A
systematic conceptual density functional theory (DFT) analysis was performed on
a series of chlorinated chalcones to study the effect of electron distribution
on antimicrobial activity. In our previous work, a series of 16 chlorinated
chalcones were synthesized to determine the antimicrobial effects of varying
the location of the halogen substituent on each aromatic ring of the chalcone. Herein is reported a DFT investigation of
those 16 chalcones and a comparison of quantum chemical properties to their
antimicrobial activity. DFT global chemical
reactivity descriptors (chemical hardness/softness, chemical potential/electronegativity,
and electrophilicity) and local reactivity descriptors (Fukui functions and
dual descriptor) were calculated for all compounds using Spartan’18 software. All calculations were carried out
at the B3LYP/6-31G* level of theory. Reactivity analysis of the Fukui dual
descriptor calculations reveals sites of nucleophilic and electrophilic
attack. These in-silico results provide a foundation for further
synthetic optimization of the chalcone skeleton to serve as novel
antimicrobial agents.
References
[1]
Frieden, T. (2013) Antibiotic Resistance Threats in the United States. Centers for Disease Control and Prevention, Atlanta.
[2]
Batovska, D., Parushev, S., Stamboliyska, B., Tsvetkova, I., Ninova, M. and Najdenski, H. (2009) Examination of Growth Inhibitory Properties of Synthetic Chalcones for Which Antibacterial Activity Was Predicted. European Journal of Medicinal Chemistry, 44, 2211-2218. https://doi.org/10.1016/j.ejmech.2008.05.010
[3]
Lahtchev, K.L., Batovska, D.I., St. Parushev, P., Ubiyvovk, V.M. and Sibirny, A.A. (2008) Antifungal Activity of Chalcones: A Mechanistic Study Using Various Yeast Strains. European Journal of Medicinal Chemistry, 43, 2220-2228. https://doi.org/10.1016/j.ejmech.2007.12.027
[4]
Baviskar, B., Patel, S., Baviskar, B., Khadabadi, S.S. and Shiradkar, M. (2008) Design and Synthesis of Some Novel Chalcones as Potent Antimicrobial Agent. Asian Journal of Research in Chemistry, 1, 67-69.
[5]
Prasad, Y., Lakshmana Rao, A. and Rambabu, R. (2008) Synthesis and Antimicrobial Activity of Some Chalcone Derivatives. E-Journal of Chemistry, 5, 461-466. https://doi.org/10.1155/2008/876257
[6]
Swamy, P.M. and Agasimundin, Y.S. (2008) Synthesis and Antimicrobial Screening of Certain Substituted Chalcones and Isoxazolines Bearing Hydroxybenzofuran. Rasayan Journal of Chemistry, 1, 421-428.
[7]
Kumbhar, D.D., Waghamare, B.Y., Pathade, G.R. and Pardeshi, S.K. (2014) Synthesis and Evaluation of Chalcones as an Anti-Bacterial and Anti-Fungal Agents. Der Pharmacia Lettre, 6, 224-229.
[8]
Paramesh, M., Niranjan, M.S., Sarfaraj, N., Shivaraja, S. and Rubbani, M.S. (2010) Synthesis and Antimicrobial Study of Some Chlorine-Containing Chalcones. International Journal of Pharmacy and Pharmaceutical Sciences, 2, 113-117.
[9]
Habib, S.I. (2018) Chemical and Biological Potential of Chalcones as a Source of Drug: A Review. International Journal of Pharmacy and Pharmaceutical Research, 11, 104-118.
[10]
Amato-Ocampo, J., Carrillo, R., Kae, H. and Ashburn, B.O. (2018) Synthesis and Antimicrobial Evaluation of a Series of Chlorinated Chalcone Derivatives. International Journal of Pharmacy and Pharmaceutical Research, 13, 112-119.
