Synthesis, Antifungal Activity, Cytotoxicity and QSAR Study of Camphor Derivatives
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials and Equipment
2.2. Synthesis of Camphor Derivatives
2.2.1. Synthesis of 2-(1,7,7-Trimethylbicyclo [2.2.1]heptan-2-ylidene)hydrazine-1-carbothioamide (3a)
2.2.2. Synthesis of N-(2-Chlorobenzyl)-2-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)hydrazine-1-carbothioamide compounds (4a–4s)
2.2.3. Synthesis of 4-Phenyl-2-(2-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)hydrazinyl)thiazole compounds (5a–5o)
2.3. In Vitro Antifungal Activity Evaluation
2.4. Cytotoxicity (MTT) Assays
2.5. Scanning Electron Microscope (SEM) Observations
2.6. Quantitative Structure−Activity Relationship (QSAR) Study
3. Results and Discussion
3.1. Chemistry
3.2. In Vitro Antifungal Activity and Structure−Activity Relationship (SAR)
3.3. Evaluation of Cytotoxicity
3.4. Effect on the Mycelium Morphology of T. versicolor
3.5. QSAR Study
N = 29, R2 = 0.911, F = 61.5, s2 = 0.0973
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Salvatore, M.M.; Andolfi, A. Phytopathogenic Fungi and Toxicity. Toxins 2021, 13, 689. [Google Scholar] [CrossRef] [PubMed]
- Wu, C.-C.; Huang, S.-L.; Ko, C.-H.; Chang, H.-T. Antifungal Sesquiterpenoids from Michelia formosana Leaf Essential Oil against Wood-Rotting Fungi. Molecules 2022, 27, 2136. [Google Scholar] [CrossRef] [PubMed]
- El-Baky, N.A.; Amara, A.A.A.F. Recent Approaches towards Control of Fungal Diseases in Plants: An Updated Review. J. Fungi 2021, 7, 900. [Google Scholar] [CrossRef] [PubMed]
- Price, C.; Parker, J.; Warrilow, A.; Kelly, D.E.; Kelly, S.L. Azole fungicides—Understanding resistance mechanisms in agricultural fungal pathogens. Pest Manag. Sci. 2015, 71, 1054–1058. [Google Scholar] [CrossRef]
- Nazzaro, F.; Fratianni, F.; Coppola, R.; De Feo, V. Essential Oils and Antifungal Activity. Pharmaceuticals 2017, 10, 86. [Google Scholar] [CrossRef] [Green Version]
- Wang, H.; Yang, Z.; Ying, G.; Yang, M.; Nian, Y.; Wei, F.; Kong, W. Antifungal evaluation of plant essential oils and their major components against toxigenic fungi. Ind. Crop. Prod. 2018, 120, 180–186. [Google Scholar] [CrossRef]
- Amini, J.; Farhang, V.; Javadi, T.; Nazemi, J. Antifungal Effect of Plant Essential Oils on Controlling Phytophthora Species. Plant Pathol. J. 2016, 32, 16–24. [Google Scholar] [CrossRef] [Green Version]
- Xie, Y.; Wang, Z.; Huang, Q.; Zhang, D. Antifungal activity of several essential oils and major components against wood-rot fungi. Ind. Crop. Prod. 2017, 108, 278–285. [Google Scholar] [CrossRef]
- Broda, M. Natural Compounds for Wood Protection against Fungi—A Review. Molecules 2020, 25, 3538. [Google Scholar] [CrossRef]
- Deepa, N.; Achar, P.N.; Sreenivasa, M.Y. Current Perspectives of Biocontrol Agents for Management of Fusarium verticillioides and Its Fumonisin in Cereals—A Review. J. Fungi 2021, 7, 776. [Google Scholar] [CrossRef]
