Synthesis, crystal structure, DFT studies and biological activity of (Z)-3-(3-bromophenyl)-1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-hydroxyprop-2-en-1-one

Tighadouini et al. Chemistry Central Journal https://doi.org/10.1186/s13065-018-0492-4 (2018) 12:122 Chemistry Central Journal Open Access RESEARCH ARTICLE Synthesis, crystal structure, DFT studies and biological activity of (Z)‑3‑ (3‑bromophenyl)‑1‑(1,5‑dimethyl‑1H‑pyrazol‑3‑ yl)‑3‑hydroxyprop‑2‑en‑1‑one Said Tighadouini1, Redouane Benabbes2, Monique Tillard3*, Driss Eddike4, Khadija Haboubi5, Khalid Karrouchi6* and Smaail Radi1 Abstract Background: Nowadays, is emerging a new generation of highly promising inhibitors bearing the β-ketoenol functionality. The present work relates to the first synthesis, the structure determination, the DFT studies and the use of a new biomolecule designed with a β-ketoenol group bounded to a pyrazolic moiety. Result: A novel β-ketoenol-pyrazole has been synthesized, well characterized and its structure was confirmed by single crystal X-ray diffraction. The electron densities and the HOMO–LUMO gap have been calculated using the DFT method with BLYP, PW91, PWC functionals and 6-31G* basis set. An evaluation of the molecule stability is provided by a NBO analysis and the calculated Fukui and Parr functions have been used to locate the reactive electrophile and nucleophile centers in the molecule. The synthesized compound, screened for its in vitro antifungal behavior against the Fusarium oxysporum f.sp. albedinis FAO fungal strains, shows a moderate activity with an inhibition percentage of 46%. The product was also tested against three bacterial strains (Escherichia coli, Bacillus subtilis and Micrococcus luteus), but no significant effect was observed against these organisms. Conclusions: Density functional calculations are used to evaluate the HOMO–LUMO energy gap, the molecular electrostatic potential and to provide a natural bond orbital analysis. The measured antimicrobial activities encourage us to continue searching for other structures, likely to be good antifungal candidates. Keywords: β-Keto-enol-pyrazole, Single-crystal structure, NBO analysis, Reactivity indices, Fukui and Parr functions, Biological activity Introduction Pyrazoles represent a class of compounds endowed with a great interest in many domains. They have been widely described in the literature as chelating ligands [1–6] and several works have been gathered in reviews [7–10]. According to numerous literature reports, these derivatives are also well-known as important *Correspondence: mtillard@univ‑montp2.fr; . ma 3 ICGM, CNRS, Université de Montpellier, ENSCM, Montpellier, France 6 Laboratoire de Chimie Thérapeutique, Faculté de médecine et de Pharmacie, Université Mohamed V, Rabat, Morocco Full list of author information is available at the end of the article heterocyclic biologically active compounds, acting as antitumor [11], antiviral [12], anti-inflammatory [13] anti-anxiety [14] or antimicrobial [15] agents. On the other hand, β-ketoenols form an important class of compounds, with an interest both in medical and pharmaceutical fields, regarded as drugs against HIV [16–18], cancer [19–22] and influenza [23] but also as antioxidant [24] and anti-inflammatory [25] substances. The β-ketoenol derivatives play also an important role in the development of coordination chemistry, as they are able to easily form stable complexes with most transition metals involving different © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tighadouini et al. Chemistry Central Journal (2018) 12:122 modes of coordination and different functionalities [26, 27]. The pyrazoles associated with β-ketoenol groups lead to compounds with promising properties in both medicinal and coordination chemistry fields. In our recent works, some heterocycles containing the β-ketoenol functionality have been reported, that show significant biological activity [28] as well as interesting coordination properties [29–33]. The intention of this work was to develop of a novel pyrazole-based compound bearing a β-ketoenol functionality. Its crystal structure was solved from X-ray single crystal data and DFT studies were realized. The compound was also evaluated for its in vitro antifungal activity against Fusarium oxysporum f.sp. albedinis FAO fungal strains and against three bacterial strains (Escherichia coli, Bacillus subtilis and Micrococcus luteus). Results and discussion Chemistry The target biomolecule based on β-ketoenol and pyrazole entities was prepared by a one-pot in situ condensation method which is similar to the procedures given in our previous works [28]. A solution of pyrazolic carboxylate was added to a suspension of sodium in toluene, then 1-(3-bromophenyl)ethanone was added at 0 °C (Scheme 1). After 2-days stirring at room temperature, the resulting precipitate has been treated and neutralized. The extracted organic layer was concentrated, dried and purified by silica gel column chromatography (see “Experimental section” part for details). The β-keto-enol form was confirmed by the 1H-NMR analysis of the compound whose spectrum (Additional file 1: Figure S1) shows a strong signal assigned to the =C–H group of the keto-enol form at 6.54 ppm, it represents 85% of the compound. The diketone form is also present in a maximal proportion of 15% and was detected by the weak signal at 4.54 ppm which was attributed to the CH2 group of the diketone form. Traces of the keto form have also been detected in DEPTQ-135, which shows quaternary carbon atoms (C) and CH2 group as Scheme 1 Synthesis of the target compound 1 Page 2 of 11 very small negative signals (Additional file 1: Figures S2 and S3). Good quality crystals of the major β-ketoenol structure were grown from methanolic solution by slow evaporation. The FT-IR spectrum confirms the formation of the ketoenol form with an enolic band at 1531 cm−1 (Additional file 1: Figure S4). Also in good agreement, the mass spectrum shows a molecular peak at 320.97. (Additional file 1: Figure S5). X‑ray crystal structure description Single crystals of (Z)-3-(3-bromophenyl)-1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-hydroxyprop-2-en-1-one (1) were analyzed by X-ray diffraction in order to determine the compound structure. The main crystal data are given with principal refinement parameters in Table 1 and the atom position and displacement parameters are listed in Table 2. The full CIF file deposited at the Cambridge Crystallographic Data Center (CCDC 1817604) is available at http://www. ccdc.cam.ac.uk/conts/retriev (...truncated)