Synthesis, X-ray structure, DFT investigation and in silico molecular docking of 1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6- trione

doi:10.21203/rs.3.rs-1764228/v1

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Synthesis, X-ray structure, DFT investigation and in silico molecular docking of 1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6- trione

https://doi.org/10.21203/rs.3.rs-1764228/v1

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published 29 Mar, 2023

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1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6-trione (TCy-TAZTO) was obtained with high chemoselectivity and excellent yield, through an efficient and simple cyclotrimerization of isocyanatocyclohexane performed at room temperature and under mild reaction condition. The newly synthesized TCy-TAZTO was characterized with FT-IR, 1H and 13C NMR spectra. Single crystal X-ray diffraction was used to investigate its molecular structure. The Hirshfeld surface, curvedness, shape index and 2D-fingerprint plots were used to evaluate various intermolecular interactions within the crystal structure. DFT calculations, intrinsic reaction coordinate (IRC), Wiberg bond index and FOMs computational studies were performed to get more insights into the stability and the reaction mechanism. Furthermore, the molecular docking of the TCy-TAZTO was studied against different proteins to investigate the efficacy against selected drug targets of platelet aggregation, blood coagulation, antithrombotic and anti HIV-1disease.

5-tricyclohexyl-1

5-triazinane-2

6-trione

X-ray diffraction

Hirshfeld surface analysis

DFT calculations

Wiberg bond indices

Molecular Docking

Isocyanates are an important class of compounds that have gained significant attention from the synthetic community [¹,²,³]. Owing to their amphoteric character, the relative reactivity of the two N=C and C=O double bonds and its high heteroatom content, the isocyanates functional group has been extensively studied [⁴,⁵]. This kind of functional group can undergo a large number of chemical transformations and acts as building blocks for a wide variety of cyclic and heterocyclic compounds [⁶] and used as synthon for pharmaceuticals and agrochemicals [⁷a-c]. Among these transformations, cyclic dimers and trimers are the most important and well-known reactions. The most widely used reaction is the trimerization reaction, which results in the formation a thermodynamically highly stable trifunctional isocyanurate ring structure [⁸]. A variety of cyclotrimerization routes have been described. Most frequently, isocyanates can be trimerized by phosphines [⁹,¹⁰,¹¹], N-heterocyclic carbenes [¹²,¹³], inorganic salts [¹⁴], phosphides [¹⁵,¹⁶], organotin [¹⁷], organolead [¹⁸], organomercury [¹⁹] or aluminum-based [²⁰] reagents and some transition metal complexes [²¹,²²,²³]. However, these synthetic pathways suffer often from several drawbacks such as high pressure, high catalyst loadings, high temperatures, extreme conditions or strong bases [²⁴,²⁵]. Hence, the need for simple and ecofriendly alternative methods is required.

From the above and in continuation of our research work on the synthesis and development of functionalized derivatives that may be found with interesting biological and complexing properties [²⁶, ²⁷a-b], we report herein a simple and economic procedure for the synthesis of 1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6-trione (TCy-TAZTO).

The synthesized compound was characterized by various spectroscopic tools including IR and NMR (¹H and ¹³C). Single crystal X-ray diffraction was used to investigate the molecular structure of the studied compound. A detailed analysis of various intermolecular interactions by Hirshfeld surfaces computational method was performed. The HOMO-LUMO energy gap, Wiberg Bond Index and other related molecular properties were predicted via computational calculations with DFT method.

Historically, computational investigations indicated that the of 3,5-triazinane-2,4,6-trione derivatives (isocyanurate) was an anti-estrogenic activity [²⁸], cytosolic phospholipase A2a inhibitors [²⁹] and antiproliferative [³⁰]. The trimethyl isocyanurate docked showed, which has a role in the macrophage activation for the destruction of Mycobacterium tuberculosis [³¹]. In order to understand the interaction energy between Ligand-Receptor and the behavior of small molecules in the binding site of target proteins, molecular docking studies were studied and investigated were investigated for their anti HIV-1 Reverse Transcriptase (RT), antiplatelet and anticoagulant effects using different pharmacological and computational assays.

