Modulation of benzofuran structure as a fluorescent probe to optimize linear and nonlinear optical properties and biological activities

Journal of Molecular Modeling (2020) 26:272 https://doi.org/10.1007/s00894-020-04539-6 ORIGINAL PAPER Modulation of benzofuran structure as a fluorescent probe to optimize linear and nonlinear optical properties and biological activities Przemysław Krawczyk 1 Received: 30 June 2020 / Accepted: 13 September 2020 # The Author(s) 2020 Abstract The study presents the influence of structure modulation by introducing selected donor and acceptor substituents on optical properties of benzofuran used in biological imaging. As the starting form, 2-(5-formylbenzofuran-2-yl)acetamide described experimentally was used. This molecule contains an aldehyde group as reactive site, through which conjugation with protein occurs. Structure modulation was carried out by attaching additional electron-donating and electron-withdrawing substituents to the amino group, namely -NH2, -NHCH3, -NO2, -OH, and -OCH3. Studies have shown that the -NH2, -NHCH3, -OH, and -OCH3 substituents do not induce a significant change in the position of maximum absorption and fluorescence relative to each other. They also do not change the parameters describing the nonlinear response. Only the presence of the -NO2 substituent results in significant solvatochromic shifts. Changing substituents also does not significantly affect the LD50 value, and all tested fluorescent probes should not be considered toxic to humans. Modulation of the benzofuran derivative structure also does not change the active center in which the biocomplex with the protein is formed. In each case, the conjugation takes place via LYS114. In addition, the study was prompted to analyze the linear and nonlinear optical properties of conjugates formed after the reaction with Concanavalin A. Keywords Linear and nonlinear optical properties . Bioimaging . Conjugation with proteins . Biological activities . Toxicology . Solvatochromism . Benzofuran Abbreviations XCon Marker determination after conjugation ConA Concanavalin A THF Tetrahydrofuran MeAc Acetone MeCN Acetonitrile DMF n,n-Dimethylformamide DMSO Dimethylsulfoxide Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00894-020-04539-6) contains supplementary material, which is available to authorized users. * Przemysław Krawczyk 1 Collegium Medicum, Faculty of Pharmacy, Department of Physical Chemistry, Nicolaus Copernicus University, Kurpińskiego 5, 85-950 Bydgoszcz, Poland Introduction Benzofuran, because of its structure made of fused benzene and furan rings, can be classified as a heterocyclic organic compound. It is mainly utilized in the production of coumarone resins and it occurs naturally in the form of a colorless, oily liquid. Light oils obtained during coal tar distillation are the main source of this compound. There are several fields of application of benzofuran including organic synthesis, where it is used as a constituent for more complex systems, as well as material science. It is also widely found in many molecules that are biologically significant. Several different biological activities can be attributed to the derivatives of benzofuran. These include antiinflammatory, antioxidant, antitubercular, antiplasmodial, antitumor, antimicrobial, cytotoxic, enzyme inhibitory, HIV, and hepatitis C virus inhibitory activities [1–4]. The properties of benzofuran that are utilized in material science include on the other hand beneficial electrochemical behavior, thermal stability, high quantum yields, and blue-light emitting [5–7]. Also, their hole- 272 Page 2 of 12 transporting material properties [8, 9] make then useful for application as organic light-emitting diodes (OLED). Another interesting derivative is the benzofurannaphthyridine, which can be characterized with high fluorescence and quantum yield with solvatochromic properties [10]. Fluorobenzofuran on the other hand is used as a high triplet energy host material in the design of green phosphorescent OLEDs [11]. Recently, there are ongoing efforts to utilize benzofuran hydrazones as potential scaffolds in the development of multifunctional drugs [12]. The use of molecular docking studies also suggested antimicrobial and antifungal activity of the probe molecules [13, 14]. Studies have also been carried out on the benzofuran derivative 2MBA in terms of its spectroscopic, quantum chemical, molecular docking, and drug likeness parameter properties. These studies suggested the pharmaceutical potential of the probe molecule [15, 16], while the molecular modeling studies on benzofuran derivatives indicate their potential as anticancer agents [17]. In the case of potential use of benzofuran derivatives as fluorescent probes, it is very important to study solvatochromic behavior. Such analysis should include an assessment of the polarity of the excited state, as they furnish information about the changes in electronic distribution and symmetry of the molecule in the excited state. The knowledge of the excited state dipole moment of the molecule would be helpful in explaining the nature of excited states, in describing the course of its photophysical/photochemical transformations, and in designing the nonlinear optical devices, and it allows one to judge the site of attack by electrophilic and nucleophilic reagents in photochemical reactions, etc. [18–28]. Currently, there is very little information in the literature on the subject of benzofuran derivatives in the context of their linear and nonlinear (NLO) optical properties. Moreover, there is no data on conjugates of these dyes with proteins and the impact of structure modulation on spectral and NLO properties. Due to the frequent use of benzofuran derivatives in the pharmaceutical and medical industry, the paper presents a detailed analysis of the 2-(5-formylbenzofuran-2yl)acetamide derivative. The analysis covers not only the molecule itself but also its derivatives resulting from the attachment of various electronodonor/acceptor substituents (Fig. 1). In addition, a thorough assessment of changes in the properties of the presented fluorescent probes after conjugation with the protein Concanavalin A (ConA) was performed. The choice of this derivative was not accidental. It is dictated by research carried out by Maridevarmath et al. [29], where a similar structure of 2-(5-methylbenzofuran-2-yl)acetohydrazide was analyzed. The differences consist in replacing the methyl group with an aldehyde group, through which the coupling with the protein occurs. J Mol Model (2020) 26:272 Computational details All geometrical parameters of investigated molecules in their ground (SGS) and excited states (SCT) were calculated using the density functional theory approach with the PBE0 functional implemented in the Gussian09 program package [30] with the TIGHT optimization threshold option and the 6311++G(d,p) basis set. In order to verify that all the structures correspond to the minima on the potential energy surface, an analysis of Hessi (...truncated)