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Recent Advances in Anti-Infective Drug Discovery

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ISSN (Print): 2772-4344
ISSN (Online): 2772-4352

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Research Article

Hybrid Compounds Containing Carvacrol Scaffold: In Vitro Antibacterial and Cytotoxicity Evaluation

Author(s): Zintle Mbese, Margo Nell, Youmbi T. Fonkui, Derek T. Ndinteh, Vanessa Steenkamp and Blessing A. Aderibigbe*

Volume 17, Issue 1, 2022

Published on: 15 March, 2022

Page: [54 - 68] Pages: 15

DOI: 10.2174/1574891X16666220124122445

Price: $65

Abstract

Background: The design of hybrid compounds is a distinct approach for developing potent bioactive agents. Carvacrol, an essential oil, exhibits antimicrobial, antifungal, antioxidant, and anticancer activity, making it a good precursor for the development of compounds with potent biological activities. Some patents have reported carvacrol derivatives with promising biological activities.

Objective: This study aimed to prepare hybrid compounds containing a carvacrol scaffold with significant antibacterial and anticancer activity.

Methods: Esterification reactions between carvacrol and known pharmacophores were performed at room temperature and characterized using 1H-NMR, 13CNMR, and UHPLC-HRMS. In vitro antibacterial study was determined using the microdilution assay and cytotoxicity evaluation using sulforhodamine B staining assay.

Results: The FTIR spectra of the carvacrol hybrids revealed prominent bands in the range of 1612-1764 cm-1 and 1014-1280 cm-1 due to (C=O) and (C-O) stretching vibrations, respectively. The structures of the carvacrol hybrids were confirmed by 1H-NMR, 13C-NMR, and UHPLC-HRMS analysis, and compound 5 exhibited superior activity when compared to the hybrid compounds against the strains of bacteria used in the study. The in vitro cytotoxicity evaluation showed that compound 3 induced cytotoxicity in all the cancer cell lines; MDA (16.57 ± 1.14 μM), MCF-7 (0.47 ± 1.14 μM), and DU145 (16.25 ± 1.08 μM), as well as the normal breast cells, MCF-12A (0.75± 1.30 μM). Compound 7 did not induce cytotoxicity in the cell lines tested (IC50 > 200 μM).

Conclusion: The modification of carvacrol through hybridization is a promising approach to develop compounds with significant antibacterial and anticancer activity.

Keywords: Gram-positive bacteria, Gram-negative bacteria, antibacterial, carvacrol, hybrid compounds, anticancer.

