A E E Huseynzada

C Jelsch

H N N Akhundzada

S Soudani

C Ben Nasr

F Doria

U A A Hasanova

M Freccero

C Ben Nasr

Synthesis, crystal structure and antibacterial properties of 6-methyl-2-oxo-4-(quinolin-2yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

Keywords: Biginelli reaction, Hirshfeld surface analysis, crystal structure, bifurcated hydrogen bond, antibacterial activity

HAL is

Introduction

One-pot multicomponent reactions are a highly powerful synthetic strategy and versatile tool for the construction of various classes of compounds with a wide spectrum of application area. Interest in multicomponent reactions is increasing due to the fact that they provide a synthetic chemist with intrinsic significant advantages over conventional linear-type synthesis mostly including simple operation, simple starting materials, high product complexity and large product diversity [1][START_REF] Honnappa | Biginelli reaction: an overview[END_REF][START_REF] Jie-Ping | Synthesis of dihydropyrimidinones and thiones by multicomponent reactions: strategies beyond the classical Biginelli reaction[END_REF]. Among such type of reactions that found application in the synthesis of heterocycles is a three-component one-pot Biginelli reaction. A combination of aldehyde, urea derivative and methylene active compound leads to the obtaining of dihydropyrimidine -a class of organic compounds which are widely used in medicine due to their broad spectrum of biological activities [START_REF] Woerly | The Biginelli Reaction: Development and Application[END_REF]. The reason of their popularity in medicine is caused by the multicomponent nature of this reaction allowing introducing various pharmacophoric groups in the structure of dihydropyrimidines [START_REF] Kappe | 100 Years of the Biginelli Dihydropyrimidine Synthesis[END_REF][START_REF] Jagir | Past, present and future of the Biginelli reaction: a critical perspective[END_REF][START_REF] Maharramov | Synthesis, investigation of the new derivatives of dihydropyrimidines and determination of their biological activity[END_REF][START_REF] Atwal | 3-Carbamoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl-5-pyrimidinecarboxylic Acid Esters as Orally Effective Antihypertensive Agents[END_REF]. Various investigations using molecular manipulations allow determining that this class of compounds demonstrate such activities as antiviral, antifungal [START_REF] Jagir | Past, present and future of the Biginelli reaction: a critical perspective[END_REF][START_REF] Maharramov | Synthesis, investigation of the new derivatives of dihydropyrimidines and determination of their biological activity[END_REF], anti-leishmanial, antiproliferative [START_REF] Zhu | 2, 4-Diaryl-4, 6, 7, 8-tetrahydroquinazolin-5 (1H)-one derivatives as anti-HBV agents targeting at capsid assembly[END_REF], antitumor [START_REF] Klein | New chemical tools for investigating human mitotic kinesin Eg5[END_REF][START_REF] Kaan | Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol[END_REF][START_REF] Wright | Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation[END_REF][START_REF] Agbaje | Synthesis and in vitro cytotoxicity evaluation of some fluorinated hexahydropyrimidine derivatives[END_REF][START_REF] Kumar | Novel Biginelli dihydropyrimidines with potential anticancer activity: a parallel synthesis and CoMSIA study[END_REF][START_REF] Ibrahim | Design, synthesis, and biological evaluation of novel pyrimidine derivatives as CDK2 inhibitors[END_REF], antibacterial [START_REF] Wang | New magnetic nanocomposites of ZrO2-Al2O3-Fe3O4 as green solid acid catalysts in organic reactions[END_REF][START_REF] October | Reversed Chloroquines Based on the 3, 4-Dihydropyrimidin-2 (1H)-one Scaffold: Synthesis and Evaluation for Antimalarial, β-Haematin Inhibition, and Cytotoxic Activity[END_REF][START_REF] Akhaja | 1, 3-Dihydro-2H-indol-2-ones derivatives: Design, synthesis, in vitro antibacterial, antifungal and antitubercular study[END_REF][START_REF] Homan | Identification and structure-function analysis of subfamily selective g protein-coupled receptor kinase inhibitors[END_REF], anti-inflammatory [START_REF] Mokale | Synthesis and anti-inflammatory activity of some 3-(4, 6-disubtituted-2thioxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl) propanoic acid derivatives[END_REF][START_REF] Bahekar | Synthesis and anti-inflammatory activity of some [4, 6-(4-substituted aryl)-2-thioxo-1, 2, 3, 4-tetrahydro-pyrimidin-5-yl]-acetic acid derivatives[END_REF][START_REF] Marathwada | Synthesis and anti-inflammatory activity of some [2-amino-6-(4-substituted aryl)-4-(4-substituted phenyl)-1, 6-dihydropyrimidine-5-yl]-acetic acid derivatives[END_REF], anti-hypertensive [START_REF] Atwal | Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4aryl-1, 4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines[END_REF][START_REF] Zorkun | Synthesis of 4-aryl-3, 4-dihydropyrimidin-2 (1H)-thione derivatives as potential calcium channel blockers[END_REF][START_REF] Chikhale | Synthesis and pharmacological investigation of 3-(substituted 1phenylethanone)-4-(substituted phenyl)-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylates[END_REF][START_REF] Alam | Antihypertensive activity of newer 1, 4-dihydro-5-pyrimidine carboxamides: Synthesis and pharmacological evaluation[END_REF][START_REF] Sehon | Potent, selective and orally bioavailable dihydropyrimidine inhibitors of Rho kinase (ROCK1) as potential therapeutic agents for cardiovascular diseases[END_REF], anti-HIV [START_REF] Patil | Novel alkaloids from the sponge Batzella sp.: inhibitors of HIV gp120human CD4 binding[END_REF], antiepileptic [START_REF] Lewis | Dihydropyrimidinone positive modulation of δ-subunit-containing γaminobutyric acid type A receptors, including an epilepsy-linked mutant variant[END_REF], antidiabetic, anti-malarial [START_REF] Folkers | Researches on Pyrimidines. CXXXVI. The Mechanism of Formation of Tetrahydropyrimidines by the Biginelli Reaction1[END_REF], mPGES-1 inhibitors [START_REF] Terracciano | Structural insights for the optimization of dihydropyrimidin-2 (1 H)-one based mPGES-1 inhibitors[END_REF], antitubercular [START_REF] Trivedi | Novel dihydropyrimidines as a potential new class of antitubercular agents[END_REF], miscellaneous [START_REF] Singh | Synthesis of 2-sulfanyl-6-methyl-1, 4-dihydropyrimidines as a new class of antifilarial agents[END_REF][START_REF] Barrow | In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective α1A receptor antagonists for the treatment of benign prostatic hyperplasia[END_REF][START_REF] Zhu | 2, 4-Diaryl-4, 6, 7, 8-tetrahydroquinazolin-5 (1H)-one derivatives as anti-HBV agents targeting at capsid assembly[END_REF], potassium [START_REF] Finlay | Discovery of ((S)-5-(Methoxymethyl)-7-(1-methyl-1 H-indol-2-yl)-2-(trifluoromethyl)-4, 7dihydropyrazolo [1, 5-a] pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl) pyrrolidin-1-yl) methanone As a Potent and Selective IKur Inhibitor[END_REF][START_REF] Lloyd | Dihydropyrazolopyrimidines containing benzimidazoles as KV1. 5 potassium channel antagonists[END_REF][START_REF] Lloyd | Pyrrolidine amides of pyrazolodihydropyrimidines as potent and selective KV1. 5 blockers[END_REF] and calcium channels [START_REF] Rovnyak | Dihydropyrimidine calcium channel blockers. 4. Basic 3substituted-4-aryl-1,4-dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents[END_REF] and α1aadrenergic antagonists [START_REF] Patil | Synthesis, optical properties, dyeing study of dihydropyrimidones (DHPMs) skeleton: Green and regioselectivity of novel Biginelli scaffold from lawsone[END_REF]. On this basis, different drugs were synthesized and found their application in medicine, such as batzelladine A and B [START_REF] Patil | Novel alkaloids from the sponge Batzella sp.: inhibitors of HIV gp120human CD4 binding[END_REF], (S)monastrol [START_REF] Klein | New chemical tools for investigating human mitotic kinesin Eg5[END_REF][START_REF] Kaan | Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol[END_REF][START_REF] Wright | Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation[END_REF][START_REF] Agbaje | Synthesis and in vitro cytotoxicity evaluation of some fluorinated hexahydropyrimidine derivatives[END_REF][START_REF] Kumar | Novel Biginelli dihydropyrimidines with potential anticancer activity: a parallel synthesis and CoMSIA study[END_REF][START_REF] Ibrahim | Design, synthesis, and biological evaluation of novel pyrimidine derivatives as CDK2 inhibitors[END_REF], (S)-enastron [START_REF] Klein | New chemical tools for investigating human mitotic kinesin Eg5[END_REF][START_REF] Kaan | Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol[END_REF][START_REF] Wright | Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation[END_REF][START_REF] Agbaje | Synthesis and in vitro cytotoxicity evaluation of some fluorinated hexahydropyrimidine derivatives[END_REF][START_REF] Kumar | Novel Biginelli dihydropyrimidines with potential anticancer activity: a parallel synthesis and CoMSIA study[END_REF][START_REF] Ibrahim | Design, synthesis, and biological evaluation of novel pyrimidine derivatives as CDK2 inhibitors[END_REF], mon-97 [START_REF] Klein | New chemical tools for investigating human mitotic kinesin Eg5[END_REF][START_REF] Kaan | Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol[END_REF][START_REF] Wright | Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation[END_REF][START_REF] Agbaje | Synthesis and in vitro cytotoxicity evaluation of some fluorinated hexahydropyrimidine derivatives[END_REF][START_REF] Kumar | Novel Biginelli dihydropyrimidines with potential anticancer activity: a parallel synthesis and CoMSIA study[END_REF][START_REF] Ibrahim | Design, synthesis, and biological evaluation of novel pyrimidine derivatives as CDK2 inhibitors[END_REF], (R)-fluorastrol [START_REF] Kaan | Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol[END_REF], terazosin [START_REF] Barrow | In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective α1A receptor antagonists for the treatment of benign prostatic hyperplasia[END_REF]. But the superiority of dihydropyrimidines goes beyond this. They are used as a favorable core for developing heterocyclic compounds with novel optical properties [START_REF] Barrow | In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective α1A receptor antagonists for the treatment of benign prostatic hyperplasia[END_REF]. It is also found that dihydropyrimidines have also been exploited as a design element in the development of functional materials such as dyes [START_REF] Patil | Synthesis, optical properties, dyeing study of dihydropyrimidones (DHPMs) skeleton: Green and regioselectivity of novel Biginelli scaffold from lawsone[END_REF], polymers [START_REF] Boukis | High glass transition temperature renewable polymers via Biginelli multicomponent polymerization[END_REF], adhesive [START_REF] Zhao | From drug to adhesive: a new application of poly (dihydropyrimidin-2 (1 H)-one) s via the Biginelli polycondensation[END_REF] etc. Such broad application of dihydropyrimidines has prompted scientists to develop their chemistry by expanding the list of building blocks in the Biginelli reaction. Analysis of modified compounds as well as structureactivity correlations allow deeper understanding of the stereochemical-conformational requirements for activity, which significantly depend on the presence of various interactions, i.e. hydrogen bonds in the structure [START_REF] Rovnyak | Calcium entry blockers and activators: conformational and structural determinants of dihydropyrimidine calcium channel modulators[END_REF][START_REF] Kappe | Conformational analysis of 4-aryldihydropyrimidine calcium channel modulators. A comparison of ab initio, semiempirical and X-ray crystallographic studies[END_REF].

