Structure-Activity Relationship of Dicoumarol Derivatives as anti- Staphylococcus aureus (Staph Infection) Agents

Author(s): Nidaa Rasheed*, Natalie J. Galant, Imre G. Csizmadia.

Journal Name: Anti-Infective Agents
Anti-Infective Agents in Medicinal Chemistry

Volume 17 , Issue 2 , 2019

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Abstract:

Introduction: Staph infection, caused by a bacterium known as Staphylococcus aureus, results in a range of diseases from cellulitis to meningitis. Dicoumarol compounds are now emerging as new anti-Staph infection agents as they possess a different chemical structure than compounds used in previous treatments, in order to combat antibiotic-resistant strains. However, it is unclear how such chemical modulations to the dicoumarol backbone structure achieve higher drug performance.

Methods: The following review analyzed various quantitative structure-activity relationship (QSAR) studies on dicoumarol compounds and compared them against the corresponding minimum inhibitory concentration and binding affinity values.

Results: Compared to the antimicrobial activity, the dicoumarol derivatives with electron withdrawing substituents, CL, NO2, and CF3 showed an inverse correlation; whereas, the opposite was observed with electron donating compounds such as OH, OMe, and amine groups. Based on the interactions of dicoumarol at the active site, an “aromatic donor-acceptor” relationship was proposed as the method of action for this drug. Furthermore, substituent positioning on the benzene ring was found to exert a greater effect on the binding affinity, speculating that the mechanism of action is two characteristics based, needing, both, the proper aromatic pi-pi interaction for stabilization and direct binding to the OH group in the Tyrosine residue, affected by the steric hindrance.

Conclusion: This foundational review can enhance productivity sought by the pharmaceutical agency to use combinational chemistry to increase the efficiency to discover new hits in the synthesis of dicoumarol drugs against Staph infection.

Keywords: S. aureus, staph infection, dicoumarol derivatives, Pi-stacking, thermodynamics, computational chemistry.