2.1 Chemistry

2.1.1 Instruments

¹H and ¹³C spectra were recorded at 300 and 75 MHz respectively on a Bruker AC-300 with TMS as internal reference for ¹H and ¹³C in CDCl₃. The infrared spectra were recorded in the 400–4000 cm⁻¹ range with a Nicolet IR200 FT-IR spectrometer using a CHCl₃ solution at room. The number of scans was 32 and the resolution 4 cm⁻¹.

2.1.2 X-ray diffraction

The X-ray diffraction pattern of compound C₂₁H₃₃N₃O₃ was collected at 100 K, on a Rigaku Oxford Diffraction Supernova Dual Source (Cu at zero) diffractometer equipped with an Atlas CCD detector using w scans and CuKa (l = 1.54184 Å) radiation. It was interpreted and integrated with the program CrysAlisPro (Rigaku Oxford Diffraction) [³²]. Using Olex2 [24], the structure was solved by direct methods using the ShelXS [³³] structure solution program and refined by full-matrix least-squares on F2 using the ShelXL[³⁴] program package. Non-hydrogen atoms were anisotropically refined and the hydrogen atoms in the riding mode and isotropic temperature factors fixed at 1.2 times U(eq) of the parent atoms (1.5 times for methyl groups). The drawings were made with Diamond [³⁵] and Mercury [³⁶]. Crystal data and experimental parameters inferred from the intensity data collection are summarized in Tab s1.

2.1.3 Hirshfeld surface calculations

The visualization of crystal contacts through the Hirshfeld surface was done by the Crystal Explorer software 3.1 [³⁷]. The Hirshfeld surfaces was mapped with d_norm, shape-index and curvedness properties [³⁸,³⁹,⁴⁰] in order to analyze packing features. 2D-fingerprint plots enable us to decode and quantify the intermolecular interaction types present in the crystal structure.

2.2 Computational details

2.2.1 DFT calculations

All calculations were performed using Gaussian 16A suite of program [⁴¹]. Electronic structure and optimized geometrical parameters were calculated by density functional theory (DFT) with B3LYP/6-311+G(d,p) basis set [⁴²]. The frontier molecular orbital surfaces were visualized by GaussView 6.1 software package [⁴³]. Intrinsic reaction coordinate (IRC) calculations were followed to check the energy profiles connecting each transition state (TS) through a vibration analysis to the expected reactants and products. The optimized structure of transition states (TS) along with their imaginary frequencies and the Wiberg bond indexes. The molecular Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) energies were used and the band energy gap (ΔE) was calculated through the expression E_HOMO-E_LUMO.

The positions of the atoms were those determined by X-ray diffraction and are examined the use of the Wiberg bond index (WBI) analysis as an efficient method for assigning trigger bonds. WBIs were determined as the sum of the squares of the off-diagonal elements of the density matrix.

2.2.2 Molecular docking analysis

The screened TCy-TAZTO was prepared for molecular docking with the target proteins of analgesic, antiplatelet, anticoagulant and anti HIV-1 effects. Our target proteins were obtained from the Protein Data Bank (PDB) (https://www.rcsb.org/) (PDB ID: 1KTS, 1RFN, 2B4X, 3CEN, 3N8X, 3VW7, 4CRC, 4CRD, 7C7N, 3V4I and 3MEC). Docking calculations of compounds were made EZACDD [⁴⁴] Smina [⁴⁵] package program and view of results were made Discovery studio software 2021 client program. The water molecules and ligands were removed first using Pymol [⁴⁶] and then hydrogens were added to both receptor and ligand individually [⁴⁷]. Automatic cavity detection was performed using fpocket3 [⁴⁸].The bonding interaction pattern and minimum binding affinity values (kcal/mol) were used to evaluate the resultant docked complexes.

