Kim K-Y, Kim H. Antifungal Activity of 1,4-Dialkoxynaphthalen-2-Acyl Imidazolium Salts by Inducing Apoptosis of Pathogenic Candida spp. Pharmaceutics. 2021; 13(3):312. https://doi.org/10.3390/pharmaceutics13030312
Chicago/Turabian StyleLee, Jisue, Jae-Goo Kim, Haena Lee, Tae Hoon Lee, Ki-Young Kim, and Hakwon Kim. 2021. "Antifungal Activity of 1,4-Dialkoxynaphthalen-2-Acyl Imidazolium Salts by Inducing Apoptosis of Pathogenic Candida spp." Pharmaceutics 13, no. 3: 312. https://doi.org/10.3390/pharmaceutics13030312