QSAR Analysis of Selected Antimicrobial Structures Belonging to Nitro-derivatives of Heterocyclic Compounds

Author(s): Piotr Kawczak*, Leszek Bober, Tomasz Bączek

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 2 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Nitro-derivatives of heterocyclic compounds were used as active agents against pathogenic microorganisms. A set of 4- and 5-nitroimidazole derivatives exhibiting antimicrobial activity was analyzed with the use of Quantitative Structure-Activity Relationships (QSAR) method. The study included compounds used both in documented treatment and those described as experimental.

Objective: The purpose of this study was to demonstrate the common and differentiating characteristics of the above-mentioned chemical compounds alike physicochemically as well as pharmacologically based on the quantum chemical calculations and microbiological activity data.

Methods: During the study PCA and MLR analysis were performed, as the types of proposed chemometric approach. The semi-empirical and ab initio level of in silico molecular modeling was performed for calculations of molecular descriptors.

Results: QSAR models were proposed based on chosen descriptors. The relationship between the nitro-derivatives structure and microbiological activity data was able to class and describe the antimicrobial activity with the use of statistically significant molecular descriptors.

Conclusion: The applied chemometric approaches revealed the influential features of the tested structures responsible for the antimicrobial activity of studied nitro-derivatives.

Keywords: Heterocyclic compounds, molecular modeling, structural analysis, descriptors, PCA, MLR.

[1]
Bryan, G.T. Nitrofurans: chemistry, metabolism, mutagenesis and carcinogenesis; Nitrofurans.; Raven Press: New York 1978
[2]
Mital, A. Synthetic Nitroimidazoles: Biological activities and mutagenicity relationships. Sci. Pharm., 2009, 77, 497-520. [http://dx.doi.org/10.3797/scipharm.0907-14].
[3]
Pires, J.R.; Saito, C.; Gomes, S.L.; Giesbrecht, A.M.; Amaral, A.T. Investigation of 5-nitrofuran derivatives: Synthesis, antibacterial activity, and quantitative structure-activity relationships. J. Med. Chem., 2001, 44(22), 3673-3681. [http://dx.doi.org/10.1021/jm0101693]. [PMID: 11606132].
[4]
Edwards, D.I. Nitroimidazole drugs-action and resistance mechanisms. I. Mechanisms of action. J. Antimicrob. Chemother., 1993, 31(1), 9-20. [http://dx.doi.org/10.1093/jac/31.1.9]. [PMID: 8444678].
[5]
Debnath, A.K.; Lopez de Compadre, R.L.; Debnath, G.; Shusterman, A.J.; Hansch, C. Structure-activity relationship of mutagenic aromatic and heteroaromatic nitro compounds. Correlation with molecular orbital energies and hydrophobicity. J. Med. Chem., 1991, 34(2), 786-797. [http://dx.doi.org/10.1021/jm00106a046]. [PMID: 1995902].
[6]
Bober, L.; Koba, M.; Judycka-Proma, U.; Bączek, T. Pharmacological classification of drugs by principal component analysis applying molecular modeling descriptors and HPLC retention data. J. Chromatogr. Sci., 2011, 49(10), 758-763. [http://dx.doi.org/10.1093/chrsci/49.10.758]. [PMID: 22080803].
[7]
Cavalleri, B.; Volpe, G.; Arioli, V.; Pizzocheri, F.; Diena, A. Synthesis and biological activity of new 2-nitroimidazole derivatives. J. Med. Chem., 1978, 21(8), 781-784. [http://dx.doi.org/10.1021/jm00206a012]. [PMID: 211235].
[8]
Ashtekar, D.R.; Costa-Perira, R.; Nagrajan, K.; Vishvanathan, N.; Bhatt, A.D.; Rittel, W. In vitro and in vivo activities of the nitroimidazole CGI 17341 against Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 1993, 37(2), 183-186. [http://dx.doi.org/10.1128/AAC.37.2.183]. [PMID: 8452346].
[9]
Edwards, D.I.; Dye, M.; Carne, H. The selective toxicity of antimicrobial nitroheterocyclic drugs. J. Gen. Microbiol., 1973, 76(1), 135-145. [http://dx.doi.org/10.1099/00221287-76-1-135]. [PMID: 4541833].
[10]
Jokipii, L.; Jokipii, A.M. Comparative evaluation of the 2-methyl-5-nitroimidazole compounds dimetridazole, metronidazole, secnidazole, ornidazole, tinidazole, carnidazole, and panidazole against Bacteroides fragilis and other bacteria of the Bacteroides fragilis group. Antimicrob. Agents Chemother., 1985, 28(4), 561-564. [http://dx.doi.org/10.1128/AAC.28.4.561]. [PMID: 4073879].
[11]
Cantelli-Forti, G.; Aicardi, G.; Guerra, M.C.; Barbaro, A.M.; Biagi, G.L. Mutagenicity of a series of 25 nitroimidazoles and two nitrothiazoles in Salmonella typhimurium. Teratog. Carcinog. Mutagen., 1983, 3(1), 51-63. [http://dx.doi.org/10.1002/1520-6866(1990)3:1<51:AID-TCM1770030107>3.0.CO;2-L]. [PMID: 6132457].
[12]
Official Gaussian Website. http://www.gaussian.com/January2018.
[13]
Tomasi, J.; Persico, M. Molecular Interactions In Solutions: An overview of Methods Based on Continuous Distributions of the Solvent. Chem. Rev., 1994, 94, 2027-2094. [http://dx.doi.org/10.1021/cr00031a013].
[14]
Tomasi, J.; Mennucci, B.; Cammi, R. Quantum mechanical continuum solvation models. Chem. Rev., 2005, 105(8), 2999-3093. [http://dx.doi.org/10.1021/cr9904009]. [PMID: 16092826].
[15]
Caricato, M.; Scalmani, G. On the Importance of the orbital relaxation in ground-state coupled cluster calculations in solution with the polarizable continuum model of solvation. J. Chem. Theory Comput., 2011, 7(12), 4012-4018. [http://dx.doi.org/10.1021/ct2006677]. [PMID: 26598347].
[16]
HyperChem® Computational Chemistry Part 1 Practical Guide. Part Theory and Methods. 1996
[17]
Todeschini, R.; Consonni, V. Molecular Descriptors for Chemoinformatics: Volume I: Alphabetical Listing / Volume II: Appendices, References, Wiley-VCH Verlag GmbH & Co.: KGaA: Weinheim, 2010; 71.
[18]
Dragon 7 molecular descriptors. Available at: https://chm.kode-solutions.net/products_dragon.php [Accessed: January 2, 2018].


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 17
ISSUE: 2
Year: 2020
Page: [214 - 225]
Pages: 12
DOI: 10.2174/1570180815666181004112947
Price: $65

Article Metrics

PDF: 16
HTML: 2
EPUB: 1
PRC: 1