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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Perillaldehyde Building Block’s Derivatives: Targeted Bioactivities and Molecular Docking

Author(s): Farid Chebrouk*, Brahim Cherfaoui, Mustapha Mounir Bouhenna, Amira Nebbak, Borhane E.C. Ziani, Farid Dahmoune, Henni Chader, Naouel Eddaikra, Zoubir Harrat and Khodir Madani

Volume 20, Issue 5, 2023

Published on: 11 August, 2022

Page: [589 - 603] Pages: 15

DOI: 10.2174/1570180819666220512145525

Price: $65

Abstract

Background: Recently, the essential oil (EO) of Ammodaucus leucotrichus has attracted particular attention in hemi-synthesis due to the reactivity of its main monoterpenes.

Objective: In vitro cytotoxic and antileishmanial activities of the EO and hemi-synthesized compounds were evaluated, and an in-silico simulation was conducted.

Methods: The EO was characterized by GC-MS. Two benzodiazepines (C1, C2), benzimidazole (C3), and Schiff base (C4) were hemi-synthesized by an in situ condensation of its major monoterpenes (perillaldehyde) with different amine derivatives. Synthesized compounds and the EO were evaluated for their cytotoxic activity against laryngeal carcinoma-Hep2 and rhabdomyosarcoma-RD cell lines and for their antileishmanial activity against Leishmania (L) major. Molecular docking was performed to pin the binding interactions of active molecules.

Results: A significant cytotoxic effect of benzodiazepines C1 and C2 was noted against Hep2 cells (IC50/C1 = 39.48 ±0.7 μM, IC50/C2 = 48.82±1.33 μM) and RD (IC50/C1 = 15.96±1.99 μM; IC50/C2 = 74.3±2.44 μM), while the EO highly inhibited Hep2 cell lines (IC50/EO = 17.3±0.85 μg/mL). C4 strongly inhibited L. major growth with an IC50 value of 8.00±1.37 Μμ. The docking scores of ligand-C4 on L. major pteridine reductase and L. major methionyl-tRNA synthetase and ligands-(C1, C2) on the human protein kinase and epidermal growth factor kinase presented significant affinity to the receptor active sites (ΔG from -7.7 to -8.8 kcal/mol).

Conclusion: The cytotoxic effect of derivatives C1, C2, and EO, as well as the anti-parasitic effect of C4, may suggest them as effective bioactive agents or pharmaceutical probes.

Keywords: Perilalldehyde, Ammodaucus leucotrichus, hemi-synthesis, essential oil, biological activity, molecular docking.