3. Experimental

3.1. Chemical preparation of 1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6-trione (TCy-TAZTO)

To a mixture of cyclohexyl isocyanate (3equiv), triethylamine (1.5equiv) and hydrochloric acid (2N) with stirring at room temperature (8 h). The progress of reaction was monitored by checking TLC at regular intervals. After completion of the reaction, the product extracted with CHCl₃. The organic phase was dried over Na₂SO₄ and concentrated under vacuum. After workup, column chromatography was performed using ether/ petroleum ether (2:1) as eluent. The component obtained recrystallized in ethanol to give a novel crystal (TCy-TAZTO) in 92 % yield.

1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6-trione (TCy-TAZTO)

Colorless crystals; Yield (92 %); mp 86 °C; IR (Neat): ν_C-N 1186 cm⁻¹; ν_C=S 1684 cm⁻¹. ¹H NMR (CDCl₃, 400.13 MHz): δ = 1.18-1.34 (m, 6H, 3 CH₂), 1.47-1.64 (m, 12H, 6 CH₂), 1.66-1.82 (m, 12H, 12 CH₂), 5.07-5.14 (m, 3 H, 3 CH). ¹³C NMR (CDCl₃, 100.61 MHz): δ = 22.6 (s, 3 CH₂), 29.5 (s, 6 CH₂), 30.7 (s, 6 CH₂), 56.6 (s, 3 CH), 159.9 (s, 3 C=O).

3.1. Synthesis of 1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6-trione

A new simple, efficient and green synthetic route was designed for the synthesis of 1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6-trione (TCy-TAZTO) as shown in Scheme 1. TCy-TAZTO was easily prepared from the trimerization reaction of cyclohexyl isocyanate in the presence of trimethylamine and the hydrochloric acid. The reaction proceeds smoothly with stirring at room temperature and led to 1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6-trione in 92 % isolated yield (Scheme 1). The structure of compound C₂₁H₃₃N₃O₃ was confirmed on the basis of its FT-IR, ¹H NMR and ¹³C NMR.

It is important to mention here that our synthetic route works well in the absence of expensive catalyst. Indeed, by changing the reaction solvent, temperature, and the amount of cyclohexyl isocyanate as starting material, TCy-TAZTO could be obtained with high yield under very mild conditions, which make this reaction suitable to be carried out on a large scale.

The ¹H NMR spectrum of TCy-TAZTO showed a multiplet at 5 ppm, ascribable to the CH group linked to the nitrogen group. It also exhibited the presence of various CH₂ groups between 1.18-1.82 ppm. ¹³C NMR spectrum displayed resonances in agreement with the structure of compound TCy-TAZTO. Of particular interest is the CH-N carbon, which appears as a singlet at 56.6 ppm indicating the trimerization of the isocyanates. The C=O appears also as a singlet at 156.6 ppm, indicating the amide cyclic group formation. The CH₂ of the three-cyclohexyl rings were less shifted and appears between 26.6 and 30.7 ppm. (fig. in supplementary section)

The IR bands of the TCy-TAZTO were assigned by comparison with the modes and frequencies observed in similar derivatives. The experimental IR spectrum of compound 2 (Fig. S1, Supplementary Information) revealed the disappearance of strong absorption band of 1630 cm⁻¹ due to C=N (isocyanate) stretching and the appearance strong absorption bands at around 1684 cm⁻¹ being characteristic of the formation of the C=O group [⁴⁹], clearly shows that the isocyanate was transformed to its corresponding amide. We also noticed the presence of absorption bands of medium intensities between 2857 and 2935 cm⁻¹ attributed to the stretching vibrations of CH, CH₂[⁵⁰]. The bands of medium intensities between 1452 and 1526 cm⁻¹ were assigned to the stretching modes of the phenyl C-N bonds [⁵¹]. In the frequency region between 723 and 1186 cm⁻¹, bands of medium intensities are present, which could be assigned to the skeletal C-C vibrations of the cycloalkane rings. The rest of absorptions between 507 and 894 cm⁻¹ were attributed to out-of-plane bending modes of C-H bonds [⁵²].