[1]
Malani, N. Preventing postoperative Staphylococcus aureus infections. JAMA, 2013, 309, 1408-1409.
[2]
Dukic, V.; Laurderdale, D.; Wilder, J.; Daum, R.; David, M. Epidemics of community-associated methicillin resistant Staphylococcus aureus in the United States: A meta-analysis. PLoS One, 2013, 8, 52722.
[3]
Vos, F.; Kullberg, J.; Sturm, P.; Dijk, A.; Wanten, G.; Oyen, W.; Bleeker, C. Metastatic infectious disease and clinical outcome in Staphylococcus aureus and Streptococcus species bacteremia. Medicine (Baltimore), 2012, 91(2), 86-94.
[4]
Thwaites, G.; Edgeworth, J.; Gkrania, E.; Kirkby, A.; Tilley, R.; Torok, M.; Walker, S.; Wertherim, H.; Wilson, P.; Llewelyn, M. Clinical management of Staphylococcus aureus bacteraemia. Lancet Infect. Dis., 2011, 11, 208-222.
[5]
Lee, K.; Crossley, K.; Gerding, N. The association between Staphylococcus aureus bacteremia and bacteriuria. Am. J. Med., 1978, 65, 303-310.
[6]
Figueroa, D.; Mangini, E.; Amodio, M.; Vardianos, B.; Melchert, A.; Fana, C.; Wehbeh, W.; Urban, C.; Segal, S. Safety of high-dose intravenous daptomycin treatment: Three-year cumulative experience in a clinical program. Clin. Infect. Dis., 2009, 49, 177-180.
[7]
Fowler, V.; Boucher, H.; Corey, R.; Abrutyn, E. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N. Engl. J. Med., 2006, 355, 653-665.
[8]
Wunderink, R.; Niderman, M.; Kollef, M.; Shorr, A.; Kunkel, M.; Baruch, A.; McGee, W.; Reisman, A.; Chastre, J. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: A randomized, controlled study. Clin. Infect. Dis., 2012, 54, 621-629.
[9]
Kang, C.; Song, J. Antimcrobial resistance in asia: Current epidemiology and clinical implications. Infect. Chemother., 2013, 45(1), 22-31.
[10]
Cosgrove, E.; Carroll, K.; Perl, T. Staphylococcus aureus with reduced susceptibility to vancomycin. Clin. Infect. Dis., 2004, 39, 539-545.
[11]
McConeghy, K.; Bleasdale, S.; Rodvold, K. The empirical combination of vancomycin and a β-lactam for Staphylococcal bacteremia. Clin. Infect. Dis., 2013, 57, 1760-1765.
[12]
Riveiro, M.; Kimpe, D.; Moglloni, A.; Vazquez, R.; Monczor, F.; Shayo, C.; Davio, C. Coumarins: Old compounds with novel promising therapeutic perspectives. Curr. Med. Chem., 2010, 17, 1325-1338.
[13]
Goth, A. The antibacterial properties of dicumarol. Science, 1945, 101, 2624.
[14]
Dadák, V.; Hoďák, K. Some relations between the structure and the antibacterial activity of natural coumarins. Experientia, 1966, 22(1), 38-39.
[15]
Bassetti, M.; Merelli, M.; Temperoni, C.; Astillean, A. New antibitoics for bad bugs: Where are we? Ann. Clin. Microbiol. Antimicrob., 2013, 12, 22.
[16]
Hutchinson, H.; Tomlinson, A. The structure of dicoumarol and related compounds. Tetrahedron, 1969, 25, 2531-2537.
[17]
Wallin, R. Vitamin K antagonism of coumarin anticoagulation. A dehydrogenase pathway in rat liver is responsible for the antagonistic effect. Biochem. J., 1986, 236(3), 685-693.
[18]
Tavares, A.; Nobre, L.; Melo, A.; Saraiva, M. A novel nitroreductase of taphylococcus aureus with S-nitrosoglutathione reductase activity. J. Bacteriol., 2009, 191, 3403-3406.
[19]
Cresteil, T.; Jaiswal, K. High levels of expression of the NAD(P)H: Quinone oxidoreductase (NQO1) gene in tumor cells compared to normal cells of the same origin. Biochem. Pharmacol., 1991, 42, 1021-1027.
[20]
Ellis, G.; West, G. Progress in medicinal chemistry, Volume 10, 1st ed.; Elsevier Science: North Holland 1974.
[21]
Hou, Z.; Zhou, Y.; Li, J.; Zhang, X.; Shi, X.; Xue, X. Selective in vivo and in vitro activities of 3,3′-4-nitrobenzylidene-bis-4-hydroxycoumarin against methicillin-resistant Staphylococcus aureus by inhibition of DNA polymerase III. Sci. Rep., 2015, 5, 13637.
[22]
Petnapapun, K.; Chavasiri, W.; Sompornpisut, P. Structure-Activity relationships of 3,3′-Phenylmethylene-bis-4-hydroxycoumarins: Selective and potent inhibitors of gram-positive bacteria. ScientificWorldJournal, 2013, 2013178649
[23]
Asher, G.; Dym, O.; Tsvetkov, P.; Adler, J.; Shaul, Y. The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol. Biochemistry, 2006, 45(20), 6372-6378.
[24]
Johansson, E.; Parkinson, N.; Denny, A.; Neidle, S. Studies on the nitroreductase prodrug-activating system. Crystal structures of complexes with the inhibitor dicoumarol and dinitrobenzamide prodrugs and of the enzyme active form. J. Med. Chem., 2003, 46(19), 4009-4020.
[25]
Ito, K.; Nakanishi, M.; Lee, C.; Zhi, Y.; Sasaki, H.; Zenno, S.; Saigo, K.; Kitade, Y.; Tanokura, M. Expansion of substrate specificity and catalytic mechanism of azoreductase by X-ray crystallography and site-directed mutagenesis. J. Biol. Chem., 2008, 283(20), 13889-13896.
[26]
