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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Research Article

New Caffeic Acid Derivatives as Antimicrobial Agents: Design, Synthesis, Evaluation and Docking

Author(s): Maia Merlani, Vakhtang Barbakadze, Lela Amiranashvili, Lali Gogilashvili, Vladimir Poroikov, Anthi Petrou, Athina Geronikaki*, Ana Ciric, Jasmina Glamoclija and Marina Sokovic

Volume 19, Issue 4, 2019

Page: [292 - 304] Pages: 13

DOI: 10.2174/1568026619666190122152957

Price: $65


Background: Phenolic acids (caffeic-, ferulic and p-coumaric acid) are widely distributed in the plant kingdom and exhibit broad spectrum of biological activities, including antimicrobial activity.

Objective: The goal of this paper is the synthesis of some caffeic acid derivatives selected based on computer-aided predictions and evaluate their in vitro antimicrobial properties against Gram positive and Gram negative bacteria and also a series of fungi.

Methods: In silico prediction of biological activity was used to identify the most promising structures for synthesis and biological testing, and the putative mechanisms of their antimicrobial action. The designed compounds were synthesized using classical organic synthesis methods. The antimicrobial activity was studied using microdilution method.

Results: Twelve tested compounds have shown good antibacterial activity. Five out of twelve tested compounds appeared to be more active than the reference drugs ampicillin and streptomycin. Despite that all compounds exhibited good activity against all bacteria tested, the sensitivity of bacteria towards compounds in general was different. The evaluation of antifungal activity revealed that all compounds were more active than ketoconazole, while seven compounds (2, 3, 4, 5, 7, 8 and 12) appeared to be more active than bifonazole. Docking results indicate that gyrase inhibition is the putative mechanism of antibacterial action while the inhibition of 14α-demethylase may be responsible for antifungal action. Prediction of cytotoxicity by PROTOX showed that compounds are not toxic (LD50 1000-2000 mg/kg).

Conclusion: Thirteen compounds, from which six are new ones, were synthesized, and twelve compounds were tested for antimicrobial activity. The studied compounds appeared to be promising potent and non-toxic antimicrobials, which could be considered as leads for new pharmaceutical agents.

Keywords: Caffeic acid derivatives, Antimicrobial activity, PASS, Docking, Gyrase, CYP51, Phenolic acids.