On the other hand, quinoline is mainly used in the production of various speciality chemicals, which provide a wide variety of effects, on which many other industry sectors rely. In addition to this, quinoline has several anti-malarial derivatives, including quinine, chloroquine, amodiaquine and primaquine [START_REF] Höke | Quinoline and isoquinoline[END_REF].

Concerning biological activity of quinoline and dihydropyrimidine core, a new dihydropyrimidine was synthesized by Biginelli reaction in microwave condition in the presence of cerium chloride on the basis of quinoline-2-carbaldehyde. As crystals of this compound were obtained, its structure was investigated by X-ray single crystal diffraction. In addition, the Hirshfeld surface and contacts enrichments analysis was done to quantify the molecular interactions and understand their importance in the crystal packing. Due to the fact that dihydropyrimidines demonstrate a wide spectrum of biological activities, their antibacterial activity was analyzed against Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) and promising results were obtained.

Materials and methods

General Information

All the solvents and reagents were purchased from commercial suppliers and were of analytical grade and used without further purification. The control of the reactions progress and the determination of the synthesized compounds purity were done by thin layer chromatography (TLC) on Merck silica gel plates (60 F254 aluminium sheets) which were visualized under UV light. Melting points were recorded in open capillary tubes on a Buchi B-540 apparatus and were uncorrected. Elemental analysis was performed on the Carlo Erba 1108 analyzer.