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[1]
Santoro, F. Dhiaul iftitah, E.; Ravasio, N. Brønsted and Lewis Solid Acid Catalysts in the Valorization of Citronellal. Catalyst, 2018, 8(10), 410-420.
[http://dx.doi.org/10.3390/catal8100410]
[2]
Khalfaoui, M.; Farid, C.; Ziani, B.E.C.; Bennamane, N.; Cherfaoui, B.; Frites, W.; Valega, M.; Mendes, R.F.; Paz, F.A.A.; Chebout, R.; Bachari, K.; Talhi, O.; Silva, A.M.S. Hemi-synthesis, in-vitro and in-silico bioactivities of new chiral-Schiff bases and benzodiazepine derivatives from Ammodaucus leucotrichus (S)-perillaldehyde. J. Mol. Struct., 2021, 1241, 130690-130700.
[http://dx.doi.org/10.1016/j.molstruc.2021.130690]
[3]
Sakirigui, A.; Gbaguidi, F.; Kasséhin, U.C.; Poupaert, J.; Accrombessi, G.C.; Kotchoni, S.O. Structural and antitrypanosomal data of different carbasones of piperitone. Data Brief, 2016, 9, 1039-1043.
[http://dx.doi.org/10.1016/j.dib.2016.11.044] [PMID: 27900358]
[4]
Acelas, M.; Bohórquez, A.R.R.; Kouznetsov, V.V. Highly diastereoselective synthesis of new trans-fused octahydroacridines via intramolecular cationic imino diels–alder reaction of N-protected anilines and citronellal or citronella essential oil. Synthesis, 2017, 49(10), 2153-2162.
[http://dx.doi.org/10.1055/s-0036-1588713]
[5]
Jacob, R.G.; Perin, G.; Botteselle, G.V.; Lenardão, E.J. Clean and atom-economic synthesis of octahydroacridines: application to essential oil of citronella. Tetrahedron Lett., 2003, 44(36), 6809-6812.
[http://dx.doi.org/10.1016/S0040-4039(03)01749-0]
[6]
Ramadhan, D.; Warsito, W. Dhiaul iftitah, E. Microwave-assisted synthesis of benzimidazole derivatives from citronellal in kaffir lime (Citrus hystrix DC.) oil. IOP Conference Series: Materials Science and Engineering In: International Conference on Chemistry and Material Science, Indonisia, 2018, 299, pp. 12076-12083.
[7]
Ouédraogo, I.W.; Boulvin, M.; Flammang, R.; Gerbaux, P.; Bonzi-Coulibaly, Y.L. Conversion of natural aldehydes from Eucalyptus citriodora, Cymbopogon citratus, and Lippia multiflora into oximes: GC-MS and FT-IR analysis. Molecules, 2009, 14(9), 3275-3285.
[http://dx.doi.org/10.3390/molecules14093275] [PMID: 19783925]
[8]
Tedjini, R.; Ziani, B.E.C.; Casimiro, T.; Viveiros, R.; Calhelha, R.C.; Barros, L.; Boukenna, L.; Hamdi, A.; Chebout, R.; Bachari, K.; Talhi, O.; Silva, A.M.S. Hemi-synthesis of novel (S)-carvone hydrazone from Carum carvi L. essential oils: Structural and crystal characterization, targeted bioassays and molecular docking on human protein kinase (CK2) and Epidermal Growth factor Kinase (EGFK). J. Mol. Struct., 2021, 1246, 131220-13233.
[http://dx.doi.org/10.1016/j.molstruc.2021.131220]
[9]
Idm’hand, E.; Msanda, F.; Cherifi, K. Medicinal uses, phytochemistry and pharmacology of Ammodaucus leucotrichus. Clin. Phytosciene, 2020, 6(6), 1-8.
[http://dx.doi.org/10.1186/s40816-020-0154-7]
[10]
Muckensturm, B.; Diyani, F.; Nouen, D.; Fkih-Tetouani, S.; Reduron, J-P. Ammolactone, a guaianolide from a medicinal plant, Ammodaucus leucotrichus. Phytochemisty, 1997, 44(5), 907-910.
[11]
