key: cord-0826041-rcgjmd3e
authors: Bouzina, Abdeslem; Berredjem, Malika; Bouacida, Sofiane; Bachari, Khaldoun; Marminon, Christelle; Borgne, Marc Le; Bouaziz, Zouhair; Bouone, Yousra Ouafa
title: Synthesis, In silico study (DFT, ADMET) and crystal structures of novel sulfamoyloxy-oxazolidinones: Interaction with SARS-CoV-2
date: 2022-02-05
journal: J Mol Struct
DOI: 10.1016/j.molstruc.2022.132579
sha: 501abe3bfa5ea6218f1dd40bee1f658bffa636c3
doc_id: 826041
cord_uid: rcgjmd3e

A new series of sulfamoyloxyoxazolidinone (SOO) derivatives have been synthesized and characterized by single-crystal X-ray diffraction, NMR, IR, MS and EA. Chemical reactivity and geometrical characteristics of the target compounds were investigated using DFT method. The possible binding mode between SOO and Main protease (Mpro) of SARS-CoV-2 and their reactivity were studied using molecular docking simulation. Single crystal X-ray diffraction showed that SOO crystallizes in a monoclinic system with P 2 1 space group. The binding energy of the SARS-CoV-2/Mpro-SOO complex and the calculated inhibition constant using docking simulation showed that the active SOO molecule has the ability to inhibit SARS-CoV2. We studied the prediction of absorption, distribution, properties of metabolism, excretion and toxicity (ADMET) of the synthesized molecules.

Compounds containing sulfonamide moiety have attracted much attention owing to their superior biological propertie [1] ; because in drug discovery, sulfonamide can be valuable analogue of sulfamate, carboxylic acid, urea, carbamate, thioamide and amide functional groups. It has the advantage in many cases to increase the potency of inhibition and decrease the toxicity [2] . A large number of sulfonamide derivatives have been reported to exibit potent biological activities such as antitumor [3] , anticonvulsant [4] , anti-hypoglycemic [5] and anti-mycobacterial [6] . Additionally, the sulfonamide derivatives demonstrate promising value in the development of enzyme inhibitors including carbonic anhydrase I [7] , HIV-1 protease [8] , AChE inhibitory [9] , metallocarboxypeptidase [10] and b3-adrenergic agonists [11] .

The introduction of oxazolidinones moiety on sulfonamide has been widely studied, some of these studies have shown that sulfamoyloxazolidinones represent a very interesting class of compounds due to their various pharmacological activities [12] .

Sulfamoyloxazolidinones are still the subject of research today in the medical field, such as compound 1 has shown modest efficacy against several strains of bacteria [13] , compounds 2 and 3 show better antibacterial activity [14, 15] . Where the oxazolidinone motif 4 is crucial for enhancing the inhibitory activity of HIV-1 as shown by a study carried out by Amin et al [16] . On the other hand, viral infections have become a serious medical problem around the world, new infections continue to emerge today, and old ones are still rife, as shown by the epidemic of Severe Acute Respiratory Syndrome (SARS) and more recently Coronavirus disease 2019 [17] . A disease which has severely crippled the entire world with the rise of more than 2,000,000 confirmed cases across the global, and a death toll exceeding 170,000. This global pandemic Covid-19 touches every aspect of people's lives including one's health, education,…etc.

In the current spread of novel coronavirus (SARS-CoV-2), antiviral drug discovery is of great importance, as of now, no potential and specific therapeutic agents is approved or available [18] there's naturally an on-going, many researchers and scientists around the world are engaged in developing specific and potential antiviral drug to treat the SARS-CoV-2 infection [19, 20] . The binding affinity and structure of protein-drug complexes play an important role in understanding the molecular mechanism in drug discovery. Moreover, the SARS-CoV-2 main protease is a key target for COVID-19 drug discovery. All in silico studies carried out on inhibitors which block SARS-CoV-2 replication by inhibition of main protease would be effective and specific measures for the development of new therapeutic agents against SARS-CoV-2 [21] [22] [23] [24] [25] [26] [27] .

In continuation to our research [28] in the field of the synthesis of sulfonamide and oxazolidinone derivatives, we report here the synthesis and computational study of ten new sulfamoyloxazolidinone derivatives on the inhibitory potential of these new molecules against the main protease (M pro: 5R80) of SARS-CoV-2. Optimization of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties has been performed.

All chemicals and solvents were purchased from common commercial sources and were used as received without any further purification. All reactions were monitored by TLC on silica Merck 60 F 254 percolated aluminum plates and were developed by spraying with ninhydrin solution (10% in EtOH). Column chromatography was performed with Merck silica gel (230-400 mesh). Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded on a Brücker spectrometer at 400 MHz. Chemical shifts are reported in δ units (ppm) with TMS as reference (δ 0.00). All coupling constants (J) are reported in Hertz. Multiplicity is indicated by one or more of the following: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), sb (singlet board), dd (doublet of doublet), dtd (doublet of triplet of doublet). Carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded on a Brücker at 100 MHz. Chemical shifts are reported in δ units (ppm) relative to 

