Abstract
Background: Griseofulvin - a mold metabolite produced by Penisilium griseofulvum is known as an antifungal drug.
Objective: Thus, the goal of this paper is the design and synthesis of new griseofulvin derivatives and evaluation of their antifungal activity.
Methods: Forty-two new compounds were synthesized using classical methods of organic synthesis and evaluated for their antimicrobial activity by microdilution method.
Results: All forty-two new compounds exhibited very good activity against eight tested micromycetes with MIC ranging from 0.0075-0.055 mg/ml and MFC from 0.02-024 mg/ml. All compounds exhibited better activity than reference drugs ketoconazole (7-42 times) and bifonazole (3-16 fold). The most promising was compound 15. The most sensitive fungal was found to be T. viride, while the most resistant, as was expected, was A. fumigatus. It should be mentioned that most of compounds exhibited better activity than griseofulvin.
The molecular docking studies revealed that the most active compound have the same hydrophobic and H-bonding interactions with Thr276 residue observed for griseofulvin forming 3 hydrogen bonds while griseofulvin only one. In general, the molecular docking results coincide with experimental.
Conclusion: Forty-two giseofulvin derivatives were designed, synthesized and evaluated for antimicrobial activity. These derivatives revealed good antifungal activity, better than reference drugs ketoconazole, bifonazole, and griseofulvin as well.
Keywords: Griseofulvin derivatives, Microdilution method, Antifungal, Ketoconazole, Bifonazole, Docking, Tubulin.
Graphical Abstract
[1]
Keller, N.P.; Turner, G.; Bennett, J.W. Fungal secondary metabolism from biochemistry to genomics. Nat. Rev. Microbiol., 2005, 3, 937-947.
[http://dx.doi.org/10.1038/nrmicro1286]
[http://dx.doi.org/10.1038/nrmicro1286]
[2]
Schueffler, A.; Anke, T. Fungal natural products in research and development. Nat. Prod. Rep., 2014, 31, 1425-1448.
[http://dx.doi.org/10.1039/c4np00060a]
[http://dx.doi.org/10.1039/c4np00060a]
[3]
Aly, A.H.; Debbab, A.; Kjer, J.; Proksch, P. Fungal endophytes from higher plants: a prolific source of phytochemicals and other bioactive natural products. Fungal Divers., 2010, 41, 1-16.
[http://dx.doi.org/https://doi.org/10.1007/s13225-010-0034-4]
[http://dx.doi.org/https://doi.org/10.1007/s13225-010-0034-4]
[4]
Geris, R.; Simpson, T.J. Meroterpenoids produced by fungi. Nat. Prod. Rep., 2009, 26, 1063-1094.
[http://dx.doi.org/10.1039/b820413f].]
[http://dx.doi.org/10.1039/b820413f].]
[5]
Schulz, B.; Boyle, C.; Draeger, S.; Rommert, A.K.; Krohn, K. Endophytic fungi: a source of novel biologically active secondary metabolites. Mycol. Res., 2002, 106, 996-1004.
[http://dx.doi.org/https://doi.org/10.1017/S0953756202006342]
[http://dx.doi.org/https://doi.org/10.1017/S0953756202006342]
[6]
Knarwar, R.; Mishra, A.; Gong, S.K.; Stierle, A.; Stierle, D. Anticancer compounds derived from fungal endophytes: their importance and future challenges. Nat. Prod. Rep., 2011, 28, 1208-1228.
[7]
Wu, W.; Gavia, D.J.; Tang, Y. Biosynthesis of fungal indole alkaloids. Nat. Prod. Rep., 2014, 31, 1474-1487.
[http://dx.doi.org/10.1039/c4np00073k]
[http://dx.doi.org/10.1039/c4np00073k]
[8]
Li, S.M. Prenylated indole derivatives from fungi: structure diversity, biological activities, biosynthesis and chemoenzymatic synthesis. Nat. Prod. Rep., 2010, 27, 57-78.
[http://dx.doi.org/10.1039/b909987p]
[http://dx.doi.org/10.1039/b909987p]
[9]
Xu, G.B.; He, G.; Bai, H.H.; Yang, T.; Zhang, G.L.; Wu, L.W.; Li, G.Y. Indol alkaloid from Chaetonium globosum. J. Nat. Prod., 2015, 78, 1479-1485.