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[1]
Ten common causes of death. 2018. Available from: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death (Accessed on 25th June 2020).
[2]
2020 Progress Report January 2020. Available from: https://www.amrindustryalliance.org/wp-content/uploads/2020/01/AMR-2020-Progress-Report.pdf Accessed 25th June 2020.
[3]
Pokrovskaya V, Baasov T. Dual-acting hybrid antibiotics: A promising strategy to combat bacterial resistance. Expert Opin Drug Discov 2010; 5(9): 883-902.
[http://dx.doi.org/10.1517/17460441.2010.508069] [PMID: 22823262]
[4]
de Oliveira AS, Llanes LC, Brighente IM, et al. New sulfonamides derived from carvacrol: Compounds with high antibacterial activity against resistant staphylococcus aureus strains. J Biosci Med 2016; 4(7): 105-14.
[http://dx.doi.org/10.4236/jbm.2016.47011]
[5]
Miladi H, Zmantar T, Chaabouni Y, et al. Antibacterial and efflux pump inhibitors of thymol and carvacrol against food-borne pathogens. Microb Pathog 2016; 99: 95-100.
[http://dx.doi.org/10.1016/j.micpath.2016.08.008] [PMID: 27521228]
[6]
Nostro A, Roccaro AS, Bisignano G, et al. Effects of oregano, carvacrol and thymol on Staphylococcus aureus and Staphylococcus epidermidis biofilms. J Med Microbiol 2007; 56(Pt 4): 519-23.
[http://dx.doi.org/10.1099/jmm.0.46804-0] [PMID: 17374894]
[7]
Hassanshahi J, Roghani M, Raoufi S. Protective effect of carvacrol in 6-hydroxydopamine hemi-parkinsonian rat model. J Basic Clin Pathophysiol 2014; 2(2): 29-34.
[8]
Memar MY, Raei P, Alizadeh N, Aghdam MA, Kafil HS. Carvacrol and thymol: Strong antimicrobial agents against resistant isolates. Rev Med Microbiol 2017; 28: 63-8.
[http://dx.doi.org/10.1097/MRM.0000000000000100]
[9]
Raut JS, Karuppayil SM. A status review on the medicinal properties of essential oils. Ind Crops Prod 2014; 62: 250-64.
[http://dx.doi.org/10.1016/j.indcrop.2014.05.055]
[10]
Bnyan IA, Abid AT, Obied HN. Antibacterial activity of carvacrol against different types of bacteria. J Nat Sci Res 2014; 4(9): 13-7.
[11]
Rajput JD, Bagul SD, Bendre RS. Design, synthesis, biological screenings and docking simulations of novel carvacrol and thymol derivatives containing acetohydrazone linkage. Res Chem Intermed 2017; 43: 4893-906.
[http://dx.doi.org/10.1007/s11164-017-2919-2]
[12]
Rajput JD, Bagul SD, Tadavi SK, Karandikar PS, Bendre RS. Design, synthesis and biological evaluation of novel class diindolyl methanes (DIMs) derived from naturally occurring phenolic monoterpenoids. Med Chem 2016; 6: 123-8.
[13]
Cui Z, Li X, Nishida Y. Synthesis and bioactivity of novel carvacrol and thymol derivatives containing 5-phenyl-2-furan. Lett Drug Des Discov 2014; 11: 877-85.
[http://dx.doi.org/10.2174/1570180811666140220005252]
[14]
Mbese Z, Aderibigbe BA. Biological efficacy of carvacrol analogues. Recent Pat Antiinfect Drug Discov 2018; 13(3): 207-16.
[http://dx.doi.org/10.2174/1574891X14666181205111821] [PMID: 30516115]
[15]
Moore S. Antimicrobial compositions containing carvacrol and thymol. US Patent US20140336271A1, 2014.
[16]
Wei W, Wei Z, Wei L, et al. Pharmaceutical composition comprising an antiviral agent, an antitumour agent or an antiparasitic agent and an active substance selected from carveol, thymol, eugenol, borneol and carvacrol. US Patent US 11/914,029, 2008.
[17]