Jouad, H.; Haloui, M.; Rhiouani, H.; El Hilaly, J.; Eddouks, M. Ethnobotanical survey of medicinal plants used for the treatment of diabetes, cardiac and renal diseases in the North centre region of Morocco (Fez-Boulemane). J. Ethnopharmacol., 2001, 77(2-3), 175-182.
[http://dx.doi.org/10.1016/S0378-8741(01)00289-6] [PMID: 11535361]
[12]
Abu Zarga, M.H.; Al-Jaber, H.I.; Baba Amer, Z.Y.; Sakhrib, L.; Al-Qudah, M.A.; Al-humaidi, J.Y.G.; Abaza, I.F.; Afifi, F.U. Chemical composition, antimicrobial and antitumor activities of essential oil of Ammodaucus leucotrichus growing in algeria. JAPN, 2013, 3(3), 224-231.
[13]
Hammiche, V.; Maiza, K. Traditional medicine in Central Sahara: pharmacopoeia of Tassili N’ajjer. J. Ethnopharmacol., 2006, 105(3), 358-367.
[http://dx.doi.org/10.1016/j.jep.2005.11.028] [PMID: 16414225]
[14]
Hadj, M.D.; Hadj Mahammed, M.; Zabeirou, H. Place des plantes spontanées dans la médecine traditionnelle de la région de Ouargla (Sahara Septentrional Est). Cds., 2003, 3, 47-51.
[15]
Halla, N.; Heleno, S.A.; Costa, P.; Fernandes, I.P.; Calhelha, R.C.; Boucherit, K.; Rodrigues, A.E.; Ferreira, I.C.F.R.; Barreiro, M.F. Chemical profile and bioactive properties of the essential oil isolated from Ammodaucus leucotrichus fruits growing in Sahara and its evaluation as a cosmeceutical ingredient. Ind. Crops Prod., 2018, 119, 249-254.
[http://dx.doi.org/10.1016/j.indcrop.2018.04.043]
[16]
Louail, Z.; Kameli, A.; Benabdelkader, T.; Bouti, K.; Hamza, K.; Krimat, S. Antimicrobial and antioxidant activity of essential oil of Ammodaucus leucotrichus Coss.& Dur.seeds. J. Mater. Environ. Sci., 2016, 7(7), 2328-2334.
[17]
Ziani, B.E.C.; Rached, W.; Bachari, K.; Alves, M.; Calhelha, R.; Barros, L.; Ferreira, I. Detailed chemical composition and functional properties of Ammodaucus leucotrichus Cross. & Dur. and Moringa oleifera Lamarck. J. Funct. Foods, 2019, 53, 237-247.
[http://dx.doi.org/10.1016/j.jff.2018.12.023]
[18]
Gourdeau, H.; McAlpine, J.B.; Ranger, M.; Simard, B.; Berger, F.; Beaudry, F.; Farnet, C.M.; Falardeau, P. Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand. Cancer Chemother. Pharmacol., 2008, 61(6), 911-921.
[http://dx.doi.org/10.1007/s00280-007-0544-2] [PMID: 17622531]
[19]
Dahmane, D.; Dob, T.; Krimat, S.; Nouasri, A.; Metidji, H.; Ksouri, A. Chemical composition, antioxidant and antibacterial activities of the essential oils of medicinal plant Ammodaucus leucotrichus from Algeria. J. Essent. Oil Res., 2017, 29(1), 48-55.
[http://dx.doi.org/10.1080/10412905.2016.1201015]
[20]
Velasco-Negueruela, A.; Pérez-Alonso, M.J.; Pérez de Paz, P.L.; Palá-Paúl, J.; Sanz, J. Analysis by gas chromatography-mass spectrometry of the volatiles from the fruits of Ammodaucus leucotrichus subsp. leucotrichus and subsp. nanocarpus grown in North Africa and the Canary Islands, respectively. J. Chromatogr. A, 2006, 1108(2), 273-275.
[http://dx.doi.org/10.1016/j.chroma.2006.01.031] [PMID: 16472529]
[21]
Alaoui, M.S.B.; Satrani, B.; Ghamni, M.; Aafi, A.; Amusant, N.; Antry, S.E.; Chaouch, A. Bioactivity and chemical quality of Ammodaucus leucotrichus ssp. leucotrichus Coss. & Durieu essential oils from Morocco. Indian J. Nat. Prod., 2014, 10(6), 208-214.