[http://dx.doi.org/[DOI:10.1021/np5007235]
[http://dx.doi.org/[DOI:10.1021/np5007235]
[10]
Chen, M.; Shao, C.L.; Fu, X.M.; Xu, R.F.; Zheng, J.J.; Zhao, D.L.; She, Z.G.; Wang, C.Y. Bioactive indole alkaloids and phenyl ether derivatives from a marine-derived Aspergillus sp. fungus. J. Nat. Prod., 2013, 76, 547-553.
[http://dx.doi.org/10.1021/np300707x]
[http://dx.doi.org/10.1021/np300707x]
[11]
Qian-Cutrone, J.; Huang, S.; Shu, Y.Z.; Vyas, D.; Fairchild, C.; Menendez, A.; Krampitz, K.; Dalterio, R.; Klohr, S.E.; Gao, Q.H. Stephacidin A and B two structuraly nivel inhibitors of the testosterone-dependent prostate LNCap cells. Amer. Chem. Soc., 2002, 124, 14556-14557.
[http://dx.doi.org/10.1021/ja028538n]
[http://dx.doi.org/10.1021/ja028538n]
[12]
Jiao, R.H.; Xu, S.; Liu, J.Y.; Ge, H.M.; Ding, H.; Xu, C.; Zhu, H.L.; Tan, R.X. Chaetominine, a cytotoxic alkaloid produced by endophytic Chaetomium sp. IFB-E015. Org. Lett., 2006, 8, 5709-5712.
[http://dx.doi.org/10.1021/ol062257t]
[http://dx.doi.org/10.1021/ol062257t]
[13]
Zhang, D.W.; Ge, H.L.; Xie, D.; Chen, R.D.; Zou, J.H.; Tao, X.Y.; Dai, J.G. Periconiasins A–C, new cytotoxic cytochalasans with an unprecedented 9/6/5 tricyclic ring system from endophytic fungus Periconia sp. Org. Lett., 2013, 15, 1674-1677.
[http://dx.doi.org/10.1021/ol400458n]
[http://dx.doi.org/10.1021/ol400458n]
[14]
Ho, Y.S.; Duh, J.S.; Jeng, J.H.; Wang, Y.J.; Liang, Y.C.; Lin, C.H. Taseng, C. J.; Yu, C. F.; Chen, R. J.; Lin, J. K. Griseofulvin potentiates antitumorigenesis effects of nocodazole through induction of apoptosis and G2/M cell cycle arrest in human colorectal cancer cells. Int. J. Cancer, 2001, 91(3), 393-401.
[http://dx.doi.org/10.1002/1097-0215(200002)9999:99993.0.CO;2-%23]
[http://dx.doi.org/10.1002/1097-0215(200002)9999:99993.0.CO;2-%23]
[15]
Kozlovsky, A.G.; Zhelifonova, V.R.; Antipova, T.V.; Adanin, V.M.; Ozerskaya, S.M.; Kochkina, G.A.; Schlegel, B.; Dahse, H.M.; Gollmick, F.A.; Grafe, U. Quinocitrinines A and B, new quinoline alkaloids from Penicillium citrinum Thom 1910, a permafrost fungus. J. Antibiot. , 2003, 56, 488-491.
[PMID: 12870815]
[PMID: 12870815]
[16]
Kochanowska-Karamyan, A.J.; Hamann, M.T. Marine indole alkaloids: Potential new drug leads for the control of depression and anxiety. Chem. Rev., 2010, 119, 4489-4497.
[http://dx.doi.org/10.1021/cr900211p]
[http://dx.doi.org/10.1021/cr900211p]
[17]
Chen, S.; Wang, J.; Lin, X.; Zhao, B.; Wei, X.; Li, G.; Kaliaperumal, K.; Liao, S.; Yang, B.; Zhou, X.; Liu, J.; Xu, S.; Liu, Y. Chrysamides A-C, three dimeric nitrophenyl trans-Epoxyamides produced by the deep-sea-derived fungus Penicillium chrysogenum SCSIO 41001. Org. Lett., 2016, 18, 3650-3653.
[http://dx.doi.org/10.1021/acs.orglett.6b01699.]
[http://dx.doi.org/10.1021/acs.orglett.6b01699.]
[18]
Cao, P.; Yang, J.; Miao, C.P.; Yan, Y.; Ma, Y.T.; Li, X.N.; Zhao, L.X.; Huang, S.X. New duclauxamide from Penicillium manginii YIM PH30375 and structure revision of the duclauxin family. Org. Lett., 2015, 17, 1146-1149.