- Gao, Y.; Tian, X.; Li, J.; Shang, S.; Song, Z.; Shen, M. Study on Amphipathic Modification and QSAR of Volatile Turpentine Analogues as Value-Added Botanical Fungicides against Crop-Threatening Pathogenic Fungi. ACS Sustain. Chem. Eng. 2016, 4, 2741–2747. [Google Scholar] [CrossRef]
- Guo, Y.Y.; Chen, J.B.; Ren, D.; Du, B.D.; Wu, L.; Zhang, Y.Y.; Wang, Z.Y.; Qian, S. Synthesis of osthol-based botanical fungicides and their antifungal application in crop protection. Bioorg. Med. Chem. 2021, 40, 116184. [Google Scholar] [CrossRef]
- Kong, W.; Huo, H.; Gu, Y.; Cao, Y.Q.; Wang, J.L.; Liang, J.Y.; Niu, S.Q. Antifungal activity of camphor against four phyto-pathogens of Fusarium. S. Afr. J. Bot. 2022, 148, 437–445. [Google Scholar] [CrossRef]
- Mokbel, A.A.; Alharbi, A.A. Antifungal effects of basil and camphor essential oils against Aspergillus flavus and A. parasiticus. Aust. J. Crop. Sci. 2015, 9, 532–537. [Google Scholar]
- Gazdağlı, A.; Sefer, Ö.; Yörük, E.; Varol, G.I.; Teker, T.; Albayrak, G. Investigation of camphor effects on Fusarium graminearum and F. culmorum at different molecular levels. Pathogens 2018, 7, 90. [Google Scholar] [CrossRef] [Green Version]
- Mahilrajan, S.; Nandakumar, J.; Kailayalingam, R.; Manoharan, N.A.; SriVijeindran, S. Screening the antifungal activity of essential oils against decay fungi from palmyrah leaf handicrafts. Biol. Res. 2014, 47, 1–5. [Google Scholar] [CrossRef] [Green Version]
- Shokova, E.A.; Kim, J.K.; Kovalev, V. Camphor and its derivatives. Unusual transformations and biological activity. Russ. J. Org. Chem. 2016, 52, 459–488. [Google Scholar] [CrossRef]
- Anjaneyulu, B.; Sangeeta; Saini, N. A Study on Camphor Derivatives and Its Applications: A Mini-Review. Curr. Org. Chem. 2021, 25, 1404–1428. [Google Scholar] [CrossRef]
- Petkova, Z.; Valcheva, V.; Momekov, G.; Petrov, P.; Dimitrov, V.; Doytchinova, I.; Stavrakov, G.; Stoyanova, M. Antimyco-bacterial activity of chiral aminoalcohols with camphane scaffold. Eur. J. Med. Chem. 2014, 81, 150–157. [Google Scholar] [CrossRef]
- Huang, Y.; Duan, W.G.; Lin, G.S.; Cen, B.; Wang, F.; Lei, F.H. Syntheses and Biological Activities of Camphor-Based Benzamide Compounds. Chem. Bull. 2014, 9, 878–882. (In Chinese) [Google Scholar]
- Ma, X.-L.; Li, F.; Duan, W.-G.; Liao, J.-N.; Lin, Z.-D.; Lin, G.-S.; Cen, B.; Lei, F.-H. Synthesis and antifungal activity of camphoric acid-based acylhydrazone compounds. Holzforschung 2014, 68, 889–895. [Google Scholar] [CrossRef]
- Abo-Bakr, A.M.; Hassan, E.A.; Mahdy, A.H.S.; Zayed, S.E. Synthetic and biological studies on some new camphor thiazoli-dinones. J. Iran. Chem. Soc. 2021, 4128, 2757–2769. [Google Scholar] [CrossRef]
- Altalhi, A.A.; Hashem, H.E.; Negm, N.A.; Mohamed, E.A.; Azmy, E.M. Synthesis, characterization, computational study, and screening of novel 1-phenyl-4-(2-phenylacetyl)-thiosemicarbazide derivatives for their antioxidant and antimicrobial activities. J. Mol. Liq. 2021, 333, 115977. [Google Scholar] [CrossRef]
- Nevagi, R.J.; Dhake, A.S.; Narkhede, H.I.; Kaur, P. Design, synthesis and biological evaluation of novel thiosemicarbazide analogues as potent anticonvulsant agents. Bioorganic Chem. 2014, 54, 68–72. [Google Scholar] [CrossRef]
