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Lipophilicity, Pharmacokinetic Properties, and Molecular Docking Study on SARS-Cov-2 Target for Betulin Triazole Derivatives with Attached 1,4-Quinone

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Lipophilicity, Pharmacokinetic Properties, and Molecular Docking Study on SARS-Cov-2 Target for Betulin Triazole Derivatives with Attached 1,4-Quinone pharmaceutics Article Lipophilicity, Pharmacokinetic Properties, and Molecular Docking Study on SARS-CoV-2 Target for Betulin Triazole Derivatives with Attached 1,4-Quinone Monika Kadela-Tomanek 1,* , Maria Jastrz˛ebska 2, Krzysztof Marciniec 1 , Elwira Chrobak 1 , Ewa B˛ebenek 1 and Stanisław Boryczka 1 1 Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, 4 Jagiello´nskaStr., 41-200 Sosnowiec, Poland; [email protected] (K.M.); [email protected] (E.C.); [email protected] (E.B.); [email protected] (S.B.) 2 Silesian Center for Education and Interdisciplinary Research, Institute of Physics, University of Silesia, 75 Pułku Piechoty 1a, 41-500 Chorzów, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-32-3641666 Abstract: A key parameter in the design of new active compounds is lipophilicity, which influences the solubility and permeability through membranes. Lipophilicity affects the pharmacodynamic and toxicological profiles of compounds. These parameters can be determined experimentally or by using different calculation methods. The aim of the research was to determine the lipophilicity of betulin triazole derivatives with attached 1,4-quinone using thin layer chromatography in a Citation: Kadela-Tomanek, M.; reverse phase system and a computer program to calculate its theoretical model. The physiochemical Jastrz˛ebska,M.; Marciniec, K.; and pharmacokinetic properties were also determined by computer programs. For all obtained Chrobak, E.; B˛ebenek,E.; Boryczka, S. parameters, the similarity analysis and multilinear regression were determined. The analyses showed Lipophilicity, Pharmacokinetic that there is a relationship between structure and properties under study. The molecular docking Properties, and Molecular Docking study showed that betulin triazole derivatives with attached 1,4-quinone could inhibit selected Study on SARS-CoV-2 Target for SARS-CoV-2 proteins. The MLR regression showed that there is a correlation between affinity scoring Betulin Triazole Derivatives with values (DG) and the physicochemical properties of the tested compounds. Attached 1,4-Quinone. Pharmaceutics 2021, 13, 781. https://doi.org/ Keywords: 1,4-quinone; betulin; lipophilicity; molecular docking; SARS-CoV-2 proteins 10.3390/pharmaceutics13060781 Academic Editor: Sourav Bhattacharjee 1. Introduction Received: 6 May 2021 Nowadays, the search for new drugs requires the application of computational chem- Accepted: 20 May 2021 istry, including experimental and in silico analysis of physicochemical properties, phar- Published: 23 May 2021 macokinetic features, ADMET analysis, and quantitative structure–activity relationship (QSAR) research [1,2]. The therapeutic potential of a drug depends on its distribution in Publisher’s Note: MDPI stays neutral the body. Often, substances with high biological activity show low bioavailability and with regard to jurisdictional claims in high toxicity to healthy tissues. Nanocarriers, including liposomes, micelles, and polymer published maps and institutional affil- nanoparticles, enable the improvement of the biodistribution of substances. Incorporation iations. of the hydrophobic core into hydrophilic nanotransporters can effectively influence the solubility of the drug, which contributes to the improvement of permeability through cell membranes [3,4]. A key parameter in the design of new active compounds is lipophilicity, which in- Copyright: © 2021 by the authors. fluences the solubility and permeability through membranes. Lipophilicity affects the Licensee MDPI, Basel, Switzerland. pharmacodynamic and toxicological profiles of compounds. These parameters can be deter- This article is an open access article mined experimentally or by using different calculation methods. Experimental lipophilicity distributed under the terms and is usually determined by chromatographic methods, such as reversed phase thin layer chro- conditions of the Creative Commons matography (RP-TLC), normal phase thin layer chromatography (NP-TLC), or reversed Attribution (CC BY) license (https:// phase high performance liquid chromatography (RP-HPLC). Theoretical methods are the creativecommons.org/licenses/by/ second way to determine lipophilicity. However, the calculated value of lipophilicity 4.0/). Pharmaceutics 2021, 13, 781. https://doi.org/10.3390/pharmaceutics13060781 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, x 2 of 22 Pharmaceutics 2021, 13, 781 2 of 21 ods are the second way to determine lipophilicity. However, the calculated value of lipo- philicitydepends depends