[http://dx.doi.org/10.1021/acs.orglett.5b00081]
[http://dx.doi.org/10.1021/acs.orglett.5b00081]
[19]
Jin, H.; Yamashita, A.; Maekawa, S.; Yang, P.; He, L.; Takayanagi, S.; Wakita, T.; Sakamoto, N.; Enomoto, N.; Ito, M. Griseofulvin, an oral antifungal agent, suppresses hepatitis C virus replication in vitro. Hepatol. Res., 2008, 38, 909-918.
[http://dx.doi.org/10.1111/j.1872-034X.2008.00352.x.]
[http://dx.doi.org/10.1111/j.1872-034X.2008.00352.x.]
[20]
Kozlovsky, A.G.; Zhelifonova, V.P.; Antipova, T.V. Biologically active metabolites of Penicillium fungi. Signpost Open Access J. Org. Biomol. Chem., 2013, 1, 11-21.
[http://dx.doi.org/10.3390/md14020037]
[http://dx.doi.org/10.3390/md14020037]
[21]
Lou, J.; Fu, L.; Peng, Y.; Zhou, L. Metabolites from Alternaria Fungi and Their Bioactivities. Molecules, 2013, 18, 5891-5935.
[http://dx.doi.org/10.3390/molecules18055891.]
[http://dx.doi.org/10.3390/molecules18055891.]
[22]
Oxford, A.E.; Raistrick, H.; Simonart, P. Studies in the biochemistry of micro-organisms: Griseofulvin, C(17)H(17)O(6)Cl, a metabolic product of Penicillium griseo-fulvum Dierckx. Biochem. J., 1939, 23, 240-248.
[http://dx.doi.org/10.1042/bj0330240]
[http://dx.doi.org/10.1042/bj0330240]
[23]
Grove, J.E.; McGowan, J.C. Identity of griseofulvin and curling factor. Nature, 1947, 160, 574.
[http://dx.doi.org/10.1038/160574a0]
[http://dx.doi.org/10.1038/160574a0]
[24]
Brian, P.W.; Curtis, P.J.; Hemming, H.G. A substance causing abnormal development of fungal hypnae produced by Penicillium janczewski ZAL.I. Biological assay, production and isolation of “curling factor. Trans. Br. Mycol. Soc., 1946, 29, 173.
[25]
McGowan, J.C. A substance causing abnormal development of fungal hyphae produced by Penicillium jancxmskii Zal. 11. Preliminary notes on the chemical and physical properties of ‘curling-factor’. Trans. Br. Mycol. Soc., 1946, 29, 188.
[26]
Brian, P.W.; Curtis, P.J.; Hemming, H.G. A substance causing abnormal developmet of fungal hyphae produced by Penicillium janczewskii. Trans. Br. Mycol. Soc., 1949, 32, 30-33.
[27]
Nishikori, S.; Takemodo, K.; Kamisuki, S.; Nakajima, S.; Kuramochi, K.; Tsukuda, S.; Iwamoto, M.; Katayama, Y.; Suzuki, T.; Kobayashi, S.; Watashi, K.; Sugawara, F. Anti-hepatitis C Virus Natural Product from a Fungus, Penicillium herquei. J. Nat. Prod., 2016, 79, 442-446.
[http://dx.doi.org/10.1021/acs.jnatprod.5b00555]
[http://dx.doi.org/10.1021/acs.jnatprod.5b00555]
[28]
Anusha, M.; Sangeetha, D. Production of griseofulvin from marine fungi Penicillium fellutanum. International. J. Appl. Res., 2016, 2, 701-704.
[29]
Sica, V.P.; Rees, E.R.; Tchegnon, E. Bardsley, R.H.; Raja, H.A.; Oberlies, N.H. Spatial and Temporal Profiling of Griseofulvin Production in Xylaria cubensis Using Mass Spectrometry Mapping. Front. Microbiol., 2016, 7, 544.
[http://dx.doi.org/10.3389/fmicb.2016.00544]
[http://dx.doi.org/10.3389/fmicb.2016.00544]
[30]
Park, J.H.; Choi, G.J.; Lee, S.W.; Lee, H.B.; Kim, K.M.; Jung, H.S.; Jang, K.S.; Cho, K.Y.; Kim, J.C. Griseofulvin from Xylaria sp. strain F0010, an endophytic fungus of Abies holophylla and its antifungal activity against plant pathogenic fungi. J. Microbiol. Biotechnol., 2005, 15, 112-117.