3.2. Single crystal X-ray diffraction analysis

Crystal data and experimental parameters used for the intensity data collection for compound C₂₁H₃₃N₃O₃ summarized in Tab s1.

The TCy-TAZTO crystallizes in the Monoclinic system with centrosymmetric P2₁/c space group (Tab s1). A perspective view of the asymmetric unit of the structure of tittle compound with 50% probability thermal ellipsoids was depicted in Fig. 1.

The single crystal of 2 exhibits a regular spatial configuration with usual distances and angles (Tab s2 and Tab s3) The mean values of C-C bonds are 1.388 and 1.391 Å respectively for the three cyclohexyl rings, which are similar to those of cyclohexyl derivatives [⁵³, ⁵⁴]. These three cyclohexyl groups on the isocyanurate ring are not co-planar.

The cyclohexyl rings are in the characteristic chair conformation and its geometrical characteristics were reported in Tab s2 indicating that the C-C distances as well as the C-C-C angles are in accordance with those observed in similar compounds [⁵⁵a-d]. The conformation of these six membered ring can be described in terms of Cremer and Pople puckering coordinates [⁵⁶], i.e. evaluating the parameters Q (total puckering amplitude), q2, q3, θ and φ. Their calculated values for the C13–C14–C15–C16–C17–C18 ring were: Q = 0.5974 Å, q2 = 0.0518 Å, q3 = 0.5952 Å, θ = 4.98 ° and φ = 56.85 °, indicating that the cyclohexyl rings have been slightly distorted from the standard chair conformation by the isocyanuarate ring.

The molecular packing of the title compound shows that the molecules was interconnected via C-H…O-C intermolecular hydrogen bonds to form dimers of C₂₁H₃₃N₃O₃ units extending parallel to the crystallographic b-axis (Fig. 2). The intermolecular hydrogen bonding between the carbonyl groups forming a dimer arrangement (Fig. 2) with O1—H1 distance of 2.319 Å. Hydrogen bonding interactions of the compound 2 was summed up in Tab s4. As illustrated in Tab s4, the molecular packing of molecular units in the crystal is highly stabilized through intermolecular interactions. Indeed, there were twelve pairs of different inter-molecular hydrogen bond interactions, which were C4—H4⋯O2, C5—H5B⋯O1, C8—H8B⋯O1, C9—H9⋯O2, C10—H10A⋯O3, C14—H14B⋯O3, C15—H15⋯O1, C16—H16B⋯O3, C20—H20A⋯O3, C6—H6A⋯O2, C7—H7A⋯O2, C12—H12B⋯O1, C18—H18A⋯O3 and C20—H20B⋯O1.

It is obvious that the packing of TCy-TAZTO was also stabilized by several H...H and H...C, interactions with interatomic distances between 2.3 and 2.7 Å (Fig. 3).

3.5. Hirshfeld surface analysis of TCy-TAZTO

Hirshfeld surface analysis is a very powerful tool for the understanding of different kinds of intermolecular interactions. This analysis serves as a convenient tool for gaining additional insight into the intermolecular interaction of molecular crystals. The size and shape of Hirshfeld surface allows the qualitative and quantitative investigation and visualization of intermolecular close contacts in molecular crystals [⁵⁷].

Graphical plots of the 3D-HS mapped with d_norm used a red–white–blue color [38, 42] scheme, where black highlights shorter contacts, white represented the contact around Van Der Waals separation and blue is for longer contact [⁵⁸]. (Fig.6a) The shape index and curvedness for the tittle compound were examined and showed in figure 6b-c. The deep red circle represented by concave regions on the shape index (Fig. 6b) indicates hydrogen-bonding contacts. The blue triangles represented by convex regions on the shape index surfaces were characteristic of π-π interactions [⁵⁹]. The existence of π-π interactions was also evident from the relatively large and green flat regions delimited by blue circles, on the corresponding curvedness surfaces (Fig. 6c) [⁶⁰].