Experimental synthesis procedure

Synthesis of 6-methyl-2-oxo-4-(quinolin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate by Biginelli reaction (Scheme 1). 0.5 mmol of quinoline-2-carbaldehyde (1), 0.75 mmol (45 mg) of urea and 0.03mmol (0,0118 mg) of CeCl3•7H2O were added to a microwave vial with a magnetic stirrer and dissolved in 1 ml of ethanol. Subsequently, 0.46 mmol (50 µl) of methyl acetoacetate were added to a vial, which was sealed and irradiated at 100⁰C in a microwave reactor for 2.5 h at a maximum power of 200W (CEM Discover System). Purification of compound (4) was performed by the Biotage Isolera One Flash Chromatography System (cyclohexane-ethylacetate-methanol). After purification and removing of the solvent, a yellow precipitate was formed. Single crystals of compound ( 4

NMR experiments

The NMR experiments were performed on a BRUKER FT NMR spectrometer AVANCE 300 (Bruker, Karlsruhe, Germany) (300 MHz for 1 H and 75 MHz for 13 C) with a BVT 3200 variable temperature unit in 5 mm sample tubes using Bruker Standard software (TopSpin 3.1). Chemical shifts were given in ppm (δ) and were referenced to internal tetramethylsilane (TMS). Multiplicities are declared as follow: s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet). Coupling constants J are given in Hz. The experimental parameters for 1 H are as follows: digital resolution=0. [START_REF] Atwal | Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4aryl-1, 4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines[END_REF] Hz, SWH=7530 Hz, TD=32 K, SI=16 K, 90⁰ pulse-length=10 ms, PL1=3 dB, ns=1, ds=0, d1=1 s and for 13 C as follows: digital resolution=0.27 Hz, SWH=17985 Hz, TD=64 K, SI=32 K, 90⁰ pulse-length=9 ms, PL1=1.5 dB, ns=300, ds=2, d1=3 s. The NMR-grade DMSO-d6 (99.7%, containing 0.3% H2O) was used for the solutions of synthesized compound.

Mass experiments

High-resolution mass spectrometry (HRMS) was performed using electrospray ionization (ESI) in positive-ion or negative-ion detection mode.

X-Ray analysis

X-Ray analyses were performed on Bruker SMART APEX II Single Crystal X-ray Diffractometer equipped with graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å) at 298(2) K, respectively. The crystal structure was solved by direct methods and refined on F 2 by full matrix least-squares using Bruker's SHELXTL-97 [START_REF] Sheldrick | Software reference manual[END_REF]. The details of the crystallographic data for synthesized compound are summarized in Table 1. Crystallographic data for the structural analysis have been deposited to the Cambridge Crystallographic Data Center under number CCDC 1988673. H atoms treatment was Uiso(H) = 1.2 Ueq of the bound atom except for the methyl group for which or Uiso(H) = 1.5 Ueq. H atoms bound to carbon were constrained at their standard geometry. H atoms bound to nitrogen were refined freely. Mercury 3.9 was used to obtain the crystalline structure images.

Biological assay

The antibacterial activity of synthesized dihydropyrimidine against E.coli, P.aeruginosa, S.aureus was assessed by determining minimal inhibitory concentrations (MIC). The MIC, which is the lowest concentration of compound that prevents the growth of bacterial cells after incubation, was determined by the twofold micro-dilution method as described in [START_REF] Martin | A new rapid and simple colorimetric method to detect pyrazinamide resistance in Mycobacterium tuberculosis using nicotinamide[END_REF]. The compounds were prepared according to CLSI guidelines and diluted in U-bottom 96 well microtiter plates which contained Muller Hinton Broth (MHB). The freshly prepared bacterial strains at about 10 5 CFU (colony forming unit) in MHB medium were added to each well of the microplate and incubated at 37 0 C for 24 hours. At the end of the experiment, the concentration of the tested compounds ranged from 256 to 2 μg/mL. The growth of the bacterial cells was determined by resazurin method. The solution of resazurin sodium salt (0.01%) was freshly prepared in sterile distilled water. After incubation, 30 μL of this solution was added in each microplate well and incubated again at the same condition for about 4 h. MIC was represented as the lowest concentration of the compounds which inhibited the color change from blue to pink since pink color indicated the growth of bacteria [START_REF] Martin | A new rapid and simple colorimetric method to detect pyrazinamide resistance in Mycobacterium tuberculosis using nicotinamide[END_REF]. MIC of the studied compound was compared with MICs of pristine antibiotics (cefotaxime and ceftriaxone).

In addition to this, the efficiency of the synthesized dihydropyrimidine against the abovementioned bacteria was also tested by disc-diffusion method as described by Mayrhofer [START_REF] Mayrhofer | Comparison of broth microdilution, Etest, and agar disk diffusion methods for antimicrobial susceptibility testing of Lactobacillus acidophilus group members[END_REF].In details, the surface of the nutrient medium (meat-peptone agar, Potato Dextrose Agar) was stratified with 1 mL of the diurnal suspension of the test culture (10 5 CFU/mL), which was used during 15 min after preparation. Previously prepared discs with certain concentrations were stratified on the surface of the nutrient medium by the sterile tweezers. Dishes were incubated at 37⁰C during 24 h. DMSO (40%V/V) was used as a solvent. Record of the results was carried out, compared with control dishes without compound and with the known drugs cefotaxime and ceftriaxone. The biological assays were carried out in triplicate. Standard deviations data were also calculated.

Results and discussion

Chemical synthesis.