[http://dx.doi.org/[https://doi.org/10.1016/j.funeco.2014.05.004]
[http://dx.doi.org/[https://doi.org/10.1016/j.funeco.2014.05.004]
[31]
Richardson, R.N.; Walker, A.K.; Nsiama, T.K.; McFarlane, J.; Sumarah, M.W.; Ibrahim, A.; Miller, J.D. Griseofulvin producing Xylaria endophytes of Pinus strobus and Vaccinium angustifolium: Evidence for a conifer-understory species endophyte ecology. Fungal Ecol., 2014, 11, 107-111.
[http://dx.doi.org/https://doi.org/10.1016/j.funeco.2014.05.004]
[http://dx.doi.org/https://doi.org/10.1016/j.funeco.2014.05.004]
[32]
Zhang, D.; Zhao, L.; Wang, L.; Fang, W.; Zhao, J.; Wang, X.; Li, L.; Liu, H.; Wei, W. Griseofulvin derivative and indole alkaloids from Penicillium griseofulvum CPCC 400528. J. Nat. Prod., 2017, 80, 371-376.
[http://dx.doi.org/10.1021/acs.jnatprod.6b00829]
[http://dx.doi.org/10.1021/acs.jnatprod.6b00829]
[33]
Cole, R.H.; Kirksey, J.W.; Holaday, C.E. Detection of griseofulvin and dechlorogriseofulvin by thin-layer chromatography and gas-liquid chromatography. Appl. Microbiol., 1970, 19, 106-108.
[PMID: 5415206]
[PMID: 5415206]
[34]
Sobue, S.; Sekiguchi, K.; Nabeshima, T. Intracutaneous Distributions of Fluconazole, Itraconazole, and Griseofulvin in Guinea Pigs and Binding to Human Stratum Corneum. Antimicrob. Agents Chemother., 2004, 48, 216-223.
[http://dx.doi.org/10.1128/aac.48.1.216-223.2004]
[http://dx.doi.org/10.1128/aac.48.1.216-223.2004]
[35]
Chaudhuri, A.R.; Luduena, R.F. Griseofulvin: interaction with normal and subtilisin-treated tubulin. Drug Dev. Res., 2001, 53, 44-49.
[http://dx.doi.org/[https://doi.org/10.1002/ddr.1168]
[http://dx.doi.org/[https://doi.org/10.1002/ddr.1168]
[36]
Ho, Y.S.; Duh, J.S.; Jeng, J.H.; Wang, Y.J.; Liang, Y.C.; Lin, C.H. Griseofulvin potentiates antitumorigenesis effects of nocodazole through induction of apoptosis and G2/M cell cycle arrest in human colorectal cancer cells. Int. J. Cancer, 2001, 91, 393-401.
[http://dx.doi.org/10.1002/1097-0215(200002)9999:99993.0.co;2-#]
[http://dx.doi.org/10.1002/1097-0215(200002)9999:99993.0.co;2-#]
[37]
Kim, Y.; Alpmann, P.; Blaum-Feder, S.; Kramer, S.; Endo, T.; Lu, D. In vivo efficacy of griseofulvin against multiple myeloma. Leuk. Res., 2011, 35, 1070-1073.
[http://dx.doi.org/10.1016/j.leukres.2010.10.008]
[http://dx.doi.org/10.1016/j.leukres.2010.10.008]
[38]
Liéby-Muller, F.; Heudré Le Baliner, Q.; Grisoni, S.; Fournier, E.; Guilbaud, N.; Marion, F. Synthesis and activities towards resistant cancer cells of sulfone and sulfoxide griseofulvin derivatives. Bioorg. Med. Chem. Lett., 2015, 25, 2078-2081.
[http://dx.doi.org/10.1016/j.bmcl.2015.03.081]
[http://dx.doi.org/10.1016/j.bmcl.2015.03.081]
[39]
Rønnest, M.H.; Raab, M.S.; Anderhub, S.; Boesen, S.; Krämer, A.; Larsen, O.; Clausen, M.H. Disparate SAR Data of Griseofulvin Analogues for the Dermatophytes Trichophyton mentagrophytes, T. rubrum, and MDA-MB-231 Cancer Cells. J. Med. Chem., 2012, 55(2), 652-660.
[http://dx.doi.org/[https://doi.org/10.1021/jm200835c]
[http://dx.doi.org/[https://doi.org/10.1021/jm200835c]
[40]
Espinel-Ingroff, A. Comparison of the E-test with the NCCLS M38-P method for antifungal susceptibility testing of common and emerging pathogenic filamentous fungi. J. Clin. Microbiol., 2001, 39, 1360-1367.