[22]
Manssouri, M.; Znini, M.; Majidi, L. Studies on the antioxidant activity of essential oil and various extracts of Ammodaucus leucotrichus Coss. & Dur. Fruits from Morocco. J. Taibah Univ. Sci., 2020, 14(1), 124-130.
[http://dx.doi.org/10.1080/16583655.2019.1710394]
[23]
Sebaa, A.; Marouf, A.; Nadia, K.; Derdour, A. Phytochemical Composition, Antioxidant and Antimicrobial Activities of Ammodaucus Leucotrichus Fruit from Algerian Sahara. Orient. J. Chem., 2018, 34, 519-525.
[http://dx.doi.org/10.13005/ojc/340158]
[24]
Khaldi, A.; Meddah, B.; Abdallah, M.; Sonnet, P. Anti-mycotoxin Effect and Antifungal Properties of Essential Oil from Ammodaucus leucotrichus Coss. & Dur. on Aspergillus flavus and Aspergillus ochraceus. J. Essent. Oil Bear., 2017, 20, 36-44.
[http://dx.doi.org/10.1080/0972060X.2017.1282840]
[25]
El-Haci, I.A.; Bekhechi, C.; Atik-Bekkara, F.; Mazari, W.; Gherib, M.; Bighelli, A.; Casanova, J.; Tomi, F. Antimicrobial activity of Ammodaucus leucotrichus fruit oil from Algerian Sahara. Nat. Prod. Commun., 2014, 9(5), 711-712.
[http://dx.doi.org/10.1177/1934578X1400900533] [PMID: 25026729]
[26]
Naima, B.; Abdelkrim, R.; Ouarda, B.; Salah, N.N.; Larbi, B.A.M. Chemical composition, antimicrobial, antioxidant and anticancer activities of essential oil from Ammodaucus leucotrichus Coss. & Dur. (Apiacae) growing in south algeria. Bull. Chem. Soc. Ethiop., 2019, 33(3), 541-549.
[http://dx.doi.org/10.4314/bcse.v33i3.14]
[27]
Chebrouk, F.; Madani, K.; Cherfaoui, B.; Boukenna, L.; Válega, M.; Mendes, R.F.; Paz, F.A.A.; Bachari, K.; Talhi, O.; Silva, A.M.S. Hemi-synthesis of chiral imine, benzimidazole and benzodiazepines from essential oil of Ammodaucus leucotrichus subsp. leucotrichus. Molecules, 2019, 24(5), 975-985.
[http://dx.doi.org/10.3390/molecules24050975] [PMID: 30857362]
[28]
Babushok, V.; Linstrom, P.; Zenkevich, I. Retention indices for frequently reported compounds of plant essential oils. J. Phys. Chem. Ref. Data, 2011, 40(4), 43101-43148.
[http://dx.doi.org/10.1063/1.3653552]
[29]
Adams, R. Identification of essential oil components by gas chromatography/mass spectrometry, 4 ed.; Allured Publishing Corporation: CarolStream, 2007.
[30]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[31]
Research Collaboratory for Structural Bioinformatics. Protein Data Bank Available from: https://www.rcsb.org/structure/1e7w (accessed November 17,2021).
[32]
Research Collaboratory for Structural Bioinformatics. Protein Data Bank Available from: https://www.rcsb.org/structure/1e7w (accessed November 17,2021).
[33]
Research Collaboratory for Structural Bioinformatics. Protein Data Bank Available from: https://www.rcsb.org/structure/1e7w (accessed November 17,2021).
[34]
Research Collaboratory for Structural Bioinformatics. Protein Data Bank Available from: https://www.rcsb.org/structure/1e7w (accessed November 17,2021).
[35]
Prudent, R.; Moucadel, V.; Nguyen, C.H.; Barette, C.; Schmidt, F.; Florent, J.C.; Lafanechère, L.; Sautel, C.F.; Duchemin-Pelletier, E.; Spreux, E.; Filhol, O.; Reiser, J.B.; Cochet, C. Antitumor activity of pyridocarbazole and benzopyridoindole derivatives that inhibit protein kinase CK2. Cancer Res., 2010, 70(23), 9865-9874.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-0917] [PMID: 21118972]
