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3D-QSAR Topomer CoMFA Studies on 10 N-Substituted Acridone Derivatives

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DOI: 10.4236/ojmc.2012.23006    3,639 Downloads   7,379 Views   Citations

ABSTRACT

Topomer CoMFA models have been used to optimize the potency of 15 biologically active acridone derivatives se- lected from the literature. Their 3D chemical structures were sliced into three acyclic R groups, to produce a fragment that is present in each training set. The analysis was successful with 3 as the number of components that provided the highest q2 results: q2 is 0.56, which is the cross-validated coefficient for the specified number of components, giving rise to 0.37 standard error of estimate (q2 stderr), and a conventional coefficient (r2) of 0.82, whose standard error of estimate is 0.24. These results provide structure-activity relationship (sar) among the compounds. The result of the To-pomer CoMFA studies was used to design novel derivatives for future studies.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

A. Ajala and C. Okoro, "3D-QSAR Topomer CoMFA Studies on 10 N-Substituted Acridone Derivatives," Open Journal of Medicinal Chemistry, Vol. 2 No. 3, 2012, pp. 43-49. doi: 10.4236/ojmc.2012.23006.

References

[1] [1] K. Ramesh and K. Meena, “Chemistry of Acridone and Its Analogues: A Review,” Journal of Chemical and Pharmaceutical Research, Vol. 3, No. 1, 2011, pp. 217-230.
[2] [2] W. D. Inman, M. O’Neill-Johnson and P. Crews, “Pyrroloacridine Alkaloids from Plakortis Quasiampkiaster: Structures and Bioactivity,” Journal of the American Chemical Society, Vol. 112, 1990, pp. 1-13.
[3] [3] P. Akanitapichat, C. T. Lowden and K. F. Bastow, “1, 3-Dihydroxyacridone Derivatives as Inhibitors of Herpes Virus Replication,” Antiviral Research, Vol. 45, No. 2, 2000, pp. 123-134.
[4] [4] J. R. Goodell, A. A. Madhok and H. Hiasa, D. M. Fergusson, “Synthesis and Evaluation of Acridineand Acridone-Based Anti-herpes Agents with Topoisomerase Activity,” Bioorganic & Medicinal Chemistry, Vol. 14, No. 16, 2006, pp. 5467-5480.
[5] [5] C. T. Lowden and K. F. Bastow, “Cell Culture Replication of Herpes Simplex Virus and, or Human Cytomegalovirus Is Inhibited by 3, 7-Dialkoxylated, 1-Hydroxyacridone Derivatives,” Antiviral Research, Vol. 59, No. 3, 2003, pp. 143-154.
[6] [6] M. Itoigawa, C. Ito, T.-S. Wu, et al., “Cancer Chemopreventive Activity of Acridone Alkaloids on Epstein-Barr Virus Activation and Two-Stage Mouse Skin Carcinogenesis,” Cancer Letters, Vol. 193, No. 2, 2003, pp. 133138.
[7] [7] V. V. Zarubaev, A. V. Slita, V. Z. Krivitskaya, A. K. Sirotkin, A. L. Kovalenko and N. K. Chatterjee, “Direct Antiviral Effect of Cycloferon (10-Carboxymethyl-9-Acridanone) against Adenovirus Type 6 in Vitro,” Antiviral Research, Vol. 58, No. 2, 2003, pp. 131-137.
[8] [8] S. S. Claudia, L. F. Mirta, B. M. Maria, L. D. Maite, F. P. Rolando, C. G. Cybele, B. D. Norma and B. D. Elsa, “Synthesis and Evaluation of N-substituted Acridones as Antiviral Agents against Haemorrhagic Fever Viruses, Antiviral Chemistry & Chemotherapy,” Short Communications, Vol. 19, 2008, pp. 41-47.
[9] [9] K. Dzierzbicka and A. M. kolodziejczyk, “Synthesis and Antitumor Activity of Conjugates of Muramyldipeptide, Normuramyldipeptide and Desmuramylpeptides with Acridine/Acridone Derivatives,” Journal of Medicinal Che-mistry, Vol. 44, No. 22, 2001, pp. 3606-3615.
[10] [10] S. A. Gamage, J. A. Spicer, G. J. Atwell, G. J. Finlay, B. C. Baguley and W. A. Denny, “Structure-Activity Relationships for Substituted Bis(Acridine-4-Carboxamides): A New Class of Anticancer Agents,” Journal of Medicinal Chemistry, Vol. 42, No. 13, 1999, pp. 2383-2393.