Fonkui TY, Ikhile MI, Muganza FM, Fotsing MC, Arderne C, Siwe-Noundou X. Synthesis, characterization and biological applications of novel Schiff bases of 2-(trifluoromethoxy) aniline. J Chin Pharm Sci 2018; 27: 307-23.
[http://dx.doi.org/10.5246/jcps.2018.05.032]
[18]
Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 2006; 1(3): 1112-6.
[http://dx.doi.org/10.1038/nprot.2006.179] [PMID: 17406391]
[19]
Anh DT, Giang LN, Hien NT, et al. Synthesis and cytotoxic evaluation of novel ester derivatives of betulin with AZT, d4T, and 3TC. Nat Prod Commun 2017; 12: 885-8.
[http://dx.doi.org/10.1177/1934578X1701200613]
[20]
Xiong J, Kashiwada Y, Chen CH, et al. Conjugates of betulin derivatives with AZT as potent anti-HIV agents. Bioorg Med Chem 2010; 18(17): 6451-69.
[http://dx.doi.org/10.1016/j.bmc.2010.06.092] [PMID: 20673723]
[21]
Snape TJ, Astles AM, Davies J. Understanding the chemical basis of drug stability and degradation. Pharm J 2010; 285: 416-7.
[http://dx.doi.org/10.1211/PJ.2021.1.72642]
[22]
Lavis LD. Ester bonds in prodrugs. ACS Chem Biol 2008; 3(4): 203-6.
[http://dx.doi.org/10.1021/cb800065s] [PMID: 18422301]
[23]
Zhao ZB, Zheng HX, Wei YG, Liu J. Synthesis of azo derivatives of 4-aminosalicylic acid. Chin Chem Lett 2007; 18: 639-42.
[http://dx.doi.org/10.1016/j.cclet.2007.04.031]
[24]
Mathela CS, Singh KK, Gupta VK. Synthesis and in vitro antibacterial activity of thymol and carvacrol derivatives. Acta Pol Pharm 2010; 67(4): 375-80.
[PMID: 20635533]
[25]
Agee BM, Mullins G, Biernacki JJ, Swartling DJ. Wolff–Kishner reduction reactions using a solar irradiation heat source and a green solvent system. Green Chem Lett Rev 2014; 7: 383-92.
[http://dx.doi.org/10.1080/17518253.2014.966866]
[26]
Bagul SD, Rajput JD, Patil MM, Bendre RS. Synthesis, characterization and antioxidant activity of carvacrol based sulfonates. Med Chem 2017; 7: 294-8.
[27]
Medapi B, Suryadevara P, Renuka J, Sridevi JP, Yogeeswari P, Sriram D. 4-Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: Structural optimization, synthesis and biological evaluation. Eur J Med Chem 2015; 103: 1-16.
[http://dx.doi.org/10.1016/j.ejmech.2015.06.032] [PMID: 26318054]
[28]
Pathak P, Thakur A, Bhat HR, Singh UP. Hybrid 4-aminoquinoline-1, 3, 5-triazine derivatives: Design, synthesis, characterization, and antibacterial evaluation. J Heterocycl Chem 2015; 52: 1108-13.
[http://dx.doi.org/10.1002/jhet.2210]
[29]
Ranjbar-Karimi R, Poorfreidoni A. Incorporation of fluorinated pyridine in the side chain of 4-aminoquinolines: Synthesis, characterization and antibacterial activity. Drug Res (Stuttg) 2018; 68(1): 17-22.
[http://dx.doi.org/10.1055/s-0043-116674] [PMID: 28847024]
[30]
Ben Arfa A, Combes S, Preziosi-Belloy L, Gontard N, Chalier P. Antimicrobial activity of carvacrol related to its chemical structure. Lett Appl Microbiol 2006; 43(2): 149-54.
[http://dx.doi.org/10.1111/j.1472-765X.2006.01938.x] [PMID: 16869897]
[31]
Ultee A, Bennik MHJ, Moezelaar R. The phenolic hydroxyl group of carvacrol is essential for action against the food-borne pathogen Bacillus cereus. Appl Environ Microbiol 2002; 68(4): 1561-8.
[http://dx.doi.org/10.1128/AEM.68.4.1561-1568.2002] [PMID: 11916669]
[32]
Cacciatore I, Di Giulio M, Fornasari E, et al. Carvacrol codrugs: A new approach in the antimicrobial plan. PLoS One 2015; 10(4): e0120937.
[http://dx.doi.org/10.1371/journal.pone.0120937] [PMID: 25859852]
[33]