[36]
Stamos, J.; Sliwkowski, M.X.; Eigenbrot, C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J. Biol. Chem., 2002, 277(48), 46265-46272.
[http://dx.doi.org/10.1074/jbc.M207135200] [PMID: 12196540]
[37]
Gourley, D.G.; Schüttelkopf, A.W.; Leonard, G.A.; Luba, J.; Hardy, L.W.; Beverley, S.M.; Hunter, W.N. Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites. Nat. Struct. Biol., 2001, 8(6), 521-525.
[http://dx.doi.org/10.1038/88584] [PMID: 11373620]
[38]
Larson, E.T.; Kim, J.E.; Zucker, F.H.; Kelley, A.; Mueller, N.; Napuli, A.J.; Verlinde, C.L.; Fan, E.; Buckner, F.S.; Van Voorhis, W.C.; Merritt, E.A.; Hol, W.G. Structure of Leishmania major methionyl-tRNA synthetase in complex with intermediate products methionyladenylate and pyrophosphate. Biochimie, 2011, 93(3), 570-582.
[http://dx.doi.org/10.1016/j.biochi.2010.11.015] [PMID: 21144880]
[39]
Hudaib, M.; Speroni, E.; Di Pietra, A.M.; Cavrini, V. GC/MS evaluation of thyme (Thymus vulgaris L.) oil composition and variations during the vegetative cycle. J. Pharm. Biomed. Anal., 2002, 29(4), 691-700.
[http://dx.doi.org/10.1016/S0731-7085(02)00119-X] [PMID: 12093498]
[40]
Bakkali, F.; Averbeck, S.; Averbeck, D.; Idaomar, M. Biological effects of essential oils-a review. Food Chem. Toxicol., 2008, 46(2), 446-475.
[http://dx.doi.org/10.1016/j.fct.2007.09.106] [PMID: 17996351]
[41]
Lemberkovics, É.; Kéry, Á.; Kakasy, A.; Szöke, E.; Simándi, B. Effect of extraction methods on the composition of essential oils. Acta Hortic., 2004, (597), 49-56.
[http://dx.doi.org/10.17660/ActaHortic.2003.597.4]
[42]
Silva, M.; Andrade, E.; Guilherme, S.; Maia, J. The essential oil of Pectis elongata Kunth occuring in North Brazil. Flavour Fragrance J., 2005, 20, 462-464.
[http://dx.doi.org/10.1002/ffj.1546]
[43]
Moridi Farimani, M.; Mirzania, F.; Sonboli, A.; Moghaddam, F. M. Chemical composition and antibacterial activity of Dracocephalum kotschyi essential oil obtained by microwave extraction and hydrodistillation. Int. J. Food Prop., 2017, 20(sup1), 306-315.
[http://dx.doi.org/10.1080/10942912.2017.1295987]
[44]
Li, L.J.; Hong, P.; Chen, F.; Sun, H.; Yang, Y.F.; Yu, X.; Huang, G.L.; Wu, L.M.; Ni, H. Characterization of the aldehydes and their transformations induced by UV irradiation and air exposure of white guanxi honey pummelo (Citrus Grandis (L.) Osbeck) essential oil. J. Agric. Food Chem., 2016, 64(24), 5000-5010.
[http://dx.doi.org/10.1021/acs.jafc.6b01369] [PMID: 27226192]
[45]
Igarashi, M.; Miyazaki, Y. A review on bioactivities of perilla: Progress in research on the functions of perilla as medicine and food. Evid. Based Complement. Alternat. Med., 2013, 2013, 925342.
[http://dx.doi.org/10.1155/2013/925342] [PMID: 24319488]
[46]
Sobral, M.V.; Xavier, A.L.; Lima, T.C.; de Sousa, D.P. Antitumor activity of monoterpenes found in essential oils. ScientificWorldJournal, 2014, 2014, 953451.
[http://dx.doi.org/10.1155/2014/953451] [PMID: 25401162]
[47]