Hunter, C.; Sanders, J. The nature of pi-pi interactions. J. Am. Chem. Soc., 1990, 112(14), 5525-5534.
[27]
Li, Z.; Li, J.; Hou, Z.; Yang, X.; Zhang, Z.; Wang, Y.; Luo, X.; Li, M. Synthesis and pharmacological evaluations of 4-hydroxycoumarin derivatives as a new class of anti-Staphylococcus aureus agent. J. Pharma. Pharmacol., 2014, 67, 573-582.
[28]
Rehman, S.; Ikram, M.; Baker, R.; Zubair, M.; Azad, E.; Min, S.; Riaz, K.; Mok, K.; Rehman, S. Synthesis, characterization, in vitro antimicrobial, and U2OS tumoricidal activities of different coumarin derivatives. Chem. Cent. J., 2013, 7, 68.
[29]
Sherill, D. Energy Component Analysis of π Interactions. Acc. Chem. Res., 2013, 46(4), 1020-1028.
[30]
Lipinski, C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1, 337-341.
[31]
Wheeler, E.; Houk, N. Are anion/π interactions actually a case of simple charge-dipole interactions? J. Phys. Chem. A, 2010, 114, 8658-8664.
[32]
Wheeler, S.E.; Houk, K.N. Substituent effects in cation/π interactions and electrostatic potentials above the center of substituted benzenes are due primarily to through-space effects of the substituents. J. Am. Chem. Soc., 2009, 131, 3126-3127.
[33]
Wheeler, S.E.; Houk, K.N. Origin of substituent effects in Edge-to-Face Aryl-Aryl interactions. Mol. Phys., 2009, 107, 749-760.
[34]
Wheeler, S.E.; Houk, K.N. Substituent effects in the benzene dimer are due to direct interactions of the substituents with the unsubstituted benzene. J. Am. Chem. Soc., 2008, 130, 10854-10855.
[35]
Wheeler, S.E. Understanding substituent effects in noncovalent interactions involving aromatic rings. J. Am. Chem. Soc., 2013, 46, 1029-1038.
[36]
Anjana, R.; Vaishnavi, M.; Sherlin, D.; Surapaneni, K.; Naveen, K.; Kanth, P.; Sekar, K. Aromatic-aromatic interactions in structures of proteins and protein-DNA complexes: A study based on orientation and distance. Bioinformation, 2012, 8(24), 1220-1224.
[37]
Burley, K.; Petsko, A. Amino-aromatic interactions in proteins. FEBS Lett., 1986, 203(2), 139-143.
[38]
Borges, F.; Roleira, F.; Milhazes, N.; Santana, H. Simple coumarins and analogoues in medicinal chemistry: Occurrence, synthesis and biological activity. Curr. Med. Chem., 2005, 12, 887.
[39]
Shi, Y.; Zhou, C.; Geng, R.; Ji, Q. Synthesis and antimicrobial evaluation of coumarin-based benzotriazoles and their synergistic effects with chloromycin and fluconazole. Yao Xue Xue Bao, 2011, 46, 798-810.
[40]
Nolan, K.; Doncaster, J.; Dunstan, M.; Scott, K.; Frenkel, A.; Siegel, D.; Ross, D.; Barnes, J.; Levy, C.; Leys, D.; Whitehead, R.; Stratford, I.; Bryce, R. Synthesis and biological evaluation of coumarin-based inhibitors of NAD(P)H: Quinone oxidoreductase-1 (NQO1). J. Med. Chem., 2009, 52(22), 7142-7156.
[41]
Liu, Y.; Liu, X.; Wang, M.; Peng, H.; Lin, L.; Feng, X. Enantioselective synthesis of 3,4-dihydropyran derivatives via organocatalytic Michael reaction of α,β-unsaturated enones. J. Org. Chem., 2012, 77, 4136-4142.
[42]
Gung, W.; Amicangelo, C. Substituent effects in C6F6-C6H5X stacking interactions. J. Org. Chem., 2006, 71, 9261-9270.
[43]
Benitex, Y.; Baranger, A. Recognition of essential purines by the U1A protein. BMC Biochem., 2007, 8, 22.
[44]
Hunter, A.; Lawson, R.; Perkins, J.; Urch, J. Aromatic Interactions. J. Chem. Soc., Perkin Trans., 2001, 5, 651-669.
[45]
Hunter, C.A.; Sanders, J.K.M. The nature of π-π interactions. J. Am. Chem. Soc., 1990, 112, 5525-5534.
[46]
Cockroft, S.L.; Hunter, C.A.; Lawson, K.R.; Perkins, J.; Urch, C.J. Electrostatic control of aromatic stacking interactions. J. Am. Chem. Soc., 2005, 127, 8594-8595.
[47]
Cockroft, S.L.; Hunter, C.A. Chemical double-mutant cycles: Dissecting non-covalent interactions. Chem. Soc. Rev., 2007, 36, 172-188.
[48]
Cockroft, S.L.; Perkins, J.; Zonta, C.; Adams, H.; Spey, S.E.; Low, C.M.R.; Vinter, J.G.; Lawson, K.R.; Urch, C.J.; Hunter, C.A. Substituent effects on aromatic stacking interactions. Org. Biomol. Chem., 2007, 5, 1062-1080.
[49]
Cravotto, G.; Nano, G.; Palmisano, G.; Tagliapierta, S. The reactivity of 4-hydroxycoumarin under heterogeneous high-intensity sonochemical conditions. Synthesis, 2003, 8, 1286-1291.
[50]
Hamd, N.; Puerta, C.; Valerga, P. Synthesis, structure, antimicrobial and antioxidant investigations of dicoumarol and related compounds. Eur. J. Med. Chem., 2008, 43, 2541-2548.
[51]
Chandler, D. Interfaces and the driving force of hydrophobic assembly. Nature, 2005, 437(7059), 640-647.


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Article Details

VOLUME: 17
ISSUE: 2
Year: 2019
Page: [93 - 98]
Pages: 6
DOI: 10.2174/2211352516666181112125458

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