Graphical Abstract
Manach, C.; Scalbert, A.; Morand, C.; Rémésy, C.; Jiménez, L. Polyphenols: food sources and bioavailability. Am. J. Clin. Nutr., 2004, 79(5), 727-747.
[] [PMID: 15113710]
Vermerris, W.; Nicholson, R. Phenolic Compound Biochemistry, 1st ed; Springer, Netherlands, 2008, pp. 1-32.
Lee, J.H.; Kim, Y.G.; Ryu, S.Y.; Cho, M.H.; Lee, J. Ginkgolic acids and Ginkgo biloba extract inhibit Escherichia coli O157:H7 and Staphylococcus aureus biofilm formation. Int. J. Food Microbiol., 2014, 174, 47-55.
[ 2013.12.030] [PMID: 24457153]
Andrade, M.; Benfeito, S.; Soares, P.; Magalhaes, D.S.; Loureiro, J.; Borgesa, A.; Borges, F.; Simoesa, M. Fine-tuning of the hydrophobicity of caffeic acid: studies on the antimicrobial activity against Staphylococcus aureus and Escherichia coli. RSC Advances, 2015, 5, 53915.
Gangana, V.D.; Jazlya, L.; Chakrabortya, S.T.; Bhatiaa, S.T.; Dubeya, R.S.; Sankheb, S.S.; Pujaric, J.S.; Satputed, M.S.; Shastrid, I. Synthesis and Antibacterial Activity of Novel Caffeic Acid Hybrid Derivatives. IJCPA, 2014, 2(1), 28-34.
Borges, A.; Ferreira, C.; Saavedra, M.J.; Simões, M. Antibacterial activity and mode of action of ferulic and gallic acids against pathogenic bacteria. Microb. Drug Resist., 2013, 19(4), 256-265.
[] [PMID: 23480526]
Rocha, L.D.; Monteiro, M.C.; Teodoro, A.J. Anticancer properties of hydroxycinnamic acids- a review. Cancer Clin. Oncol., 2012, 1(2), 109.
Barbakadze, V.; Kemertelidze, E.; Targamadze, I.; Mulkijanyan, K.; Shashkov, A.S.; Usov, A.I. Poly[3-(3,4-dihydroxyphenyl) glyceric acid], a new biologically active polymer from Symphytum asperum Lepech. and S. caucasicum Bieb. (Boraginaceae). Molecules, 2005, 10(9), 1135-1144.
[] [PMID: 18007379]
Barbakadze, V.; Gogilashvili, L.; Amiranashvili, L.; Merlani, M.; Mulkijanyan, K.; Churadze, M.; Salgado, A.; Chankvetadze, B. Poly(3-(3,4-dihydroxyphenyl)glyceric acid) from Anchusa italica roots. Nat. Prod. Commun., 2010, 5(7), 1091-1095.
[PMID: 20734947]
Shrotriya, S.; Gagan, D.; Ramasamy, K.; Raina, K.; Barbakadze, V.; Merlani, M.; Gogilashvili, L.; Amiranashvili, L.; Mulkijanyan, K.; Papadopoulos, K.; Agarwal, C.; Agarwal, R. Poly[3-(3, 4-dihydroxyphenyl) glyceric acid] from Comfrey exerts anti-cancer efficacy against human prostate cancer via targeting androgen receptor, cell cycle arrest and apoptosis. Carcinogenesis, 2012, 33(8), 1572-1580.
[] [PMID: 22693258]
Merlani, M.; Barbakadze, V.; Amiranashvili, L.; Gogilashvili, L.; Yannakopoulou, E.; Papadopoulos, K.; Chankvetadze, B. Enantioselective synthesis and antioxidant activity of 3-(3,4-dihydroxyphenyl)-glyceric acid--basic monomeric moiety of a biologically active polyether from Symphytum asperum and S. caucasicum. Chirality, 2010, 22(8), 717-725.
[PMID: 20143412]
Online, P.A.S.S. (Accessed October 8, 2018)
Poroikov, V.V.; Filimonov, D.A.; Borodina, Y.V.; Lagunin, A.A.; Kos, A. Robustness of biological activity spectra predicting by computer program PASS for noncongeneric sets of chemical compounds. J. Chem. Inf. Comput. Sci., 2000, 40(6), 1349-1355.
[] [PMID: 11128093]
Stepanchikova, A.V.; Lagunin, A.A.; Filimonov, D.A.; Poroikov, V.V. Prediction of biological activity spectra for substances: evaluation on the diverse sets of drug-like structures. Curr. Med. Chem., 2003, 10(3), 225-233.
[] [PMID: 12570709]
Poroikov, V.V.; Filimonov, D.A. How to acquire new biological activities in old compounds by computer prediction. J. Comput. Aided Mol. Des., 2002, 16(11), 819-824.
[] [PMID: 12825794]
Filimonov, D.A.; Lagunin, A.A.; Gloriozova, T.A.; Rudik, A.V.; Druzhilovskiy, D.S.; Pogodin, P.V.; Poroikov, V.V. Chem. Heterocycl. Compd., 2014, 50(3), 444-457. [Prediction of the biological activity spectra of organic compounds using the PASS online web resource.]
[ 10.1007/s10593-014-1496-1]
Tatar, E.; Karakuş, S.; Küçükgüzel, Ş.G.; Öktem Okullu, S.; Ünübol, N.; Kocagöz, T.; De Clercq, E.; Andrei, G.; Snoeck, R.; Pannecouque, C.; Kalaycı, S.; Şahin, F.; Sriram, D.; Yogeeswari, P.; Küçükgüzel, İ. Design, Synthesis, and Molecular Docking Studies of a Conjugated Thiadiazole-Thiourea Scaffold as Antituberculosis Agents. Biol. Pharm. Bull., 2016, 39(4), 502-515.
