Generic placeholder image

The Natural Products Journal

Author(s): Mohamed E.I. Badawy*, Entsar I. Rabea and Samir A.M. Abdelgaleil

DOI: 10.2174/2210315509666190117150153

DownloadDownload PDF Flyer Cite As
Studies on the EC50 of Natural Monoterpenes as Fungal Inhibitors with Quantitative Structure-Activity Relationships (QSARs)

Page: [44 - 60] Pages: 17

  • * (Excluding Mailing and Handling)

Abstract

Background: Monoterpenes are the main constituents of the essential oils obtained from plants. These natural products offered wide spectra of biological activity and extensively tested against microbial pathogens and other agricultural pests.

Methods: Antifungal activity of 10 monoterpenes, including two hydrocarbons (camphene and (S)- limonene) and eight oxygenated hydrocarbons ((R)-camphor, (R)-carvone, (S)-fenchone, geraniol, (R)-linalool, (+)-menthol, menthone, and thymol), was determined against fungi of Alternaria alternata, Botrytis cinerea, Botryodiplodia theobromae, Fusarium graminearum, Phoma exigua, Phytophthora infestans, and Sclerotinia sclerotiorum by the mycelia radial growth technique. Subsequently, Quantitative Structure-Activity Relationship (QSAR) analysis using different molecular descriptors with multiple regression analysis based on systematic search and LOOCV technique was performed. Moreover, pharmacophore modelling was carried out using LigandScout software to evaluate the common features essential for the activity and the hypothetical geometries adopted by these ligands in their most active forms.

Results: The results showed that the antifungal activities were high, but depended on the chemical structure and the type of microorganism. Thymol showed the highest effect against all fungi tested with respective EC50 in the range of 10-86 mg/L. The QSAR study proved that the molecular descriptors HBA, MR, Pz, tPSA, and Vp were correlated positively with the biological activity in all of the best models with a correlation coefficient (r) ≥ 0.98 and cross-validated values (Q2) ≥ 0.77.

Conclusion: The results of this work offer the opportunity to choose monoterpenes with preferential antimicrobial activity against a wide range of plant pathogens.

Keywords: Monoterpenes, antifungal activity, EC50, molecular descriptors, QSAR, antimicrobial activity.