- Qin, Y.K.; Xing, R.; Liu, S.; Li, K.C.; Meng, X.T.; Li, R.F.; Cui, J.H.; Li, B.; Li, P.C. Novel thiosemicarbazone chitosan derivatives: Preparation, characterization, and antifungal activity. Carbohydr. Polym. 2012, 87, 2664–2670. [Google Scholar] [CrossRef]
- Yamaguchi, M.U.; Barbosada, S.A.; Ueda-Nakamura, T.; Dias, F.B.; Conceicaoda, S.C.; Nakamura, C.V. Effects of a thio-semicarbazide camphene derivative on Trichophyton mentagrophytes. Molecules 2009, 14, 1796–1807. [Google Scholar] [CrossRef]
- Mao, S.; Wu, C.; Gao, Y.; Hao, J.; He, X.; Tao, P.; Li, J.; Shang, S.; Song, Z.; Song, J. Pine Rosin as a Valuable Natural Resource in the Synthesis of Fungicide Candidates for Controlling Fusarium oxysporum on Cucumber. J. Agric. Food Chem. 2021, 69, 6475–6484. [Google Scholar] [CrossRef]
- Chao, Z.; Wu, J.; Reinhart-King, C.A.; Chu, C.C. Synthesis, characterization and cytotoxicity of photo-crosslinked maleic chitosan-polyethylene glycol diacrylate hybrid hydrogels. Acta Biomater. 2010, 6, 3908–3918. [Google Scholar]
- Wang, W.; Cheng, X.; Cui, X.; Xia, D.G.; Wang, Z.Q.; Lv, X.H. Synthesis and biological activity of novel Pyrazolo [3,4-d]pyrimidin-4-one derivatives as potent antifungal agent. Pest. Manag. Sci. 2021, 77, 3529–3537. [Google Scholar] [CrossRef] [PubMed]
- Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; et al. Gaussian 09; Gaussian, Inc.: Wallingford, CT, USA, 2009. [Google Scholar]
- Dewar, M.J.S.; Holder, A.J.; Dennington, R.D.; Liotard, D.A.; Truhlar, D.G.; Keith, T.A.; Millam, J.M.; Harris, C.D. AMPAC 8 User Manual; Semichem, Inc.: Shawnee, KS, USA, 2004. [Google Scholar]
- Katritsky, A.; Karelson, M.; Lobanov, V.S.; Dennington, R.; Keith, T. CODESSA 2.7.10.; Semichem, Inc.: Shawnee, KS, USA, 2004. [Google Scholar]
- Katritzky, A.R.; Dobchev, D.A.; Tulp, I.; Karelson, M.; Carlson, D.A. QSAR study of mosquito repellents using Codessa Pro. Bioorganic Med. Chem. Lett. 2006, 16, 2306–2311. [Google Scholar] [CrossRef] [PubMed]
- Tämm, K.; Fara, D.C.; Katritzky, A.R.; Burk, A.P.; Karelson, M. A Quantitative Structure−Property Relationship Study of Lithium Cation Basicities. J. Phys. Chem. A 2004, 108, 4812–4818. [Google Scholar] [CrossRef]
- Sokolova, A.S.; Yarovaya, O.L.; Bormotov, N.L.; Shishkina, L.N.; Salakhutdinov, N.F. Synthesis and antiviral activity of camphor-based 1,3-thiazolidin-4-one and thiazole derivatives as orthopoxvirus-reproduction inhibitors. RSC Med. Chem. 2018, 9, 1746–1753. [Google Scholar] [CrossRef]
- Borba, J.V.V.B.; Tauhata, S.B.F.; Oliveira, C.M.A.D.; Marques, M.F.; Bailao, A.M.; Soares, C.M.D.A. Chemoproteomic identi-fication of molecular targets of antifungal prototypes, thiosemicarbazide and a camphene derivative of thiosemicarbazide, in paracoccidioides brasiliensis. PLoS ONE 2018, 13, e0201948. [Google Scholar] [CrossRef]