on the on algorithmthe algorithm employed employed for calculation,for calculation, and and for manyfor many compounds compounds it differs it differsfrom from the the experimental experimental ones ones [5– [5–7].7]. NaturalNatural substances, substances, especially especially secondary secondary metabolites, metabolites, are are often often an an inspiration inspiration to to ob- obtain tain semisyntheticsemisyntheticcompounds, compounds, which which exhibit exhibi hight high biological biological activity. activity. Microorganisms Microorganisms produce producemany many secondary secondary metabolites metabolites that affectthat affect antibacterial, antibacterial, antiviral, antiviral, and anticancer and anticancer activities. activities.The Streptomyces The Streptomycesspecies species produce produce compounds compounds containing containing the 5,8-quinolinedionethe 5,8-quinolinedione moiety, moiety,such such as streptonigrin as streptonigrin, lavendamycin, lavendamycin, and, andstreptonigron streptonigron, which, which exhibit exhibit a wide a wide spectrum spec- of trumbiological of biological activity activity (Figure (Figure1)[ 1)8, 9[8,9].]. Previous Previous studies studies dealt dealt with with thethe modificationmodification of 5,8- 5,8-quinolinedionequinolinedione moiety moiety at at the the C-2, C-2, C-6, C-6, and and C-7 C-7 positions positions and and they they showed showed that thatsuch such modificationmodification can lead can leadto changes to changes in biological in biological activity activity [10–19]. [10– 19]. O H3CO 6 2 N COOH 7 H2N N O H2N CH3 OH H3CO OCH3 Streptonigrin FigureFigure 1. Chemical 1. Chemical structure structure of 7-amino-5,8-quinolinedione of 7-amino-5,8-quinolinedione antibiotics. antibiotics. StudiesStudies on the on lipophilicity the lipophilicity of 5,8-quinolinedione of 5,8-quinolinedione derivatives derivatives were were carried carried out apply- out apply- ing theing RP-TLC the RP-TLC and andRP-HPLC RP-HPLC methods. methods. It was It wasfound found that thatthere there is a relationship is a relationship between between lipophilicitylipophilicity and andin silico in silico pharmacokinetic pharmacokinetic properties properties of ofsynthetic synthetic 5,8-quinolinedione 5,8-quinolinedione de- deriva- rivativestives [20–23]. [20–23]. As aa continuationcontinuation of of our our previous previous research, research, we we determined determined the the lipophilicity lipo- philicityexperimentally experimentally as well as aswell by as using by using computational computational methods methods for the for betulin the betulin triazole tria- deriva- zole tivesderivatives with attached with attached 1,4-quinone. 1,4-quinone. The physicochemical The physicochemical and pharmacokinetic and pharmacokinetic properties in- propertiesfluence influence the bioavailability the bioavailability and biological and bi activityological of activity compounds of compounds when they arewhen determined they are determinedby computer by programs.computer programs. The correlation The correlation between lipophilicitybetween lipophilicity and in silico and determinedin silico determinedstructural structural parameters parameters have been have analyzed been analyzed in this study. in this study. The Thetested tested compounds compounds contain contain two active two activemoieties, moieties, i.e., 1,4-quinone i.e., 1,4-quinone and betulin. and The betulin. mainThe mechanism main mechanism of activity of for activity 1,4-quinone for 1,4-quinone derivatives derivatives is the interaction is the interaction with NQO1 with pro- NQO1 tein,protein, for which for the which overexpression the overexpression is observed is observed in many in manytypes typesof cancer of cancer cell lines cell lines[8,10,24]. [8,10 ,24]. The betulin derivatives show a wide spectrum of activities including anticancer, antiviral, The betulin derivatives show a wide spectrum of activities including anticancer, antiviral, antibacterial, and anti-inflammatory effects. The use of betulin and its derivatives in antibacterial, and anti-inflammatory effects. The use of betulin and its derivatives in treat- treatment is limited due to low bioavailability and low water solubility. For these reasons, ment is limited due to low bioavailability and low water solubility. For these reasons, the the use of new drug nanoencapsulation procedures and/or nanoparticle-based delivery use of new drug nanoencapsulation procedures and/or nanoparticle-based delivery meth- methods are a key issue. These are issues of nanomedicine interest [25,26]. ods are a key issue. These are issues of nanomedicine interest [25,26]. Over the past decade, many betulin derivatives exhibiting high antiviral activity Over the past decade, many betulin derivatives exhibiting high antiviral activity against human immunodeficiency virus (HIV-1), herpes simplex (HSV-1), enteric cy-
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