The 2D fingerprint plots have been used to quantify the relative contribution of the intermolecular contacts to crystal stability of compound 2, showing the crucial importance of weak interactions in building a supramolecular self-assembly of title compound. The relative contributions of the main intermolecular contacts in compound 2 were reciprocal H⋯H, O⋯H/H⋯O, C⋯H/H⋯C, N⋯H/H⋯N and C⋯O/O⋯C with the values of 81.1 %, 13.1 % 3.2 %, 1.8 % and 0.6 % respectively. (Fig. 5)

3.5.1 Transition state calculations

The plausible mechanistic pathways for the studied reaction were showed in scheme 2. Most probably the reaction is initiated by a nucleophilic addition of one isocyanate that can cyclize intramolecularly to form the four-membered 1,3-dicyclohexyl-2,4-uretidinedione (Pathway 1). The second path suggest that three isocyanate react all together to provide directly the TCy-TAZTO as the thermodynamic product. Another possibility for the formation of the title compound involve two-step dimerization-trimerization reaction (Pathway 3).

In order to explore the possible reaction paths, theoretical calculations were performed and the structures of the transition states were determinate at the B3LYP/6-311+G(d,p) level. The corresponding reaction paths were obtained by plotting the energy profiles as a function of the intrinsic coordinate of the reaction (IRC) (Scheme 2).

The transition state (TS₁) leading to a four-membered ring was found the most stable one with activation energy of 27.7 kcal.mol^-1, which could confirm that the four-membered ring is the kinetic product. However, the TS₃ of the TCy-TAZTO obtained as a thermodynamic product through a dimerization followed by the ring-opening and trimerization (six membered ring formation) was also found to be more stable than the direct trimerization (TS₂) with activation energy of 35.5 and 38.4 kcal.mol^-1 respectively. Further, experimentally the four-membered ring was not obtained (ΔG = 34.2 kcal.mol^-1), this may be due to the excess of the isocyanate reagent leading to the formation of the six-ring.

These calculations were in good agreement with the experimental observations by promoting a trimerization reaction instead a dimerisation one, giving rise the desired TCy-TAZTO in a highly regioselective fashion. (Figure 7).

3.5.2 Analysis of Wiberg Bond Indices

Wiberg bond indices (WBIs) analysis, which are also known as quantitative indicators were conducted to predict the activity of the various sites within isocyanates moieties. As depicted in figure 8, the double bonds of 4-7 and 2-3 in isocyantes breaks (disappearance of π links) and the appearance of σ links in transition structures is observed, showing the beginning of the formation of the six-membered ring. This could be due to due to the electron-withdrawing effect of the carbonyl groups in their side chains. Their calculated bonds length were found to be 1.402 Å and 1.401Å respectively. Simultaneously, a π links in transition structures of 2-4 and 3-5 was formed with corresponding values 1.407Å° and 1.408Å respectively.

Subsequently, the 5-10 (1.396Å) bond loses its double character leading to a new single bond 7-10 (1.411Å) forming at the end the desired TCy-TAZTO.

Molecular electrostatic potential

Electrostatic potential surfaces mapped with electron density is now in the list of well-established methods that were able to reveal the reactivity of organic functional groups through their electronic properties [⁶¹]. Visually this can be plotted with electron density surfaces using rainbow colors in the increasing order of their wavelength. Such maps are able clearly to illustrate electronic variations in a molecule and consequently may give electrophilic and nucleophilic areas. In the figure 9, the negative charges colored in red in the electronic map correspond to electrophilic sites and the oxygen and carbon atoms occupy the most negative. The positive region, colored in blue over the electronic map corresponds to nucleophilic sites and the carbonyl and hydroxyl groups occupy the most positive [42].