Marinelli L, Di Stefano A, Cacciatore I. Carvacrol and its derivatives as antibacterial agents. Phytochem Rev 2018; 17: 903-21.
[http://dx.doi.org/10.1007/s11101-018-9569-x]
[34]
Lopez-Romero JC, González-Ríos H, Borges A, Simões M. Antibacterial effects and mode of action of selected essential oils components against Escherichia coli and Staphylococcus aureus. Evid Based Complement Alternat Med 2015; 2015: 9.
[http://dx.doi.org/10.1155/2015/795435] [PMID: 26221178]
[35]
Davin-Regli A, Pagès JM. Enterobacter aerogenes and Enterobacter cloacae; versatile bacterial pathogens confronting antibiotic treatment. Front Microbiol 2015; 6: 392.
[http://dx.doi.org/10.3389/fmicb.2015.00392] [PMID: 26042091]
[36]
Riquelme SA, Ahn D, Prince A. Pseudomonas aeruginosa and Klebsiella pneumoniae adaptation to innate immune clearance mechanisms in the lung. J Innate Immun 2018; 10(5-6): 442-54.
[http://dx.doi.org/10.1159/000487515] [PMID: 29617698]
[37]
La Storia A, Ercolini D, Marinello F, Di Pasqua R, Villani F, Mauriello G. Atomic force microscopy analysis shows surface structure changes in carvacrol-treated bacterial cells. Res Microbiol 2011; 162(2): 164-72.
[http://dx.doi.org/10.1016/j.resmic.2010.11.006] [PMID: 21168481]
[38]
Nikumbh VP, Tare VS, Mahulikar PP. Eco-friendly pest management using monoterpenoids-III: Antibacterial efficacy of carvacrol derivatives. J Sci Ind Res (India) 2003; 62: 1086-9.
[39]
Arunasree KM. Anti-proliferative effects of carvacrol on a human metastatic breast cancer cell line, MDA-MB 231. Phytomedicine 2010; 17(8-9): 581-8.
[http://dx.doi.org/10.1016/j.phymed.2009.12.008] [PMID: 20096548]
[40]
Al-Fatlawi AA, Rahisuddin AA. Cytotoxicity and pro-apoptotic activity of carvacrol on human breast cancer cell line MCF-7. World J Pharm Sci 2014; 2: 1218-23.
[41]
Thakkar Y. Carvacrol as an anti-cancer agent on human metastatic breast cancer cell line, MDA-MB-231 Doctoral dissertation, Long Island University, The Brooklyn Center 2013.
[42]
Mari A, Mani G, Nagabhishek SN, et al. Carvacrol promotes cell cycle arrest and apoptosis through PI3K/AKT signaling pathway in MCF-7 breast cancer cells. Chin J Integr Med 2021; 27(9): 680-7.
[http://dx.doi.org/10.1007/s11655-020-3193-5] [PMID: 32572774]
[43]
Greenshields AL, Fernando W, Hoskin DW. The anti-malarial drug artesunate causes cell cycle arrest and apoptosis of triple-negative MDA-MB-468 and HER2-enriched SK-BR-3 breast cancer cells. Exp Mol Pathol 2019; 107: 10-22.
[http://dx.doi.org/10.1016/j.yexmp.2019.01.006] [PMID: 30660598]
[44]
Jamalzadeh L, Ghafoori H, Aghamaali M, Sariri R. Induction of apoptosis in human breast cancer MCF-7 cells by a semi-synthetic derivative of artemisinin: A caspase-related mechanism. Iran J Biotechnol 2017; 15(3): 157-65.
[http://dx.doi.org/10.15171/ijb.1567] [PMID: 29845064]
[45]
Zhou Y, Wang X, Zhang J, et al. Artesunate suppresses the viability and mobility of prostate cancer cells through UCA1, the sponge of miR-184. Oncotarget 2017; 8(11): 18260-70.
[http://dx.doi.org/10.18632/oncotarget.15353] [PMID: 28209917]
[46]
Lian S, Shi R, Huang X, et al. Artesunate attenuates glioma proliferation, migration and invasion by affecting cellular mechanical properties. Oncol Rep 2016; 36(2): 984-90.
[http://dx.doi.org/10.3892/or.2016.4847] [PMID: 27279152]
[47]
Tong Y, Liu Y, Zheng H, et al. Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/β-catenin signaling. Oncotarget 2016; 7(21): 31413-28.