It is known that a lot of protocols were developed for performing Biginelli reaction, leading to the synthesis of dihydropyrimidines with high yields and simple work-up procedure. Using catalyst types such as Cu(OTf)2, InCl3, InBr3, CF3COOH, Yb(OTf)3, YbCl3, HCl, acetic acid, CeCl3 and others [1][START_REF] Honnappa | Biginelli reaction: an overview[END_REF][START_REF] Jie-Ping | Synthesis of dihydropyrimidinones and thiones by multicomponent reactions: strategies beyond the classical Biginelli reaction[END_REF][START_REF] Woerly | The Biginelli Reaction: Development and Application[END_REF][START_REF] Kappe | 100 Years of the Biginelli Dihydropyrimidine Synthesis[END_REF][START_REF] Jagir | Past, present and future of the Biginelli reaction: a critical perspective[END_REF][START_REF] Kappe | Conformational analysis of 4-aryldihydropyrimidine calcium channel modulators. A comparison of ab initio, semiempirical and X-ray crystallographic studies[END_REF], it was not possible to perform a Biginelli reaction on the basis of quinoline-2-carbaldehyde (1), urea (2) and methylacetoacetate (3). Only improving the procedure [START_REF] Bose | Green chemistry approaches to the synthesis of 5alkoxycarbonyl-4-aryl-3, 4-dihydropyrimidin-2 (1 H)-ones by a three-component coupling of one-pot condensation reaction: Comparison of ethanol, water, and solvent-free conditions[END_REF] by performing the reaction in microwave conditions allowed us to obtain a targeted dihydropyrimidine (Scheme 1). The structure of synthesized novel dihydropyrimidine was determined by 1 H, 13 C NMR, mass spectroscopy and elemental analysis. As it can be seen from 1 H NMR spectrum, the signals from methyl and methoxy groups are observed at 2.47 and 3.39 ppm correspondingly, whereas CH group position is at 6.1 ppm. Their positions on 13 C NMR spectra are at 17.97, [START_REF] Nayak | Effect of substitution on molecular conformation and packing features in a series of aryl substituted ethyl-6-methyl-4-phenyl-2thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates[END_REF].09 and 50.77 ppm. The signals from amine groups of dihydropyrimidine core are observed at 7.83 and 9.34 ppm respectively (Supplementary material).

Structure description.

It was also possible to obtain single crystals of the title compound (Fig. 1). Crystallographic data and details of refinement for the synthesized compound are given in Table 1. The synthesized dihydropyrimidine crystallizes in the monoclinic space group P21/c with Z=4 molecules in the unit cell (Table 1). The molecular structure of the 6-methyl-2-oxo-4-(quinolin-2-yl)-1,2,3,4tetrahydropyrimidine-5-carboxylate (DHPM) from single crystal X-ray data is shown in Fig. 1. The asymmetric unit of the title compound contains two C16H15N3O3 moieties (Fig. 1). The two molecules have a very different conformation as the dihedral angles on the bond linking the two rings are N3-C5-C4-N1=71.1° and N6-C21-C20-N4 = 114.4°. The tetrahydropyrimidine ring in both molecules is significantly twisted with twist angles C1-N1-C4-C3 equal to 36.5° and C17-N5-C18-C19 equal to -7.4° with the presence of the C2=C3 and C18=C19 double bonds [START_REF] Nayak | Effect of substitution on molecular conformation and packing features in a series of aryl substituted ethyl-6-methyl-4-phenyl-2thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates[END_REF][START_REF] Kappe | X-Ray Structure, Conformational Analysis, Enantioseparation, and Determination of Absolute Configuration of the Mitotic Kinesin Eg5 Inhibitor Monastrol[END_REF]. The tetrahydropyrimidine ring is in twist-boat conformation; the C4 and N2 atoms form the flagpole atoms in the first molecule and the C20 and N5 atoms in the second molecule (Fig. 1) [START_REF] Nayak | Effect of substitution on molecular conformation and packing features in a series of aryl substituted ethyl-6-methyl-4-phenyl-2thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates[END_REF][START_REF] Kappe | X-Ray Structure, Conformational Analysis, Enantioseparation, and Determination of Absolute Configuration of the Mitotic Kinesin Eg5 Inhibitor Monastrol[END_REF]. The main bond lengths and bond angles are depicted in Table 2 (Supplementary material). The intermolecular hydrogen bonds observed in the crystal structure are listed in Table 3. The dihedral angles between the planes of the quinoline rings and the six membered rings in both molecules of the title compound are 80.84 and 87.35° respectively, underlining non-orthogonal arrangement of these rings (Fig. 2 Molecules of the DHPM are interconnected via N-H…O=C and C-H…O=C hydrogen bonds giving rise to a sheet-like structure, forming polar sheets involving polar functional groups while the quinoline moieties takes the role of hydrophobic spacer [START_REF] Martin | A new rapid and simple colorimetric method to detect pyrazinamide resistance in Mycobacterium tuberculosis using nicotinamide[END_REF][START_REF] Mayrhofer | Comparison of broth microdilution, Etest, and agar disk diffusion methods for antimicrobial susceptibility testing of Lactobacillus acidophilus group members[END_REF]. These polar sheets are extended parallel to the c-axis (Fig. 3, Table 3) [START_REF] Kappe | X-Ray Structure, Conformational Analysis, Enantioseparation, and Determination of Absolute Configuration of the Mitotic Kinesin Eg5 Inhibitor Monastrol[END_REF].

Furthermore, there are two characteristic distances d1 and d2, which are defined between the polar sheets in the like-sheet structure. The d1 distance represents the special separation between the successive polar sheets including the quinoline moieties (hydrophobic moieties) and d2 represents the spatial separation between two consecutive polar sheets. The corresponding distances d1 and d2 are 10.261Å and 4.622 Å, respectively (Fig. 3) [START_REF] Nayak | Effect of substitution on molecular conformation and packing features in a series of aryl substituted ethyl-6-methyl-4-phenyl-2thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates[END_REF].

The crystal packing of the title compound, C16H15N3O3 is consolidated by several intermolecular N-H…O strong hydrogen bond, involving namely the donors H1N, H2N, H4N and H5N and the four potential acceptors O1, O1, O2, O4 and O5 (Fig. 4a, Table 3). The crystal packing is also stabilized by an intermolecular C-H…O=C hydrogen bond connecting the quinoline moieties to the carbonyl oxygen O5 (C9-H9•••O5 v (v=x+1, y, z) and by intramolecular interaction (C16-H16A•••O2) involving the methyl hydrogen of C16 with the carbonyl oxygen O2 to form a S(6) motif (Fig. 4a) [START_REF] Sallum | Synthesis, conformational analysis and molecular docking studies on three novel dihydropyrimidine derivatives[END_REF][START_REF] Dhandapani | Synthesis, single crystal structure, Hirshfeld surface and theoretical investigations on pyrimidine derivative[END_REF]. Some of hydrogen bonds are bifurcated on the acceptors (O2, O1, Fig. 4a). A R 2 2(8) graph-set motif connecting two adjacent molecules is observed within the sheets (Fig. 4a). Previous studies have been performed on the packing motifs of the tetrahydropyrimidine (DHPM) [START_REF] Shang | Ethyl 4-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate[END_REF][START_REF] Desiraju | Supramolecular synthons in crystal engineering a new organic synthesis[END_REF]. No aromatic stacking interactions are observed between neighbouring six membered rings and quinoline moieties.