3.5.2 Frontier molecular orbital calculations

Frontier molecular orbitals (FMOs) are the key factors in defining quantum chemical interactions [⁶²,⁶³]. They are commonly used to provide additional information about the energy gap which is a good indicator of the chemical reactivity, kinetic stability, optical polarizability and chemical hardness-softness of chemical species [⁶⁴]. The highest occupied molecular orbital (HOMO) energies, the lowest unoccupied molecular orbital (LUMO) energies, and their related quantities and orbital distributions of the compound 2 were computed starting from the crystal data of the compound 2 and using the DFT/B3LYP method and 6-311G+(d,p) basis set. The obtained values of HOMO and LUMO levels for the studied compound and the isocyanates starting materials, their distributions and consequently their energy gap are given in Figure 10.

It could be noted that the lowest unoccupied molecular orbital (LUMO) in this compound is mainly localized on two cyclohexyl groups with participation of amides, with calculated energy E_LUMO = −0.493 eV. While the highest occupied molecular orbital (HOMO) is concentrated on the isocyanurate ring, with calculated energy E_HOMO = −7.537 eV. The HOMO-LUMO energy gap was calculated as 7.044 eV (Fig. 10). This high value of energy gap indicate that the TCy-TAZTO is an insulator.

3.5.3. Global reactivity

Some electronic properties were calculated, as well as the graphical representations of HOMO and LUMO. Electrostatic potential and molecular orbital simulations of the reactants (PES) calculated using B3LYP /6-311+G(d,p).

In particular, the electronic chemical potentials μ, chemical hardnesses η and softness S of the reactants studied here were evaluated in terms of the one-electron energies of the frontier molecular orbitals using the following equations [42].

μ = (E_HOMO + E_LUMO)/2 (1)

η = E_LUMO−E_HOMO(2)

S =1/ η (3)

The values of μ and η were then used to calculate ω according to the formula:

ω = μ²/2η (4)

The tab s6 summarized the global electronic properties of the TCy-TAZTO.

The medium energy gap between the HOMO and LUMO orbitals of TCy-TAZTO, calculated as 7.044 eV, characterizes a high chemical hardness and a good kinetic stability of the studied molecule [⁶⁵a-d].

3.6. Molecular docking studies

3.6.1. Molecular docking results for antithrombin agent:

The molecular docking was widely computer simulation procedure to predict the interaction between ligand selected (TCy-TAZTO) and receptor according to conformations and binding free energies, which were expressed as ligand-receptor complex binding forces in (kcal/mol) [⁶⁶]. Protein-Ligand docking were performed using the ezCADD Smina program against selected targets of platelet aggregation and blood coagulation. Eleven of them being involved in regulation of platelet aggregation were cyclooxygenase-1 (COX-1), glycoprotein- VI (GP-VI), purino receptor P2Y12 and protein activated receptor-1 (PAR-with PDB-IDs: 3N8X and 3VW7 respectively. The target proteins mediating blood coagulation process were antithrombin, antithrombin III (ATIII), factor-X (F-X) and factor-IX (F-IX) having PDB-IDs: 1KTS, 2B4X and 1RFN respectively. The blood clotting activated factor Xa having PDB-ID: 3CEN and FXIa from 4CRC and 4CRD.

The results of the docking exploration showed that 1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6-trione (TCy-TAZTO) gain binding affinities ranging from -7.29 to -7.9 kcal/mol. 2D-interactions between ligand selected showed some hydrogen bond interactions in green color with GLY216, TYR99, GLN334, GLN192 and ASN230. TRP215, PRO125, PRO368, PRO397, LEU66, LEU119, LEU162, LEU369, PHE127, PHE174, PHE329, ILE76, LYS70, VAL126, VAL 232, VAL210, VAL400, TYR133, ARG130, ALA123 and HIS57 were observed due to Pi-alkyl and alkyl interactions. An electrostatic bond (pi-sigma) was also found with TRP600, TYR99 and ILE181. (Fig.12a- g and 13a-g)

Similarly, Energy scores of the molecular docking of TCy-TAZTO was docked with E. coli DNA (7C7N) and with human COX-1 (3N8X). These results revealed that ligand selected improved the highest binding affinity values were found to be -6.87, -8.735kcal/mol. Most of the receptors studied with ligand selected out here could bind near the crucial catalytic binding site: ASN34, ARG49 and PRO79 found to form a hydrogen bond and conventional hydrogen bond. An electrostatic bond (Pi cation and Pi anion) was also found with ARG76 and GLU50. TCy-TAZTO was most likely to make hydrophobic (Alkyl and Pi alkyl) contacts with CYS36, PRO156, ALA53 and ILE78. (Fig.12h-i and 13h-i)