Graphical Abstract

[1]
Maltby, L.; Brock, T.C.M.; van den Brink, P.J. Fungicide risk assessment for aquatic ecosystems: importance of interspecific variation, toxic mode of action, and exposure regime. Environ. Sci. Technol., 2009, 43, 7556-7563.
[2]
Waard, M.A.; Georgopoulos, S.G.; Hollomon, D.W.; Ishii, H.; Leroux, P.; Ragsdale, N.N.; Schwinn, F.J. Chemical control of plant diseases: Problems and prospects. Annu. Rev. Phytopathol., 1993, 31, 403-421.
[3]
Igbedioh, S.O. Effects of agricultural pesticides on humans, animals, and higher plants in developing countries. Arch. Environ. Health: . An Int. J., 1991, 46, 218-224.
[4]
Badawy, M.E.I.; Rabea, E.I. Synthesis and structure–activity relationship of N-(cinnamyl) chitosan analogs as antimicrobial agents. Int. J. Biol. Macromol., 2013, 57, 185-192.
[5]
Jacometti, M.A.; Wratten, S.D.; Walter, M. Review: alternatives to synthetic fungicides for Botrytis cinerea management in vineyards. Aust. J. Grape Wine Res., 2010, 16, 154-172.
[6]
Rabea, E.I.; Badawy, M.E-T.; Stevens, C.V.; Smagghe, G.; Steurbaut, W. Chitosan as antimicrobial agent: applications and mode of action. Biomacromolecules, 2003, 4, 1457-1465.
[7]
Marei, G.I.K.; Rabea, E.I.; Badawy, M.E.I. Preparation and characterizations of chitosan/citral nanoemulsions and their antimicrobial activity. Appl. Food Biotech, 2018, 5, 69-78.
[8]
Windholz, M.; Budavari, S.; Blumetti, R.F.; Otterbein, E.S. The Merck Index; Rahway, NJ: Merck. , 1983.
[9]
Templeton, W. An introduction to the chemistry of the terpenoids and steroids., 1969.
[10]
Budzikiewicz, H.; Djerassi, C.; Williams, D.H. Structure elucidation of natural products by mass spectrometry: Steroids, terpenoids, sugars, and miscellaneous classes; San Francisco Holden-Day,. , 1964, Vol. 2, .
[11]
Garcia, R.; Alves, E.S.S.; Santos, M.P.; Aquije, G.M.F.; Fernandes, A.A.R.; Santos, R.B.D.; Ventura, J.A.; Fernandes, P. Antimicrobial activity and potential use of monoterpenes as tropical fruits preservatives. Braz. J. Microbiol., 2008, 39, 163-168.
[12]
Kordali, S.; Kesdek, M.; Cakir, A. Toxicity of monoterpenes against larvae and adults of Colorado-potato beetle, Leptinotarsa decemlineata Say (Coleoptera: Chrysomelidae). Ind. Crops and Prod., 2007, 26, 278-297.
[13]
Abdelgaleil, S.A.M.; Mohamed, M. I.E.; Badawy M.E.I.; El-arami S.A.A. Fumigant and contact toxicities of monoterpenes to Sitophilus oryzae (L.) and Tribolium castaneum (Herbst) and their inhibitory effects on acetylcholinesterase activity. J. Chem. Ecol., 2009, 35, 518-525.
[14]
Badawy, M.E.I.; El-Arami, S.A.A.; Abdelgaleil, S.A.M. Acaricidal and quantitative structure activity relationship of monoterpenes against the two-spotted spider mite, Tetranychus urticae. Exp. Appl. Acarol., 2010, 52, 261-274.
[15]
Rabea, E.I.; Badawy, M.E.I. Antimicrobial activity of biopolymer chitosans and monoterpenes against the honeybee pathogens Paenibacillus larvae and Ascosphaera apis. J. Chitin Chitosan Sci, 2014, 2, 306-310.
[16]
Grodnitzky, J.A.; Coats, J.R. QSAR evaluation of monoterpenoids’ insecticidal activity. J. Agric. Food Chem., 2002, 50, 4576-4580.
[17]
Hansch, C.; Leo, A.; Hoekman, D.; Leo, A. Exploring QSAR: fundamentals and applications in chemistry and biology; American Chemical Society: Washington, DC, 1995.
[18]
Devillers, J.; Balaban, A.T. Topological indices and related descriptors in QSAR and QSPAR; CRC Press: Singapore, 2000.
[19]
Rabea, E.I.; Badawy, M.E.I.; Ismail, R.I.A. In-vitro antimicrobial and Quantitative Structure Activity Relationship (QSAR) of natural monoterpenes against plant pathogenic bacteria. Glob. J. Agric. Food Saf. Sci., 2015, 2, 111-130.