[http://dx.doi.org/10.18632/oncotarget.8920] [PMID: 27119499]
[48]
Zhang T, Jiang G, Wen S, et al. Para-aminosalicylic acid increases the susceptibility to isoniazid in clinical isolates of Mycobacterium tuberculosis. Infect Drug Resist 2019; 12: 825-9.
[http://dx.doi.org/10.2147/IDR.S200697] [PMID: 31114264]
[49]
Alibek K, Bekmurzayeva A, Mussabekova A, Sultankulov B. Using antimicrobial adjuvant therapy in cancer treatment: A review. Infect Agents Cancer 2012; 7: 33.
[http://dx.doi.org/10.1186/1750-9378-7-33]
[50]
De P, Baltas M, Bedos-Belval F. Cinnamic acid derivatives as anticancer agents-a review. Curr Med Chem 2011; 18(11): 1672-703.
[http://dx.doi.org/10.2174/092986711795471347] [PMID: 21434850]
[51]
Jornada DH, dos Santos Fernandes GF, Chiba DE, De Melo TR, Dos Santos JL, Chung MC. The prodrug approach: A successful tool for improving drug solubility. Molecules 2015; 21(1): 42.
[http://dx.doi.org/10.2174/092986711795471347] [PMID: 26729077]
[52]
Pawełczyk A, Sowa-Kasprzak K, Olender D, Zaprutko L. Molecular consortia-various structural and synthetic concepts for more effective therapeutics synthesis. Int J Mol Sci 2018; 19(4): 1104.
[http://dx.doi.org/10.3390/ijms19041104] [PMID: 29642417]
[53]
Peter S, Aderibigbe BA. Ferrocene-based compounds with antimalaria/anticancer activity. Molecules 2019; 24(19): 3604.
[http://dx.doi.org/10.3390/molecules24193604] [PMID: 31591298]
[54]
Wang R, Chen H, Yan W, Zheng M, Zhang T, Zhang Y. Ferrocene-containing hybrids as potential anticancer agents: Current developments, mechanisms of action and structure-activity relationships. Eur J Med Chem 2020; 190: 112109.
[http://dx.doi.org/10.1016/j.ejmech.2020.112109] [PMID: 32032851]
[55]
Wei G, Luan W, Wang S, et al. A library of 1,2,3-triazole-substituted oleanolic acid derivatives as anticancer agents: Design, synthesis, and biological evaluation. Org Biomol Chem 2015; 13(5): 1507-14.
[http://dx.doi.org/10.1039/C4OB01605J] [PMID: 25476168]
[56]
Lin C, Wen X, Sun H. Oleanolic acid derivatives for pharmaceutical use: A patent review. Expert Opin Ther Pat 2016; 26(6): 643-55.
[http://dx.doi.org/10.1080/13543776.2016.1182988] [PMID: 27113324]
[57]
Wang Y, Pigeon P, Mcglinchey MJ, Top S, Jaouen G. Synthesis and antiproliferative evaluation of novel hydroxypropyl-ferrociphenol derivatives, resulting from the modification of hydroxyl groups. J Organomet Chem 2017; 829: 108-15.
[http://dx.doi.org/10.1016/j.jorganchem.2016.09.005]
[58]
Pérez WI, Soto Y, Ortíz C, Matta J, Meléndez E. Ferrocenes as potential chemotherapeutic drugs: Synthesis, cytotoxic activity, reactive oxygen species production and micronucleus assay. Bioorg Med Chem 2015; 23(3): 471-9.
[http://dx.doi.org/10.1016/j.bmc.2014.12.023] [PMID: 25555734]
[59]
Luo Y, Wu JY, Lu MH, Shi Z, Na N, Di JM. Carvacrol alleviates prostate cancer cell proliferation, migration, and invasion through the regulation of PI3K/Akt and MAPK signaling pathways. Oxid Med Cell Longev 2016; 2016: 1469693.
[http://dx.doi.org/10.1155/2016/1469693] [PMID: 27803760]
[60]
Khan F, Khan I, Farooqui A, Ansari IA. Carvacrol induces reactive oxygen species (ROS)-mediated apoptosis along with cell cycle arrest at G0/G1 in human prostate cancer cells. Nutr Cancer 2017; 69(7): 1075-87.
[http://dx.doi.org/10.1080/01635581.2017.1359321] [PMID: 28872904]

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