The molecular packing is stabilized by weak C-H…π intermolecular interactions between the quinoline moieties (Fig. 4b). The distances between the hydrogen atoms and the different centroids of the quinoline rings vary between 3.262 Å and 3.788 Å. Analysis of intermolecular interactions using the Hirshfeld surface represents a major tool to gain insights into understanding the crystal packing. Crystal Explorer software [START_REF] Spackman | Fingerprinting intermolecular interactions in molecular crystals[END_REF] enables to compute distances of atoms external, de, and internal, di, to the surface. The intermolecular distance information on the surface can be condensed into a two-dimensional histogram of de and di, which is a unique fingerprint for molecules in a crystal structure (Fig. 5). The spikes in the fingerprint plot at the shortest distance can be attributed to the O•••H hydrogen bonds. The N5-H5N…O4=C17 contact is the shortest hydrogen bond with d(O…H)==1.96 Å. The N…H contacts appear at much longer distances in the fingerprint plot, as there is only one N…H hydrogen bond (N4-H4N…N4) at dHN= 2.680 Å. The H•••H contacts appear in the middle of the scattered points in the two-dimensional fingerprint map (Fig. 5b) with shortest distance in the packing at ca 2.2 Å. C...C contact arise at a minimal distance of ca. 3.4 Å and involve both the aromatic double ring and the non-flat 6-membered ring.

Interactions d(D-H) d(H•••A) d(D•••A) <D-H•••A Symmetry code N1-H1N•••O1 i 0.
The different chemical contact types and their enrichment in the crystal packing were also analyzed with MoProViewer software [START_REF] Guillot | MoProViewer: a tool to study proteins from a charge density science perspective[END_REF]. The enrichment ratio EXY for a pair of elements (X,Y) is defined as the ratio between the proportion of actual contacts CXY in the crystal and the theoretical proportion RXY of equi-distributed random contacts [START_REF] Jelsch | The enrichment ratio of atomic contacts in crystals, an indicator derived from the Hirshfeld surface analysis[END_REF]. An enrichment ratio larger The nature of the intermolecular contacts and their enrichments in the crystal structure is shown in Table 4 and proportions Cxy of the actual contacts around the two independent molecules are given in Table 5 (Supplementary material). The Hirshfeld surfaces, which highlight the regions of the surface with the strongest electron density, are shown in Fig. [START_REF] Jagir | Past, present and future of the Biginelli reaction: a critical perspective[END_REF]. The proportion of contact types are 95% correlated on the two independent molecules of the asymmetric unit. Therefore, the contacts statistical analysis was performed on the ensemble of two molecules. Two molecules, not in contact with each other in the crystal were selected in order to obtain integral Hirshfeld surfaces.

More than three quarters of the Hirshfeld surface is associated to hydrophobic atoms Hc and C (Table 4). The contacts involving Hc and C represent 65% of the contacts, of which only C…C is significantly enriched at Ecc=1.41 due to several cycle stacking occurring. Table 4. Analysis of contacts on the Hirshfeld surface. Reciprocal contacts X…Y and Y…X are merged. The second line shows the chemical content on the surface. The % of contact types between chemical species is given followed by their enrichment ratio. The major contacts as well as the major enriched ones are highlighted in bold characters. The hydrophobic hydrogen atoms bound to carbon (Hc) were distinguished from the more polar one bound to nitrogen (Hn). Three chemically different oxygen types were distinguished: O=c (carbonyl), Occ (ether oxygen within ester group) and O=coc (carbonyl oxygen within ester group). e/Å The three kinds of oxygen atoms have differentiated behaviors. The Hn…O=c hydrogen bond with the most electronegative O atom represents the most enriched contact at E=7. This is due to a bifurcated hydrogen bond between C1=O1 acceptor and the N2-H2N + N1-H1N donors of molecule #1. A similar double hydrogen bond (O4…H5N, H5N…O4) occurs within a dimer of molecule #2 around an inversion centre.

The Hn…O strong hydrogen bond involving the other carbonyl O=coc atom type is the next most enriched contact (E=3.27), as there is one such interaction: O2…H4N-N4.

The ether Occ oxygen atom which is less electronegative prefers to interact with Hc less polar hydrogen atoms (E=1.76). The nitrogen N3 and N6 atoms which are potential strong acceptors interact also more with the Hc atoms. This is related to the fact that the molecule has only two strong H-bond donors (Hn) compared to four strong acceptors but there is an abundance of Hc weak donors.

Biological assays

The antibacterial activity of the synthesized dihydropyrimidine was investigated against E. coli, P. aeruginosa and S. aureus bacteria. At first, minimum inhibitory concentration (MIC) for the investigated compound and pristine antibiotics (cefotaxime and ceftriaxone) was studied by twofold micro-dilution method. As shown in Table 6, the synthesized dihydropyrimidine demonstrated a similar MIC to that of Cefotaxime for all three bacteria. Compound (4) displayed a high activity at the concentration of 2 µg/µl against E. coli and this result was better than that of ceftriaxone (3µg/µL). MIC in case of P. aeruginosa and S. aureus was a bit weaker (3µg/µL), but it was better than the effect of ceftriaxone in case of P. aeruginosa (5µg/µL). Table 6. Minimum inhibitory concentration (MIC, µg/µL) of the studied compounds.

Bacteria

Compound (4) Cefotaxime Ceftriaxone E.coli 2 2 3 P.aeruginosa 3 3 5

S.aureus 3 3 3

Taking into account the MIC of the compounds, antibacterial activity was also investigated by disc-diffusion method. Results were compared with the antibacterial activity of pristine antibiotics. As it can be seen from Table 7, antibacterial activity of the studied compound against E. coli was higher than that of pristine antibiotics, equal to 28, 20 and 19 mm inhibition disk radius correspondingly. The same tendency was not observed in the case of P. aeruginosa (Table 7), where the inhibition zone of dihydropyrimidine was equal to that of cefotaxime and a bit higher than the ceftriaxone one. In case of gram-positive bacteria S. aureus, dihydropyrimidine and both antibiotics demonstrated the same results equal to 35 mm (Table 7). As DMSO was used as a solvent, the record of the results was also carried out with control dishes, without investigated compound. It was determined that DMSO does not influence on the above mentioned gram-positive and gramnegative bacteria.

Conclusion.

The new derivative 4 of dihydropyrimidine and quinolone was synthesized by Biginelli reaction in microwave conditions in presence of cerium chloride. The structure of it was investigated by X-ray single crystal diffraction. Along with it, Hirshfeld surface analysis was carried out to gain insight into crystal packing and molecular interactions. The crystal structure is made of an alternation of hydrophobic and hydrophilic layers parallel to the (b,c) plane. The shortest hydrogen bond N5-H5N…O4=C17 with d(O…H)=1.96Å involves an electronegative carbonyl group. Considering that the proposed substance 4 can have an ability to act as an antibacterial drug, it was tested for the biological activity against E. coli, P. aeruginosa and S. aureus bacteria. In addition, its activity was also compared with that of pristine antibiotics. The results obtained are promising and suggest that the synthesized compound indeed represents interest as it is potential biologically active with antibacterial activity.