- De Mello, F.E.; Lopes-Caitar, V.S.; Prudente, H.; Xavier-Valencio, S.A.; Franzenburg, S.; Mehl, A.; Marcelino-Guimaraes, F.C.; Verreet, J.-A.; Balbi-Peña, M.I.; Godoy, C.V. Sensitivity of Cercospora spp. from soybean to quinone outside inhibitors and methyl benzimidazole carbamate fungicides in Brazil. Trop. Plant Pathol. 2021, 46, 69–80. [Google Scholar] [CrossRef]
- Chen, Y.; Mi, Y.; Sun, X.; Zhang, J.; Li, Q.; Ji, N.; Guo, Z. Novel Inulin Derivatives Modified with Schiff Bases: Synthesis, Characterization, and Antifungal Activity. Polymers 2019, 11, 998. [Google Scholar] [CrossRef] [Green Version]
- Pan, T.; Geng, Y.X.; Hao, J.; He, X.H.; Li, J.; Gao, Y.Q.; Shang, S.B.; Song, Z.Q. Taking advantage of the renewable forest bio-resource turpentine to prepare α,β- unsaturated compounds as highly efficient fungicidal candidates. J. Agric. Food. Chem. 2021, 69, 12985–12993. [Google Scholar] [CrossRef]
- Zhang, L.; Shi, Y.; Duan, X.; He, W.; Si, H.; Wang, P.; Chen, S.; Luo, H.; Rao, X.; Wang, Z.; et al. Novel Citral-thiazolyl Hydrazine Derivatives as Promising Antifungal Agents against Phytopathogenic Fungi. J. Agric. Food Chem. 2021, 69, 14512–14519. [Google Scholar] [CrossRef]
- Zhang, L.; Feng, X.Z.; Xiao, Z.Q.; Fan, G.R.; Chen, S.X.; Liao, S.L.; Luo, H.; Wang, Z.D. Design, Synthesis, Antibacterial, An-tifungal and Anticancer Evaluations of Novel β-Pinene Quaternary Ammonium Salts. Int. J. Mol. Sci. 2021, 22, 11299. [Google Scholar] [CrossRef]
- Katritzky, A.R.; Lobanov, V.; Karelson, M. CODESSA: Reference Manual; University of Florida: Gainesville, FL, USA, 1994. [Google Scholar]
- Katritzky, A.R.; Petrukhin, R.; Yang, H.; Karelson, M. CODESSA PRO User’s manual (Comprehensive Descriptors for Structural and Statistical Analysis); University of Florida: Gainesville, FL, USA, 2002. [Google Scholar]
- Johnson, B.M.; Shu, Y.-Z.; Zhuo, X.; Meanwell, N.A. Metabolic and Pharmaceutical Aspects of Fluorinated Compounds. J. Med. Chem. 2020, 63, 6315–6386. [Google Scholar] [CrossRef]
- Li, Q.; Kang, C.B. Mechanisms of action for small molecules revealed by structural biology in drug discovery. Int. J. Mol. Sci. 2020, 21, 5262. [Google Scholar] [CrossRef]
- Girgis, A.S.; Saleh, D.O.; George, R.F.; Srour, A.M.; Pillai, G.G.; Panda, C.S.; Katritzky, A.R. Synthesis, bioassay, and QSAR study of bronchodilatory active 4H-pyrano [3,2-c]pyridine-3-carbonitriles. Eur. J. Med. Chem. 2015, 89, 835–843. [Google Scholar] [CrossRef]
- Holder, A.J.; Ye, L.; Yourtee, D.M.; Agarwal, A.; Eick, J.D.; Chappelow, C.C. An application of the QM-QSAR method to predict and rationalize lipophilicity of simple monomers. Dent. Mater. 2005, 21, 591–598. [Google Scholar] [CrossRef]
Compd. | EC50 (mg/L) | |||||
---|---|---|---|---|---|---|
PN | FV | CG | SS | FO | TV | |
1 | >1000 | >1000 | >1000 | >1000 | 597.01 | >1000 |
2 | 215.66 | 172.24 | 92.44 | 159.50 | 118.14 | 150.55 |
3a | 25.08 | 40.18 | 12.85 | 17.09 | 19.30 | 0.43 |
4a | 207.80 | 82.34 | 36.51 | 93.51 | 38.56 | 6.80 |
4b | 253.14 | 88.85 | 34.94 | 109.93 | 15.89 | 99.70 |
4c | 176.72 | 63.91 | 28.91 | 86.14 | 16.24 | 35.78 |
4d | 158.81 | 69.10 | 30.62 | 101.23 | 19.97 | 7.67 |
4e | 89.92 | 62.16 | 80.49 | 100.08 | 20.05 | 593.17 |
4f | >1000 | >1000 | 74.00 | >1000 | 734.52 | 361.20 |