[11] [11] T. Bentin and P. E. Nielsen, “Superior Duplex DNA Strand Invasion by Acridine Conjugated Peptide Nucleic Acids,” Journal of the American Chemical Society, Vol. 125, No. 21, 2003, pp. 6378-6379.
[12] [12] X. K. Jane, J. S. Martin, A. C. Roland, D. L. Kristin, A. J. Robert, J. Aaron, A. D. Rozalia, J. H. David, W. Rolf and R. Michael, “Design, Synthesis and Evaluation of 10-NSubstituted Acridones as Novel Chemosensitizers in Plasmodium Falciparum,” Antimicrobial Agents and Chemotherapy, Vol. 51, No. 11, 2007, pp. 4133-4140.
[13] [13] L. L. Zhu, T. J. Hou, L. R. Chen and X. J. Xu, “3DQSAR Analyses of Novel Tyrosine Kinase Inhibitors Based on Pharmacophore Alignment,” Journal of Chemical Information and Modeling, Vol. 41, No. 4, 2001, pp. 1032-1040.
[14] [14] H. Kubinyi, “3D-QSAR in Drug Design: Theory, Methods and Applications,” ESCOM, Leiden, 1993.
[15] [15] H. Kubinyi, G. Folkers and Y. C. Martin, “3D-QSAR in Drug Design: Recent Advances,” Perspectives in Drug Discovery and Design, Vol. 12, No. 13, 1997 pp. 3-23.
[16] [16] R. D. Cramer, D. E. Patterson and J. D. Bunce, “Comparative Molecular Field Analysis (C0MFA). 1. Effect of Binding on Steroids to Carrier Proteins,” Journal of the American Chemical Society, Vol. 110, No. 18, 1988, pp. 5959-5967.
[17] [17] Other Approaches Do Exist with Promising Direct 3D Database Searching with Potency Predictions, Such as Pseudo-Receptor Modeling, the Catalyst Suite, and Post3D-Searching CoMFA. However, They Are Limited in Speed, and Perhaps, Range of Applicability.
[18] [18] Y. C. Martin, “3D QSAR: Current State, Scope and Limitations,” In: H. Kubinyi, G. Folkers and Y. C. Martin, Eds., Three-Dimensional Quantitative Structure Activity Relationships, Vol. 3, Springer, Netherlands, 2002, pp. 3-23.
[19] [19] R. Bursi and P. D. G. Grootenhuis, “Comparative Molecular Field Analysis and Energy Interaction Studies of Thrombin-Inhibitor Complexes,” Journal of ComputerAided Molecular Design, Vol. 13, No. 3, 1999, pp. 221232.
[20] [20] S. S. Sao and M. Karplus, “Evaluation of Design Ligands by Multiple Screening Method: Application of Glycogen Phosphorylase Inhibitors Constructed with a Variety of Approaches,” Journal of Computer-Aided Molecular Design, Vol. 15, No. 7, 2001, pp. 613-647.
[21] [21] R. D. Cramer, R. D. Clark, D. E. Patterson and A. M. Fergusson, “Bioisosterism as a Molecular Diversity Descriptor: Steric Fields of Single ‘Topomeric’ Conformers,” Journal of Medicinal Chemistry, Vol. 39, No. 16, 1996, pp. 3060-3069.
[22] [22] R. D. Cramer, “Topomer CoMFA: A Design Methodology for Rapid Lead Optimization,” Journal of Medicinal Chemistry, Vol. 46, No. 3, 2003, pp. 374-388.
[23] [23] Sybyl-X 1.3, St. Louis, 2010. http://www.tripos.com
[24] [24] T. A. Halgren, “A General Program for Modeling Molecules and their Interactions,” Journal of Computational Chemistry, Vol. 17, 1996, pp. 520-552.
[25] [25] T. A. Halgren, “Merck Molecular Force Field III. Geometries and Vibrational Frequencies for MMFF94,” Journal of Computational Chemistry, Vol. 17, 1996, pp. 553-586.
[26] [26] T. A. Halgren, “Merck Molecular Force Field V. Extension of MMFF94 Using Experimental Data, Additional computation Data, and Empirical Rules,” Journal of Computational Chemistry, Vol. 17, 1996, pp. 616-641.
[27] [27] T. A. Halgren, “Merck Molecular Force Field I. Basis, Form, Scope, Parameterization and Performance of MMFF94,” Journal of Computational Chemistry, Vol. 17, 1996, pp. 490-519.
[28] [28] T. A. Halgren and R. B. Nachbar, “Merck Molecular Force Field IV. Conformational Energies and Geometries for MMFF94,” Journal of Computational Chemistry, Vol. 17, 1996, pp. 587-615.

  
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