3.6.3. Molecular docking results for HIV-1 reverse transcriptase (RT) agent:

The cytotoxic prediction and molecular docking studies was also performed against HIV-1 reverse transcriptase (RT) (PDB IDs: 3V4I and 3MEC). TCy-TAZTO showed some similar binding pockets with residues ILE94, TYR405, LYS366, ARG35r through hydrogen bonds. The TAZTO was surrounded by other active site residues like GLY359, LYS385 and ASN418 through carbon hydrogen bonds. ALA508 and PRO157 were observed due to alkyl interactions and TRP88 was showed due to pi-sigma interactions. (Fig.12j-k and 13j-j).

According in the literature [⁶⁷, ⁶⁸], it could be concluded that a 1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6-trione can be used to design effective antiviral agents against HIV-1.

The graphical depiction of binding affinity values of selected ligand with different proteins summarized in the figure 11 and the different interactions of TCy-TAZTO with breast proteins, using the molecular docking study were revealed and illustrated as 3D and 2D in Fig. 12a-k and 13a-k.

In summary, a new 1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6-trione (TCy-TAZTO) was obtained with high chemoselectivity and excellent yield, through a simple synthetic route under mild reaction condition. The structure of (TCy-TAZTO) was characterized by FT-IR, NMR (¹H, & ¹³C) and single crystal X-ray diffraction. All intermolecular interactions included in the molecular packing of molecular units in the crystal were determined quantitatively using Hirshfeld surface analysis, curvedness, shape index and 2D-fingerprint plots. DFT-transition state along with Wiberg bond index and FOMs computational studies were performed to get more insights about the stability, the reaction mechanism and the HOMO-LUMO energies of the formed compound.

A molecular docking was successfully employed to suggest that the ligand selected showed antiplatelet and anticoagulant activities. Further, the molecular interactions of test TCy-TAZTO were investigated by molecular docking studies against selected targets of blood aggregation and coagulation pathways. Test compounds possessed high affinity for COX-1, GPIIb/IIIa, GP-VI, PG-I2 and F-X receptors. Molecular docking was also performed to suggest the best HIV-1 resistance against HIV-1 reverse transcriptase (RT) may be responsible for anti-tyrosinase property.

Funding

No funding to declare

Conflict of interest

The authors declare no competing interests.

Data availability

Crystallographic data for the structures of compounds have been deposited at the CCDC as supplementary data, deposition no. CCDC No. 1992904 and copie of the data can be obtained, free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033; or [email protected]).

Code availability

ChemDraw Professional 15.1, Gaussian 16, GaussView 6.1, Discovery Studio (2021), Pymol 2.5.2, Crystal Explorer software 3.1,

Author’s contributions

Rania Omrani: Carried out the experiments, Performed the synthesis of novel component, Hirshfeld analysis and Molecular Docking Ligand-Receptor, Writing-original draft preparation

Nejib Jebli: Performed the calculations and X-ray analysis, Writing draft preparation

Youssef Arfaoui: DFT study, Reviewed the manuscript

Yves Chevalier: X-ray data collection

Azaîez Ben Akacha: Supervisor, reviewed the manuscript

All authors discussed and reviewed the manuscript.

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Scheme 1-2 are available in Supplementary Files section.

No competing interests reported.

Supplementarymaterials.docx
scheme1.png
Scheme 1. Synthesis of (TCy-TAZTO)
scheme2.png
Scheme 2. Cyclization of isocyanate through either dimerization or trimerization reactions.

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Synthesis, X-ray structure, DFT investigation and in silico molecular docking of 1,3,5-tricyclohexyl-1,3,5-triazinane-2,4,6- trione

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