4g | >1000 | >1000 | 771.99 | >1000 | >1000 | >1000 |
4h | 79.78 | 34.39 | 65.66 | 69.47 | 29.85 | 101.99 |
4i | >1000 | 45.97 | 330.96 | >1000 | 899.39 | >1000 |
4j | 101.81 | 39.68 | 26.90 | 54.04 | 38.55 | 68.47 |
4k | 91.87 | 40.54 | 24.09 | 77.58 | 21.03 | 17.18 |
4l | 178.16 | 58.83 | 59.23 | 120.53 | 20.80 | 204.45 |
4m | 137.26 | 31.32 | 34.65 | / | 25.05 | 107.66 |
4n | 174.28 | 66.43 | 35.03 | 127.07 | 16.33 | 342.56 |
4o | >1000 | 206.14 | 136.85 | >1000 | 42.63 | 6.89 |
4p | 341.97 | 131.69 | 33.22 | 162.35 | 38.88 | 18.86 |
4q | >1000 | >1000 | 52.24 | >1000 | 730.69 | 51.49 |
4r | 73.59 | 645.97 | 80.55 | 101.04 | 26.50 | >1000 |
4s | 112.39 | 723.36 | 82.85 | 76.73 | 56.45 | >1000 |
5a | >1000 | 125.46 | 371.75 | >1000 | >1000 | 4.42 |
5b | >1000 | >1000 | 364.55 | >1000 | 486.83 | 11.30 |
5c | >1000 | 816.15 | 639.90 | >1000 | >1000 | 7.40 |
5d | >1000 | >1000 | 769.85 | >1000 | >1000 | 40.93 |
5e | >1000 | >1000 | 522.47 | >1000 | >1000 | 139.57 |
5f | >1000 | >1000 | >1000 | >1000 | >1000 | 101.56 |
5g | >1000 | >1000 | 652.17 | >1000 | >1000 | 7.85 |
5h | >1000 | >1000 | 233.73 | >1000 | >1000 | 12.37 |
5i | >1000 | >1000 | >1000 | >1000 | / | / |
5j | >1000 | >1000 | 474.68 | >1000 | >1000 | 16.24 |
5k | >1000 | >1000 | 489.08 | >1000 | >1000 | 4.86 |
5l | >1000 | >1000 | 33.64 | >1000 | >1000 | 5.09 |
5m | >1000 | >1000 | >1000 | >1000 | / | 294.86 |
5n | >1000 | >1000 | >1000 | >1000 | >1000 | >1000 |
5o | >1000 | >1000 | 634.710 | >1000 | / | >1000 |
tricyclazole | 80.58 | 185.93 | 79.39 | 268.37 | 66.78 | 118.20 |
carbendazim | 1.49 | 0.55 | 0.20 | 4.67 | 0.45 | 1.20 |
Descriptor No. | Regression Coefficient (X) | Standard Error (ΔX) | t-Test | Descriptors |
---|---|---|---|---|
0 | 1.757 | 1.904 | 0.922 | Intercept |
1 | 0.416 | 0.052 | 8.067 | NOF a |
2 | 0.903 | 0.1008 | 8.960 | RMW b |
3 | −11.104 | 2.862 | −3.880 | MAOEP c |
4 | 0.528 | 0.203 | 2.578 | FPSA-2 d |
R2 | Rloo2 | Training Set | N | R2 (Fit) | Test Set | N | R2 (Fit) |
---|---|---|---|---|---|---|---|
0.911 | 0.844 | A + B | 20 | 0.924 | C | 9 | 0.886 |
B + C | 19 | 0.886 | A | 10 | 0.831 | ||
A + C | 19 | 0.882 | B | 10 | 0.922 | ||
Average | - | 0.897 | Average | - | 0.880 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Duan, X.; Zhang, L.; Si, H.; Song, J.; Wang, P.; Chen, S.; Luo, H.; Rao, X.; Wang, Z.; Liao, S. Synthesis, Antifungal Activity, Cytotoxicity and QSAR Study of Camphor Derivatives. J. Fungi 2022, 8, 762. https://doi.org/10.3390/jof8080762
Duan X, Zhang L, Si H, Song J, Wang P, Chen S, Luo H, Rao X, Wang Z, Liao S. Synthesis, Antifungal Activity, Cytotoxicity and QSAR Study of Camphor Derivatives. Journal of Fungi. 2022; 8(8):762. https://doi.org/10.3390/jof8080762
Chicago/Turabian StyleDuan, Xinying, Li Zhang, Hongyan Si, Jie Song, Peng Wang, Shangxing Chen, Hai Luo, Xiaoping Rao, Zongde Wang, and Shengliang Liao. 2022. "Synthesis, Antifungal Activity, Cytotoxicity and QSAR Study of Camphor Derivatives" Journal of Fungi 8, no. 8: 762. https://doi.org/10.3390/jof8080762