Sonboli, A.; Esmaeili, M.A.; Gholipour, A.; Kanani, M.R. Composition, cytotoxicity and antioxidant activity of the essential oil of Dracocephalum surmandinum from Iran. Nat. Prod. Commun., 2010, 5(2), 341-344.
[http://dx.doi.org/10.1177/1934578X1000500234] [PMID: 20334155]
[48]
Karpińska, G.; Mazurek, A.P.; Dobrowolski, J.C. On substituent effect on the benzodiazepinone system. Comput. Theor. Chem., 2012, 993, 13-19.
[http://dx.doi.org/10.1016/j.comptc.2012.05.019]
[49]
Khan, I. Anupama; Singh, B. 1,4-Benzodiazepine: An overview of biological propreties. Sci. Revs. Chem. Commun., 2015, 5(1), 13-20.
[50]
Dourlat, J.; Liu, W-Q.; Gresh, N.; Garbay, C. Novel 1,4-benzodiazepine derivatives with antiproliferative properties on tumor cell lines. Bioorg. Med. Chem. Lett., 2007, 17(9), 2527-2530.
[http://dx.doi.org/10.1016/j.bmcl.2007.02.016] [PMID: 17317183]
[51]
Sandra, C.M.; Eduardo, C.C.; Simon, H.O.; Teresa, R.A.; Antonio, N.C.; Lijanova, I.V.; Marcos, M.G. Anticancer activity and anti-inflammatory studies of 5-aryl-1,4-benzodiazepine derivatives. Anticancer. Agents Med. Chem., 2012, 12(6), 611-618.
[http://dx.doi.org/10.2174/187152012800617713] [PMID: 22263787]
[52]
Tardibono, L.P.; Miller, M.J. Synthesis and anticancer activity of new hydroxamic acid containing 1,4-benzodiazepines. Org. Lett., 2009, 11(7), 1575-1578.
[http://dx.doi.org/10.1021/ol900210h] [PMID: 19320504]
[53]
Costa, E.C.; Cassamale, T.B.; Carvalho, D.B.; Bosquiroli, L.S.; Ojeda, M.; Ximenes, T.V.; Matos, M.F.; Kadri, M.C.; Baroni, A.C.; Arruda, C.C. Antileishmanial activity and structure-activity relationship of triazolic compounds derived from the neolignans grandisin, veraguensin, and machilin G. Molecules, 2016, 21(6), 802-813.
[http://dx.doi.org/10.3390/molecules21060802] [PMID: 27331807]
[54]
da Trindade Granato, J.; Dos Santos, J.A.; Calixto, S.L.; Prado da Silva, N.; da Silva Martins, J.; da Silva, A.D.; Coimbra, E.S. Novel steroid derivatives: Synthesis, antileishmanial activity, mechanism of action, and in silico physicochemical and pharmacokinetics studies. Biomed. Pharmacother., 2018, 106, 1082-1090.
[http://dx.doi.org/10.1016/j.biopha.2018.07.056] [PMID: 30119174]
[55]
Rathelot, P.; Azas, N.; El-Kashef, H.; Delmas, F.; Di Giorgio, C.; Timon-David, P.; Maldonado, J.; Vanelle, P. 1,3-Diphenylpyrazoles: synthesis and antiparasitic activities of azomethine derivatives. Eur. J. Med. Chem., 2002, 37(8), 671-679.
[http://dx.doi.org/10.1016/S0223-5234(02)01388-0] [PMID: 12161064]
[56]
Bernardino, A.M.R.; Gomes, A.O.; Charret, K.S.; Freitas, A.C.C.; Machado, G.M.C.; Canto-Cavalheiro, M.M.; Leon, L.L.; Amaral, V.F. Synthesis and leishmanicidal activities of 1-(4-X-phenyl)-N′-[(4-Y-phenyl)methylene]-1H-pyrazole-4-carbohydrazides. Eur. J. Med. Chem., 2006, 41(1), 80-87.
[http://dx.doi.org/10.1016/j.ejmech.2005.10.007] [PMID: 16300859]
[57]
Al-Kahraman, Y.M.S.A.; Madkour, H.M.F.; Ali, D.; Yasinzai, M. Antileishmanial, antimicrobial and antifungal activities of some new aryl azomethines. Molecules, 2010, 15(2), 660-671.
[http://dx.doi.org/10.3390/molecules15020660] [PMID: 20335936]

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