[20]
Paluch, G.; Grodnitzky, J.; Bartholomay, L.; Coats, J. Quantitative structure− activity relationship of botanical sesquiterpenes: Spatial and contact repellency to the yellow fever mosquito, Aedes aegypti. J. Agric. Food Chem., 2009, 57, 7618-7625.
[21]
Dwivedi, N.; Mishra, S.; Mishra, B.N.; Singh, R.; Katoch, V.M. 3D QSAR Based study of potent growth inhibitors of terpenes as antimycobacterial agents. Open Nutr. J., 2011, 4, 119-124.
[22]
Tong, F.; Coats, J.R. Quantitative structure–activity relationships of monoterpenoid binding activities to the housefly GABA receptor. Pest Manag. Sci., 2012, 68, 1122-1129.
[23]
Andrade-Ochoa, S.; Nevárez-Moorillón, G.V.; Sánchez-Torres, L.E.; Villanueva-García, M.; Sánchez-Ramírez, B.E.; Rodríguez-Valdez, L.M.; Rivera-Chavira, B.E. Quantitative structure-activity relationship of molecules constituent of different essential oils with antimycobacterial activity against Mycobacterium tuberculosis and Mycobacterium bovis. BMC Complement. Altern. Med., 2015, 15, 1.
[24]
Dambolena, J.S.; López, A.G.; Meriles, J.M.; Rubinstein, H.R.; Zygadlo, J.A. Inhibitory effect of 10 natural phenolic compounds on Fusarium verticillioides. A structure–property–activity relationship study. Food Control, 2012, 28, 163-170.
[25]
Gao, Y.; Wang, Y.; Li, J.; Shang, S.; Song, Z. Improved application of natural forest product terpene for discovery of potential botanical fungicide. Ind. Crops and Prod., 2018, 126, 103-112.
[26]
Badawy, M.E.I.; Rabea, E.I.; Taktak, N.E.M. Antimicrobial and inhibitory enzyme activity of N-(benzyl) and quaternary N-(benzyl) chitosan derivatives on plant pathogens. Carbohydr. Polym., 2014.
[27]
Finney, D.J. Probit Analysis, 3rd ed; Cambridge University Press, 1971.
[28]
Tetko, I.V.; Gasteiger, J.; Todeschini, R.; Mauri, A.; Livingstone, D.; Ertl, P.; Palyulin, V.A.; Radchenko, E.V.; Zefirov, N.S.; Makarenko, A.S. Virtual computational chemistry laboratory-design and description. J. Comput. Aided Mol. Des., 2005, 19, 453-463.
[29]
Hansch, C.; Fujita, T. p-σ-π Analysis. A method for the correlation of biological activity and chemical structure. J. Am. Chem. Soc., 1964, 86, 1616-1626.
[30]
Stoll, F.; Liesener, S.; Hohlfeld, T.; Schrör, K.; Fuchs, P.L.; Höltje, H-D. Pharmacophore definition and three-dimensional quantitative structure-activity relationship study on structurally diverse prostacyclin receptor agonists. Mol. Pharmacol., 2002, 62, 1103-1111.
[31]
Wolber, G.; Langer, T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J. Chem. Inf. Model., 2005, 45, 160-169.
[32]
Wolber, G.; Dornhofer, A.A.; Langer, T. Efficient overlay of small organic molecules using 3D pharmacophores. J. Comput. Aided Mol. Des., 2006, 20, 773-788.
[33]
Halgren, T.A. MMFF VI. MMFF94s option for energy minimization studies. J. Comput. Chem., 1999, 20(7), 720-729.
[34]
De Oliveira, D.B.; Gaudio, A.C. BuildQSAR: A New Computer Program for QSAR Analysis. Quant. Struct.-. Act. Relat, 2001, 19, 599-601.
[35]
Gramatica, P. Principles of QSAR models validation: internal and external. QSAR and Combinat Sci., 2007, 26, 694-701.
[36]
Alexander, D.L.J.; Tropsha, A.; Winkler, D.A. Beware of R2: simple, unambiguous assessment of the prediction accuracy of QSAR and QSPR models. J. Chem. Inf. Model., 2015, 55, 1316-1322.
[37]
Cowan, M.M. Plant products as antimicrobial agents. Clin. Microbiol. Rev., 1999, 12, 564-582.
[38]