[http://dx.doi.org/10.1128/JCM.39.4.1360-1367.2001]
[http://dx.doi.org/10.1128/JCM.39.4.1360-1367.2001]
[41]
Hanel, H.; Raether, A. More sophisticated method of determining the pungicidal effect of water-insoluble preparations W. with a cell Harvester, using miconazole as an example. MYCOSES, 1988, 31, 148-154.
[PMID: [PMID: 3292912]
[PMID: [PMID: 3292912]
[42]
Ronnest, M.H.; Harris, P.; Gotfredsen, C.H.; Larsen, T.O.; Clausen, M.H. Synthesis and single crystal X-ray analysis of two griseofulvin metabolites. Tetrahedron Lett., 2010, 51(45), 5881-5882.
[http://dx.doi.org/https://doi.org/10.1016/j.tetlet.2010.08.095]
[http://dx.doi.org/https://doi.org/10.1016/j.tetlet.2010.08.095]
[43]
Grisham, M.L.; Wilson, L.; Bensch, K.G. Antimitotic action of griseofulvin does not involve disruption of microtubules. Nature, 1973, 244, 294-296.
[http://dx.doi.org/10.1038/244294a0]
[http://dx.doi.org/10.1038/244294a0]
[44]
Wilson, L. Bryan, Biochemical and Pharmacological properties of microtubules. Adv. Mol. Biol., 1973, 3, 21-72.
[45]
Sloboda, R.D.; Van Blaricom, G.; Creasey, W.A.; Rosenbaum, J.L.; Malawista, S.E. Griseofulvin: association with tubulin and inhibition of in vitro microtubule assembly. Biochem. Biophys. Res. Commun., 1982, 105, 882-888.
[http://dx.doi.org/10.1016/0006-291x(82)91052-x]
[http://dx.doi.org/10.1016/0006-291x(82)91052-x]
[46]
Wehland, J.; Herzog, W.; Weber, K. Interaction of Griseofulvin with Microtubules, Microtubule Protein and Tubulin. J. Mol. Biol., 1977, 111, 329-342.
[http://dx.doi.org/10.1016/s0022-2836(77)80055-7]
[http://dx.doi.org/10.1016/s0022-2836(77)80055-7]
[47]
Roobol, A.; Gull, K.; Pogson, C.L. Evidence that griseofulvin binds to a microtubule associated protein. FEBS Lett., 1977, 75, 149-153.
[http://dx.doi.org/10.1016/0014-5793(77)80073-2]
[http://dx.doi.org/10.1016/0014-5793(77)80073-2]
[48]
Cleveland, D.W. Autoregulated instability of tubulin mRNAs: a novel eukaryotic regulatory mechanism. Trends Biochem. Sci., 1988, 13, 339-343.
[PMID: [PMID: 3072712]
[PMID: [PMID: 3072712]
[49]
Rathinasamy, K.; Jindal, B.; Asthana, J.; Sing, P.; Balaj, P.V.; Panda, D. Griseofulvin stabilizes microtubule dynamics, activates p53 and inhibits the proliferation of MCF-7 cells synergistically with vinblastine. BMC Cancer, 2010, 10, 213-226.
[http://dx.doi.org/10.1186/1471-2407-10-213]
[http://dx.doi.org/10.1186/1471-2407-10-213]
Related Journals
Current Medicinal Chemistry
Current Pharmaceutical Design
Current Respiratory Medicine Reviews
Medicinal Chemistry
Infectious Disorders - Drug Targets
Mini-Reviews in Medicinal Chemistry
Endocrine, Metabolic & Immune Disorders - Drug Targets
Anti-Infective Agents
Coronaviruses
Recent Advances in Inflammation & Allergy Drug Discovery
Related Books
Science of Spices and Culinary Herbs - Latest Laboratory, Pre-clinical, and Clinical Studies
Frontiers in Natural Product Chemistry
Therapeutic Use of Plant Secondary Metabolites
Therapeutic Implications of Natural Bioactive Compounds
Frontiers in Bioactive Compounds
Mitochondrial DNA and the Immuno-inflammatory Response: New Frontiers to Control Specific Microbial Diseases
Frontiers in Natural Product Chemistry
Frontiers in Clinical Drug Research – Anti Allergy Agents
Frontiers in Natural Product Chemistry
Science of Spices and Culinary Herbs - Latest Laboratory, Pre-clinical, and Clinical Studies
Article Metrics
43
4
1