[] [PMID: 27040623]
Geronikaki, A.A.; Dearden, J.C.; Filimonov, D.; Galaeva, I.; Garibova, T.L.; Gloriozova, T.; Krajneva, V.; Lagunin, A.; Macaev, F.Z.; Molodavkin, G.; Poroikov, V.V.; Pogrebnoi, S.I.; Shepeli, F.; Voronina, T.A.; Tsitlakidou, M.; Vlad, L. Design of new cognition enhancers: from computer prediction to synthesis and biological evaluation. J. Med. Chem., 2004, 47(11), 2870-2876.
[] [PMID: 15139765]
Geronikaki, A.; Babaev, E.; Dearden, J.; Dehaen, W.; Filimonov, D.; Galaeva, I.; Krajneva, V.; Lagunin, A.; Macaev, F.; Molodavkin, G.; Poroikov, V.; Pogrebnoi, S.; Saloutin, V.; Stepanchikova, A.; Stingaci, E.; Tkach, N.; Vlad, L.; Voronina, T. Design, synthesis, computational and biological evaluation of new anxiolytics. Bioorg. Med. Chem., 2004, 12(24), 6559-6568.
[] [PMID: 15556772]
Benaamane, N.; Nedjar-Kolli, B.; Bentarzi, Y.; Hammal, L.; Geronikaki, A.; Eleftheriou, P.; Lagunin, A. Synthesis and in silico biological activity evaluation of new N-substituted pyrazolo-oxazin-2-one systems. Bioorg. Med. Chem., 2008, 16(6), 3059-3066.
[] [PMID: 18191402]
Lagunin, A.A.; Geronikaki, A.; Eleftheriou, Ph.; Hadjipavlou-Litina, D.I.; Filimonov, D.I.; Poroikov, V.V. Computer-aided discovery of potential anti-inflammatory thiazolidinones with dual 5- LOX/COX inhibition. J. Med. Chem., 2008, 51(6), 1601-1609.
[] [PMID: 18311898]
Akita, H.; Nozawa, M.; Mitsuda, A.; Ohsawa, H. A convenient synthesis of (+)-albicanol based on enzymatic function: total syntheses of (+)-albicanyl acetate, (-)-albicanyl 3,4-dihydroxy-cinnamate, (-)-drimenol, (-)-drimenin and (-)-ambrox. Tetrahedron Asymmetry, 2000, 11, 1375-1388.
Merlani, M.; Barbakadze, V.; Amiranashvili, L.; Gogilashvili, L.; Mulkijanyan, K. Synthesis of some caffeic and 2,3-dihydroxy-3-(3,4-dihydroxyphenyl)-propanoic acids amides. Bull. Georg. Natl. Acad. Sci., 2011, 5(3), 107-111.
Jazlya, L.; Gangana, V. D.; Chakrabortya, C. T.; Tamhankarb, A V. Methyl Caffeate Ether Derivatives as Future Potential Drug. J. Chem. Bio. Phy. Sci. Sec. A, Nov. 2013-Jan., 2014, 1(1), 139-146.
Barontini, M. Bernini, R.Carastro, I.; Gentili, P.; Romani., A. Synthesis and DPPH radical scavenging activity of novel compounds obtained from tyrosol and cinnamic acid derivatives. New J. Chem., 2014, 38, 809-816.
Dorigundla, A.R.; Gurrapu, R.; Bathu, V.R. Stereoselective synthesis of peracetylated (-)-gloeosporiol via acid catalysed intramolecular etherification. Tetrahedron Lett., 2017, 58, 563-565.
Kumar, N.Y.; Bechtoldt, A.; Raghuvanshi, K.; Ackermann, L. Ruthenium(II)-Catalyzed Decarboxylative C-H Activation: Versatile Routes to meta-Alkenylated Arenes. Angew. Chem. Int. Ed. Engl., 2016, 55(24), 6929-6932.
[] [PMID: 26996920]
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(4), 1360-1367.
[] [PMID: 11283057]
Hänel, H.; Raether, W. A more sophisticated method of determining the fungicidal effect of water-insoluble preparations with a cell harvester, using miconazole as an example. Mycoses, 1988, 31(3), 148-154.
[] [PMID: 3292912]
Tratrat, Ch.; Hroun, M.; Xenikakis, I. Liaras, k.; Tsolaki, E.; Eleftheriou, Ph.; Petrou, A.; Aldhubiab, B.; Attimarad, M.; Venugopala, K.N.; Harsha, S.; Elsewedy, H.S.; Geronikaki, A.; Glamočlija, J.; Ćirić, A.; Sokovic, M. Design, synthesis, evaluation of antimicrobial activity and docking studies of new thiazole-based chalcones. MedChemComm, 2018, 9, 870-882.
[PMID: 30108976]
Tsolaki, E.; Eleftheriou, P.; Kartsev, V.; Geronikaki, A.; Saxena, A.K. Application of docking analysis in the prediction and biological evaluation of the lipoxygenase inhibitory action of thiazolyl derivatives of mycophenolic acid. Molecules, 2018, 23(7), 1621-1650.
[] [PMID: 29970872]
OpenTox. Available at: . (Accessed on October 8, 2018).
ToxPredict.. (Accessed on October 8, 2018).
PROTOX. (Accessed on October 8, 2018).
GHS-unece. (Accessed on October 8, 2018).
Clarivate Analytics Integrity. (Accessed on October 8, 2018).

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