Scheme 1 .

 1 Scheme 1. Synthesis of targeted dihydropyrimidine.

  a & b).

Figure 1 .

 1 Figure 1. View of the two independent molecules of the asymmetric unit in the crystal structure. Thermal ellipsoids are shown 40% probability.

Figure 2 .

 2 Figure 2. Dihedral angle between the planes of quinoline rings and tetrahydropyrimidine moieties (a) in the first molecule (b) in the second molecule of the asymmetric unit.

Figure 3 .

 3 Figure 3. (a) Crystallographic autostereogram view of a sheet-like structure along the c axis in (C16H15N3O3)2. Dotted lines indicate N-H…O and C-H…O hydrogen bonds. d1 represents the spatial separation between the polar sheets intercalating the hydrophobic quinoline moieties while d2 represents the spatial separation between two consecutive polar sheets. (b) crystallographic autostereogram of the crystal packing along the c axis.

Figure 4 .

 4 Figure 4. (a) View of different motifs in the crystalline lattice. The non-participating hydrogen atoms and quinoline moieties have been omitted for clarity. (b) Cristallographic autostereogram illustration of C-H…π intermolecular interactions in the synthesized compound.

Figure 5 .

 5 Figure[START_REF] Kappe | 100 Years of the Biginelli Dihydropyrimidine Synthesis[END_REF]. 2D fingerprint (di,de) plots of the Hirshfeld surface around the two independent molecules. The areas of main intermolecular contact types are shown and the reciprocal contacts can be deduced from the plots as they are symmetrical.

Figure 6 .

 6 Figure 6. View of the Hirshfeld surface around the two independent molecules.(a) The surface is colored according to the inner atom type; blue: nitrogen, red: oxygen, black: carbon, light blue: Hn, grey: Hc. (b) according to the inner electron density value (e/Å 3 ).

Table 1 .

 1 Crystal data and structure parameters of the title compound.

	Crystal data

Table 3 .

 3 Geometric details (distances in Å, angles in º) of hydrogen bonds (D-donor; A-acceptor; H-hydrogen) of the synthesized DHPM.

Table 7 .

 7 Antibacterial activity of studied compound.

	Escherichia coli			compound (4)			cefotaxime ceftriaxone
	Concentration	2	4	8	16	32	32	32
	(µg/µl)
	Inhibition zone	3±0.5 5±0.44 9±0.47 15±0.5 28±0.38 20±0.32	19±0.48
	(mm)
	Pseudomonas			compound (4)			cefotaxime ceftriaxone
	aeruginosa
	Concentration	3	6	12	24	48	48	48
	(µg/µl)
	Inhibition zone	2±0.46 5±0.4 9±0.4 19±0.5 39±0.5	39±0.45	36±0.48
	(mm)
	Staphyloccocus			compound (4)			cefotaxime ceftriaxone
	aureus
	Concentration	3	6	12	24	48	48	48
	(µg/µl)
	Inhibition zone	2±0.4 4±0.38 7±0.43 16±0.5 35±0.52	35±0.5	35±0.46
	(mm)

  -0.005899 0.0792931.346054 11.00000 0.09384 0.07716 = 0.09793 0.01234 0.04535 0.01598 AFIX 43 H24 2 -0.027062 0.084865 1.460003 11.00000 -1.20000 AFIX 0 C25 1 -0.077845 0.065760 1.207444 11.00000 0.07807 0..379681 0.123098 0.389576 11.00000 -1.50000 H32B 2 0.497435 0.110722 0.410880 11.00000 -1.50000 H32C 2 0.458307 0.153184 0.507491 11.00000 -1.50000 AFIX 0 N1 3 0.655583 0.195949 0.647950 11.00000 0.06334 0.04934 = 0.03869 0.00299 0.00793 0.00184 H1N 2 0.649837 0.210423 0.542772 11.00000 -1.20000 N2 3 0.655911 0.194409 0.954900 11.00000 0.07034 0.05066 = 0.03920 -0.00045 0.00911 0.00014 H2N 2 0.644323 0.208865 1.056928 11.00000 -1.20000 N3 3 0.843266 0.176532 0.467194 11.00000 0.06692 0.06029 = 0.05845 0.00322 0.01821 -0.00200 N4 3 0.414073 0.032595 0.896149 11.00000 0.08777 0.11118 = 0.05522 0.03214 0.02546 0.04464 H4N 2 0.412762 0.010430 0.977347 11.00000 -1.20000 N5 3 0.443317 0.050920 0.606934 11.00000 0.08068 0.07974 = 0.04466 0.01138 0.01145 0.00415 H5N 2 0.467559 0.041068 0.504617 11.00000 -1.20000 N6 3 0.231575 0.081387 1.122610 11.00000 0.06590 0.06471 = 0.04927 0.00003 0.00753 0.00354 O1 4 0.617720 0.258549 0.798811 11.00000 0.07558 0.04595 = 0.05204 -0.00026 0.00706 0.00275 O2 4 0.678493 0.051336 0.912614 11.00000 0.11456 0.05664 = 0.08161 0.01490 0.02580 -0.00793 O3 4 0.735083 0.066381 0.645551 11.00000 0.10854 0.04706 = 0.06908 -0.00650 0.02212 -0.00060 O4 4 0.473592 -0.019314 0.712851 11.00000 0.11627 0.10303 = 0.06879 0.02799 0.03558 0.04849 O5 4 0.376087 0.187114 0.721629 11.00000 = 0.07836 0.01064 0.00633 0.00230 O6 4 0.387489 0.165270 1.006634 11.00000 0.09790 0.09515 = 0.06720 -0.00716 0.01197 0.00957 HKLF 4 REM DOR24_CCD run in space group P 1 21/c 1 REM R1 = 0.0580 for 2938 Fo > 4sig(Fo) and 0.1095 for all 5063 data REM 413 parameters refined using 4 restraints END WGHT 0.0595 0.3676