[11]
Simirgiotis, M.J., Adachi, S., To, S., Yang, H., Reynertson, K.A., Basile, M.J., Roberto, G.R., Weinstein, I.B. and Kennelly, E.J. (2008) Cytotoxic Chalcones and Antioxidants from the Fruits of Syzygium samarangense (Wax Jambu). Food Chemistry, 107, 813-819. https://doi.org/10.1016/j.foodchem.2007.08.086
[12]
Gacche, R.N., Dhole, N.A., Kamble, S.G. and Bandgar, B.P. (2008) In-Vitro Evaluation of Selected Chalcones for Antioxidant Activity. Journal of Enzyme Inhibition and Medicinal Chemistry, 23, 28-31. https://doi.org/10.1080/14756360701306370
[13]
Nowakowska, Z. (2007) A Review of Anti-Infective and Anti-Inflammatory Chalcones. European Journal of Medicinal Chemistry, 42, 125-137. https://doi.org/10.1016/j.ejmech.2006.09.019
[14]
Jin, F., Jin, X.Y., Jin, Y.L., Sohn, D.W., Kim, S.A., Sohn, D.H., Kim, Y.C. and Kim, H.S. (2007) Structural Requirements of 2’,4’,6’-tris(methoxymethoxy) Chalcone Derivatives for Anti-Inflammatory Activity: The Importance of a 2’-Hydroxy Moiety. Archives of Pharmacal Research, 30, 1359-1367. https://doi.org/10.1007/BF02977357
[15]
Zhang, X.W., Zhao, D.H., Quan, Y.C., Sun, L.P., Yin, X.M. and Guan, L.P. (2010) Synthesis and Evaluation of Anti-Inflammatory Activity of Substituted Chalcone Derivatives. Medicinal Chemistry Research, 19, 403-412. https://doi.org/10.1007/s00044-009-9202-z
[16]
Lawrence, N.J., Patterson, R.P., Ooi, L.L., Cook, D. and Ducki, S. (2006) Effects of α-Substitutions on Structure and Biological Activity of Anticancer Chalcones. Bioorganic & Medicinal Chemistry Letters, 16, 5844-5848. https://doi.org/10.1016/j.bmcl.2006.08.065
[17]
Goniotaki, M., Hatziantoniou, S., Dimas, K., Wagner, M. and Demetzos, C.J. (2004) Encapsulation of Naturally Occurring Flavonoids into Liposomes: Physicochemical Properties and Biological Activity against Human Cancer Cell Lines. Journal of Pharmacy and Pharmacology, 56, 1217-1224. https://doi.org/10.1211/0022357044382
[18]
Modzelewska, A., Pettit, C., Achanta, G., Davidson, N.E., Huang, P. and Khan, S.R. (2006) Anticancer Activities of Novel Chalcone and Bis-Chalcone Derivatives. Bioorganic & Medicinal Chemistry, 14, 3491-3495. https://doi.org/10.1016/j.bmc.2006.01.003
[19]
Apalangya, V.A., Bakupog, T., Tutson, C., Sefadzi, S., Early, B., Troy, R.M., Curry, M.L., Robinson, P.M.L., Powell, N.L. and Russell, A.E. (2012) Inhibition of MDA-MB-231 Breast Cancer Cell Proliferation by Simple Diphenyl Chalcone and Its Chlorinated Derivative. Research & Reviews: Journal of Oncology and Hematology, 1, 7.
[20]
Parr, R.G. and Yang, W. (1989) Density-Functional Theory of Atoms and Molecules. Oxford University Press, Oxford.
[21]
Kohn, W. and Sham, L.J. (1965) Self-Consistent Equations Including Exchange and Correlation Effects. Physical Review, 140, 1133-1138. https://doi.org/10.1103/PhysRev.140.A1133
[22]
Becke, A.D. (1997) Density-Functional Thermochemistry. V. Systematic Optimization of Exchange-Correlation Functionals. The Journal of Chemical Physics, 107, 8554-8560. https://doi.org/10.1063/1.475007
[23]
Domingo, L.R., Rios-Gutierrez, M. and Perez, P. (2016) Applications of the Conceptual Density Functional Theory Indices to Organic Chemistry Reactivity. Molecules, 21, 748-770. https://doi.org/10.3390/molecules21060748
[24]
Koch, W. and Holthausen, M.C. (2011) A Chemist’s Guide to Density Functional Theory. 2nd Edition, Wiley-VCH, Hoboken.
[25]
Frau, J., Flores-Holguín, N. and Glossman-Mitnik, D. (2019) Conceptual Density Functional Theory Study of the Chemical Reactivity Properties and Bioactivity Scores of the Leu-Enkephalin Opioid Peptide Neurotransmitter. Computational Molecular Bioscience, 9, 13-26. https://doi.org/10.4236/cmb.2019.91002
[26]
Ashburn, B.O., Le, D.J. and Nishimura, C.K. (2018) Computational Analysis of Theacrine, a Purported Nootropic and Energy-Enhancing Nutritional Supplement. Computational Chemistry, 7, 27-37. https://doi.org/10.4236/cc.2019.71002
[27]
Parr, R.G. and Pearson, R.G. (1983) Absolute Hardness: Companion Parameter to Absolute Electronegativity. Journal of the American Chemical Society, 105, 7512-7516. https://doi.org/10.1021/ja00364a005
[28]
Parr, R.G. and Yang, W. (1989) Density Functional Theory of Atoms and Molecules. Oxford University Press, New York.