Trombetta, D.; Castelli, F.; Sarpietro, M.G.; Venuti, V.; Cristani, M.; Daniele, C.; Saija, A.; Mazzanti, G.; Bisignano, G. Mechanisms of antibacterial action of three monoterpenes. Antimicrob. Agents Chemother., 2005, 49, 2474-2478.
[39]
Cristani, M.; D’Arrigo, M.; Mandalari, G.; Castelli, F.; Sarpietro, M.G.; Micieli, D.; Venuti, V.; Bisignano, G.; Saija, A.; Trombetta, D. Interaction of four monoterpenes contained in essential oils with model membranes: implications for their antibacterial activity. J. Agric. Food Chem., 2007, 55, 6300-6308.
[40]
Sikkema, J.; De Bont, J.A.; Poolman, B. Mechanisms of membrane toxicity of hydrocarbons. Microbiol. Rev., 1995, 59, 201-222.
[41]
Marei, G.I.K.; Rasoul, M.A.A.; Abdelgaleil, S.A.M. Comparative antifungal activities and biochemical effects of monoterpenes on plant pathogenic fungi. Pestic. Biochem. Physiol., 2012, 103, 56-61.
[42]
Tsao, R.; Zhou, T. Antifungal activity of monoterpenoids against postharvest pathogens Botrytis cinerea and Monilinia fructicola. J. Essent. Oil Res., 2000, 12, 113-121.
[43]
Kordali, S.; Cakir, A.; Ozer, H.; Cakmakci, R.; Kesdek, M.; Mete, E. Antifungal, phytotoxic and insecticidal properties of essential oil isolated from Turkish Origanum acutidens and its three components, carvacrol, thymol and p-cymene. Bioresour. Technol., 2008, 99, 8788-8795.
[44]
Hartmans, K.J.; Diepenhorst, P.; Bakker, W.; Gorris, L.G.M. The use of carvone in agriculture: sprout suppression of potatoes and antifungal activity against potato tuber and other plant diseases. Ind. Crops Prod., 1995, 4, 3-13.
[45]
Penalver, P.; Huerta, B.; Borge, C.; Astorga, R.; Romero, R.; Perea, A. Antimicrobial activity of five essential oils against origin strains of the Enterobacteriaceae family. APMIS, 2005, 113, 1-6.
[46]
Jalali-Heravi, M.; Kyani, A. Use of computer-assisted methods for the modeling of the retention time of a variety of volatile organic compounds: a PCA-MLR-ANN approach. J. Chem. Inf. Comput. Sci., 2004, 44, 1328-1335.
[47]
Gupta, M.K.; Mishra, P.; Prathipati, P.; Saxena, A.K. 2D-QSAR in hydroxamic acid derivatives as peptide deformylase inhibitors and antibacterial agents. Bioorg. Med. Chem., 2002, 10, 3713-3716.
[48]
Xu, M.; Zhang, A.; Han, S.; Wang, L. Studies of 3D-quantitative structure–activity relationships on a set of nitroaromatic compounds: CoMFA, advanced CoMFA and CoMSIA. Chemosphere, 2002, 48, 707-715.
[49]
Gupta, M.K.; Mishra, P.; Prathipati, P.; Saxena, A.K. 2D-QSAR in hydroxamic acid derivatives as peptide deformylase inhibitors and antibacterial agents. Bioorg. Med. Chem., 2002, 10, 3713-3716.
[50]
Chang, H-J.; Kim, H.J.; Chun, H.S. Quantitative Structure-Activity Relationship (QSAR) for neuroprotective activity of terpenoids. Life Sci., 2007, 80, 835-841.
[51]
Kumar, P.; Narasimhan, B.; Sharma, D.; Judge, V.; Narang, R. Hansch analysis of substituted benzoic acid benzylidene/furan-2-yl-methylene hydrazides as antimicrobial agents. Eur. J. Med. Chem., 2009, 44, 1853-1863.
[52]
Takayama, C.; Fujinami, A. Quantitative structure-activity relationships of antifungal N-phenylsuccinimides and N-phenyl-1, 2-dimethylcyclopropanedicarboximides. Pestic. Biochem. Physiol., 1979, 12, 163-171.
[53]
Perdih, A.; Kovač, A.; Wolber, G.; Blanot, D.; Gobec, S.; Solmajer, T. Discovery of novel benzene 1, 3-dicarboxylic acid inhibitors of bacterial MurD and MurE ligases by structure-based virtual screening approach. Bioorg. Med. Chem. Lett., 2009, 19, 2668-2673.
[54]
Brvar, M.; Perdih, A.; Oblak, M.; Mašič, L.P.; Solmajer, T. In silico discovery of 2-amino-4-(2, 4-dihydroxyphenyl) thiazoles as novel inhibitors of DNA gyrase B. Bioorg. Med. Chem. Lett., 2010, 20, 958-962.