	_cell_measurement_temperature 298(2) Reflections were merged by SHELXL according to the crystal C17 N5 H5N 113(2) . . ? C8 1 1.024976 0.180877 0.573012 11.00000 0.06545 0.06850 = AFIX 0
	_cell_measurement_reflns_used 2034 _cell_measurement_theta_min 2 _cell_measurement_theta_max 20 _exptl_crystal_description 'BLADED' _exptl_crystal_colour 'PALE-ORANGE' class for the calculation of statistics and refinement. _reflns_Friedel_fraction is defined as the number of unique Friedel pairs measured divided by the number that would be possible theoretically, ignoring centric projections and systematic absences. C18 N5 H5N 121(2) . . ? C21 N6 C22 117.6(3) . . ? C14 O3 C15 117.0(3) . . ? C30 O6 C31 117.1(3) . . ? _refine_diff_density_max 0.188 0.10112 -0.01531 0.02678 -0.01273 C9 1 1.127257 0.190271 0.530420 11.00000 0.07104 0.09742 = 0.15540 -0.03515 0.03567 -0.01654 AFIX 43 H9 2 1.182492 0.187187 0.618423 11.00000 -1.20000 AFIX 0 C24 1 09035 =
	_exptl_crystal_density_meas ? ; _refine_diff_density_min -0.171 C10 1 1.144218 0.203638 0.362648 11.00000 0.10327 0.10915 = 0.12296 0.02889 0.03380 0.01781
	_exptl_crystal_density_method ? _refine_diff_density_rms 0.034 0.18539 -0.04034 0.08234 -0.03493 AFIX 43
	_exptl_crystal_density_diffrn 1.372 _computing_data_collection 'SMART (Bruker-Axs Inc)' AFIX 43 H25 2 -0.146797 0.062417 1.229055 11.00000 -1.20000
	_exptl_crystal_F_000 _computing_cell_refinement 1248 'SAINT (Bruker-Axs Inc)' _shelx_res_file H10 2 1.211421 0.209133 0.334976 11.00000 -1.20000 AFIX 0
	_exptl_transmission_factor_min ? _computing_data_reduction 'SAINT (Bruker-Axs Inc)' ; AFIX 0 C26 1 -0.048625 0.057447 1.042199 11.00000 0.06592 0.09294 =
	_exptl_transmission_factor_max ? _computing_structure_solution 'SIR-97 (Altomare et al., 1999)' TITL DOR24_CCD run in space group P 1 21/c 1 C11 1 1.062706 0.209272 0.231146 11.00000 0.14911 0.08839 = 0.10695 0.02066 0.00655 0.00184
	_exptl_crystal_size_max _computing_structure_refinement 'SHELXL-2018/1 (Sheldrick, 2018)' 0.430 shelx.res 0.14535 -0.00408 0.09366 -0.02738 AFIX 43
	_exptl_crystal_size_mid _computing_molecular_graphics 'Mercury (Macrae et al., 2008)' 0.110 created by SHELXL-2018/1 at 09:40:58 on 05-Mar-2018 AFIX 43 H26 2 -0.097605 0.048353 0.950382 11.00000 -1.20000
	_exptl_crystal_size_min _computing_publication_material 'WinGX publication routines (Farrugia, 1999)' 0.030 CELL 0.7107 12.9912 29.9305 7.4380 90.000 95.312 90.000 H11 2 1.076197 0.218923 0.116816 11.00000 -1.20000 AFIX 0
	_exptl_absorpt_coefficient_mu 0.097 ZERR 4.00 0.0031 0.0071 0.0018 0.000 0.005 0.000 AFIX 0 C27 1 0.055638 0.062354 1.006213 11.00000 0.06272 0.06508 =
	_exptl_absorpt_correction_type 'multi-scan' _refine_special_details ? LATT 1 C12 1 0.963044 0.201023 0.265026 11.00000 0.11329 0.08479 = 0.07165 0.01437 0.00878 0.00779
	_exptl_absorpt_correction_T_min 0.886 _refine_ls_structure_factor_coef Fsqd SYMM -X, 1/2 + Y, 1/2 -Z 0.09748 0.01128 0.05451 -0.01152 C28 1 0.091796 0.054190 0.837495 11.00000 0.06903 0.08937 =
	_exptl_absorpt_correction_T_max 0.997 _refine_ls_matrix_type full SFAC C H N O AFIX 43 0.06526 0.00213 -0.00820 -0.00844
	_exptl_absorpt_process_details 'Sadabs (Krause et al., 2015)' _refine_ls_weighting_scheme calc UNIT 128 120 24 24 H12 2 0.909139 0.205166 0.175272 11.00000 -1.20000 AFIX 43
	_exptl_absorpt_special_details ? _refine_ls_weighting_details MERG 2 AFIX 0 H28 2 0.046140 0.044866 0.741110 11.00000 -1.20000
	'w=1/[\s^2^(Fo^2^)+(0.0649P)^2^+0.3048P] where P=(Fo^2^+2Fc^2^)/3' FMAP 2 C13 1 0.943024 0.186117 0.438234 11.00000 0.07260 0.05803 = AFIX 0
	_diffrn_ambient_temperature 298(2) _atom_sites_solution_primary DIRECT PLAN 25 0.08015 -0.00223 0.02630 -0.00634 C29 1 0.192213 0.059818 0.815001 11.00000 0.07035 0.08595 =
	_diffrn_radiation_wavelength 0.7107 _atom_sites_solution_secondary DIFMAP ACTA C14 1 0.698197 0.078433 0.801482 11.00000 0.05896 0.05676 = 0.04832 -0.00161 0.00419 0.00432
	_diffrn_radiation_type _atom_sites_solution_hydrogens mixed MoK\a BOND $H 0.05580 0.00201 0.00527 -0.00570 AFIX 43
	_diffrn_radiation_source _refine_ls_hydrogen_treatment mixed 'fine-focus sealed tube' DFIX 0.9 0.01 N1 H1N C15 1 0.749146 0.019211 0.616213 11.00000 0.13158 0.04678 = H29 2 0.216273 0.054882 0.702754 11.00000 -1.20000
	_diffrn_radiation_monochromator graphite _refine_ls_extinction_method none DFIX 0.9 0.01 N2 H2N 0.10820 -0.01306 0.01111 0.00121 AFIX 0
	_diffrn_measurement_device_type 'Bruker-Axs Smart-Apex CCD' _refine_ls_extinction_coef . DFIX 0.9 0.01 N4 H4N AFIX 137 C30 1 0.385383 0.157100 0.829857 11.00000 0.05878 0.10131 =