[29]
Koopmans, T. (1934) über die Zuordnung von Wellenfunktionen und Eigenwertenzu den Einzelnen Elektronen Eines Atoms. Physica, 1, 104-113. https://doi.org/10.1016/S0031-8914(34)90011-2
[30]
Pearson, R.G. and Songstad, J. (1967) Application of the Principle of Hard and Soft Acids and Bases to Organic Chemistry. Journal of the American Chemical Society, 89, 1827-1836. https://doi.org/10.1021/ja00984a014
[31]
Pearson, R.G. (1973) Hard and Soft Acids and Bases. Dowden, Hutchinson and Ross, Stroudsberg.
[32]
Pearson, R.G. (1997) Chemical Hardness: Applications from Molecules to Solids. Wiley-VCH Verlag GMBH, Weinheim.
[33]
Yang, W. and Parr, R.G. (1985) Hardness, Softness, and the Fukui Function in the Electronic Theory of Metals and Catalysis. Proceedings of the National Academy of Sciences of the United States of America, 82, 6723-6726. https://doi.org/10.1073/pnas.82.20.6723
[34]
Maynard, A.T., Huang, M., Rice, W.G. and Covel, D.G. (1998) Reactivity of the HIV-1 Nucleocapsid Protein p7 Zinc Finger Domains from the Perspective of Density-Functional Theory. Proceedings of the National Academy of Sciences of the United States of America, 95, 11578-11583. https://doi.org/10.1073/pnas.95.20.11578
[35]
Parr, R.G., von Szentpaly, L. and Liu, S. (1999) Electrophilicity Index. Journal of the American Chemical Society, 121, 1922-1924. https://doi.org/10.1021/ja983494x
[36]
Fukui, K. (1982) Role of Frontier Orbitals in Chemical Reactions. Science, 218, 747-754. https://doi.org/10.1126/science.218.4574.747
[37]
Parr, R.G. and Yang, W. (1984) Density Functional Approach to the Frontier-Electron Theory of Chemical Reactivity. Journal of the American Chemical Society, 106, 4049-4050. https://doi.org/10.1021/ja00326a036
[38]
Yang, W., Parr, R.G. and Pucci, R. (1984) Electron Density, Kohn-Sham Frontier Orbitals, and Fukui Functions, The Journal of Chemical Physics, 81, 2862-2863. https://doi.org/10.1063/1.447964
[39]
Morell, C., Grand, A. and Toro-Labbe, A. (2005) New Dual Descriptor for Chemical Reactivity. The Journal of Physical Chemistry A, 109, 205-212. https://doi.org/10.1021/jp046577a
[40]
Morell, C., Grand, A. and Toro-Labbe, A. (2016) New Theoretical Support for Using the f(r) Descriptor. Chemical Physics Letters, 425, 342-346. https://doi.org/10.1016/j.cplett.2006.05.003
[41]
Martinez-Araya, J.I. (2014) Why Is the Dual Descriptor a More Accurate Local Reactivity Descriptor than Fukui Functions? Journal of Mathematical Chemistry, 53, 451-465. https://doi.org/10.1007/s10910-014-0437-7
[42]
Shao, et al. (2006) Advances in Methods and Algorithms in a Modern Quantum Chemistry Program Package. Physical Chemistry Chemical Physics, 8, 3172-3191.
[43]
Becke, A.D. (1988) Density-Functional Exchange-Energy Approximation with Correct Asymptotic Behavior. Physical Review A, 38, 3098-3100. https://doi.org/10.1103/PhysRevA.38.3098
[44]
Lee, C., Yang, W. and Parr, R.G. (1988) Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density. Physical Review B, 37, 785-789. https://doi.org/10.1103/PhysRevB.37.785
[45]
Nkungli, N.K., Ghogomu, J.N., Nogheu, L.N. and Gadre, S.R. (2015) DFT and TD-DFT Study of Bis[2-(5-Amino-[1,3,4]-Oxadiazol-2-yl)Phenol](Diaqua)M(II) Complexes [M = Cu, Ni and Zn]: Electronic Structures, Properties and Analyses. Computational Chemistry, 3, 29-44. https://doi.org/10.4236/cc.2015.33005
[46]
Leo, A., Hansch, C. and Elkins, D. (1971) Partition Coefficients and Their Uses. Chemical Reviews, 71, 525-616. https://doi.org/10.1021/cr60274a001
[47]
Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J. (2001) Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Advanced Drug Delivery Reviews, 46, 3-26. https://doi.org/10.1016/S0169-409X(96)00423-1
[48]
Lipinski, C.A. (2004) Lead- and Drug-Like Compounds: The Rule-of-Five Revolution. Drug Discovery Today: Technologies, 1, 337-341. https://doi.org/10.1016/j.ddtec.2004.11.007