	_diffrn_measurement_method _refine_ls_number_reflns 5063 'omega scan' DFIX 0.9 0.01 N5 H5N H15A 2 0.801367 0.007898 0.704270 11.00000 -1.50000 0.05764 0.00683 0.00391 -0.00240
	_diffrn_detector_area_resol_mean 8.333 _refine_ls_number_parameters 413 OMIT 0 2 0 H15B 2 0.770204 0.014520 0.497303 11.00000 -1.50000 C31 1 0.379730 0.211406 1.061242 11.00000 0.11026 0.09843 =
	_diffrn_standards_decay_% _refine_ls_number_restraints 4 0 L.S. 10 H15C 2 0.685226 0.003828 0.627543 11.00000 -1.50000 0.09605 -0.01613 0.01800 0.00647
	_diffrn_reflns_number _refine_ls_R_factor_all TEMP 25.00 AFIX 0 AFIX 137	20297 0.1095
	_diffrn_reflns_av_unetI/netI 0.0491 _refine_ls_R_factor_gt 0.0580 SIZE 0.43 0.11 0.03 C16 1 0.646834 0.128884 1.137810 11.00000 0.07675 0.06952 = H31A 2 0.428653 0.229075 1.003090 11.00000 -1.50000
	_diffrn_reflns_av_R_equivalents 0.0528 _refine_ls_wR_factor_ref 0.1553 WGHT 0.064900 0.304800 0.04560 0.01056 0.01108 -0.00310 H31B 2 0.394295 0.213616 1.189841 11.00000 -1.50000
	_diffrn_reflns_limit_h_min _refine_ls_wR_factor_gt FVAR 0.10851 AFIX 137 H31C 2 0.311088 0.222168 1.027061 11.00000 -1.50000 -15 0.1289
	_diffrn_reflns_limit_h_max _refine_ls_goodness_of_fit_ref 1.017 15 C1 1 0.642275 0.218654 0.797081 11.00000 0.05105 0.05136 = H16A 2 0.636311 0.097245 1.125410 11.00000 -1.50000 AFIX 0
	_diffrn_reflns_limit_k_min _refine_ls_restrained_S_all 1.016 -34 0.04286 0.00154 0.00515 -0.00540 H16B 2 0.586767 0.142347 1.181115 11.00000 -1.50000 C32 1 0.441596 0.123100 0.470750 11.00000 0.07796 0.08666 =
	_diffrn_reflns_limit_k_max _refine_ls_shift/su_max C2 1 0.664616 0.148337 0.959529 11.00000 0.04813 0.05355 = 35 0.006 H16C 2 0.705936 0.134490 1.222099 11.00000 -1.50000 0.05859 0.01084 0.00927 -0.01521
	_diffrn_reflns_limit_l_min _refine_ls_shift/su_mean 0.04431 0.00597 0.00077 -0.00354 -8 0.000 AFIX 0 AFIX 137
	_diffrn_reflns_limit_l_max C3 1 0.688539 0.126913 0.810821 11.00000 0.05206 0.04814 = 8 C17 1 0.444961 0.019050 0.739765 11.00000 0.07133 0.09536 = H32A 2 0
	_diffrn_reflns_theta_min loop_ 0.04461 0.00410 0.00528 -0.00267 1.574 0.05250 0.01847 0.01420 0.01874
	_diffrn_reflns_theta_max _atom_site_label C4 1 0.710857 0.153609 0.647151 11.00000 0.05935 0.04462 = 25.016 C18 1 0.425098 0.095637 0.632559 11.00000 0.05431 0.08178 =
	_diffrn_reflns_theta_full _atom_site_type_symbol 0.04155 0.00072 0.00548 -0.00149 25.016 0.04684 0.00881 0.00022 -0.00888
	_diffrn_measured_fraction_theta_max 0.995 _atom_site_fract_x AFIX 13 C19 1 0.396194 0.109367 0.791442 11.00000 0.05087 0.08097 =
	_diffrn_measured_fraction_theta_full 0.995 _atom_site_fract_y H4 2 0.683006 0.136920 0.540160 11.00000 -1.20000 0.04989 0.00596 0.00149 0.00178
	_diffrn_reflns_Laue_measured_fraction_max 0.995 _atom_site_fract_z AFIX 0 C20 1 0.374499 0.076718 0.937809 11.00000 0.06072 0.08933 =
	_diffrn_reflns_Laue_measured_fraction_full 0.995 _atom_site_U_iso_or_equiv C5 1 0.824537 0.162392 0.628154 11.00000 0.05728 0.04709 = 0.04412 0.00834 0.00378 0.01000
	_diffrn_reflns_point_group_measured_fraction_max 0.995 _atom_site_adp_type 0.04833 -0.00004 0.00895 -0.00139 AFIX 13
	_diffrn_reflns_point_group_measured_fraction_full 0.995 _atom_site_occupancy C6 1 0.901949 0.157026 0.771011 11.00000 0.06407 0.07103 = H20 2 0.410811 0.086934 1.051762 11.00000 -1.20000
	_reflns_number_total _atom_site_site_symmetry_order 5063 0.05905 0.00323 0.00319 -0.00400 AFIX 0
	_reflns_number_gt _atom_site_calc_flag AFIX 43 C21 1 0.260865 0.073242 0.962413 11.00000 0.06118 0.05865 = 2938
	_reflns_threshold_expression 'I > 2\s(I)' _atom_site_refinement_flags_posn H6 2 0.885404 0.147288 0.883530 11.00000 -1.20000 0.04408 0.00500 0.00425 0.00856
	_reflns_Friedel_coverage _atom_site_refinement_flags_adp 0.000 AFIX 0 C22 1 0.128342 0.076286 1.145793 11.00000 0.06388 0.04986 =
	_reflns_Friedel_fraction_max . _atom_site_refinement_flags_occupancy C7 1 1.001166 0.166261 0.742354 11.00000 0.05958 0.09056 = 0.05953 0.00611 0.01159 0.00848
	_reflns_Friedel_fraction_full . _atom_site_disorder_assembly 0.08626 -0.00930 -0.00254 -0.00363 C23 1 0.095925 0.084548 1.317109 11.00000 0.08605 0.07770 =
	_atom_site_disorder_group AFIX 43 0.06817 -0.00363 0.02681 0.00808
	_reflns_special_details C1 C 0.6423(2) 0.21865(9) 0.7971(3) 0.0484(7) Uani 1 1 d . . . . . H7 2 1.053423 0.162859 0.835578 11.00000 -1.20000 AFIX 43
	; C2 C 0.6646(2) 0.14834(9) 0.9595(3) 0.0489(7) Uani 1 1 d . . . . . AFIX 0 H23 2 0.143542 0.093597 1.411123 11.00000 -1.20000

Funding

This work was supported by the Scientific Fund of SOCAR under grant № 26LR (2019-2020).

Conflict of Interest

The authors declare no conflict of interest.

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