A solution of oxazolidinone (1 equiv) in anhydrous CH 2 Cl 2 (5 mL) was added to a stirring solution of chlorosulfonylisocyanate (CSI) (1.1 equiv) in (5 mL) of anhydrous CH 2 Cl 2 at 0 °C dropwise over a period of 30 min. The resulting solution was transferred to a mixture of primary or secondary amine (1.0 equiv) in CH 2 Cl 2 (5 mL) in the presence of triethylamine (1.3 equiv) . The solution was stirred at 0 °C for less than 1.5 h. The reaction mixture was washed with HCl 0.1 N and water, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography; or (9/1) mixture of diethyl ether and ethanol was added to the reaction mixture and pure product was crystallized to 6 °C overnight to give sulfamoyloxazolidinonecarboxamides in excellent yields. = 41.02, 53.71, 69.57, 119.84, 120.66, 121.53, 127.02, 129.06, 129.25, 135.88, 136.37, 151.68, 160.21; Ms (m/ 39; H, 4.56; N, 11.19; S, 8.54; Found: C, 54.45; H, 4.63; N, 11.26; S, 8 .60. 46.67, 49.49, 58.56, 64.37, 117.10, 124.14, 130.00, 147.50, 150.55, 155.69 

Cristal (91%); m.p. 139-141 °C. IR (KBr, cm -1 ): 3186. 20, 1754.34, 1723.16, 1362.12, 1167 = 38.11, 46.69, 49.63, 55.04, 67.23, 117.22, 127.75, 128.24, 129.47, 129.51, 134.43, 147.55, 155.15 , 5.44; N, 12.60; S, 7.21; Found: C, 56.81; H, 5.48; N, 12.53; S, 7.27 . 41.11; H, 5.96; N, 13.08; S, 9.98; Found: C, 41.17; H, 5.92; N, 13.02; S, 9. 94. (Table 1 50, 14.69, 28.44, 28.68, 44.56, 47.68, 58.40, 64.21, 126.34, 126.50, 126.88, 128.85, 131.77, 133.37, 147.30, 155.20 52.30; H, 5.76; N, 11.44; S, 8.73; Found: C, 52.37; H, 5.72; N, 11.47; S, 8.71 . (Table 1 10, 46.62, 49.51, 62.90, 117.14, 121.19, 129.43, 147.59, 150.48, 155.27; Ms (m/z): 355.1 [M+1]; Anal. Calc. for C 14 H 18 N 4 O 5 S: C, 47.45; H, 5.12; N, 15.81; S, 9.05; Found: C, 47.51; H, 5.18; N, 15.85; S, 9. 01. Table 1 38.04, 44.72, 47.80, 54.95, 67.18, 126.49, 126.67, 127.07, 127.71, 129.01, 129.20, 129.51, 131.87, 133.51, 134.49, 147.45, 155.12 , 5.10; N, 10.11; S, 7.72; Found: C, 57.88; H, 5.17; N, 10. 13; S, 7.74.

Crystallographic data for the studied compound (S)-4-benzyl-2-oxo-N-((4-phenylpiperazin-1yl)sulfonyl)oxazolidine-3-carboxamide (6C) was collected on a Bruker APEX three-circle diffractometer equipped with an Apex II CCD detector using Mo-Kα (microfocus sealed tube with a graphite monochromator) radiation, at 150(2) K. The crystal was coated with Paratone oil and mounted on loops for data collection.

The crystallographic data and experimental details for structural analysis are summarized in (Table 2 ). The reported structure was solved by direct methods with SIR2002 [29] to locate all the non-H atoms which were refined anisotropically with SHELXL97 [30] using fullmatrix least-squares on F2 procedure from within the WinGX [31] suite of software used to prepare material for publication. All absorption corrections were performed with the SADABS program [32] . All non-hydrogen atoms were located in difference Fourier maps and were refined anisotropically. Hydrogen atoms were placed in idealized geometrical positions and refined with Uiso tied to the parent atom with the riding model. CCDC 2078929, contain the supplementary crystallographic data for compound 6C. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

The X-ray crystal structure of SARS-CoV-2 main protease (PDB ID: 5R80) was obtained from the Protein Data Bank [33] , and was prepared with Protein Preparation Wizard tool implemented in Schrodinger suite, assigning bond orders, adding hydrogens and optimizing H-bonding networks. The three-dimensional structures of the derivatives were constructed using Maestro software, and prepared with Ligprep using Optimized Potentials for Liquid Simulation (OPLS3e) force field with a convergence of heavy atoms of 0.30 Å [34] . The Grid was centered on the centroid of the co-crystallized ligand (Methyl 4-sulfamoylbenzoate).

The final prepared PDB file of the protein and synthesized N-acylsulfamoyloxazolidinones C(1-10) were submitted in order to run docking process. Docking studies were performed by Glide software [35] at Extra Precision [36] . Output files of Methyl 4-sulfamoylbenzoate and docked compounds along with SARS-CoV-2 main protease protein were visualized on Chimera software.

Molecular geometry the gas phase structure optimization of sulfamoyloxy-oxazolidinones derivatives (1-10)C is optimized using DFT at B3LYP method [37, 38] , with the basis set of 6-31 G (d,p) implemented by Gaussian 09 package [39, 40] . Frontier molecular orbitals and global reactivity descriptors the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) [41] , energy gap and chemical reactivity descriptors are calculated at DFT/B3LYP/6-31 G (d, p) method.

Recently, a great deal of research has been devoted to the synthesis and development of new sulfamides [42] , the synthesis of these compounds has an important place in the perspective of interfering with biological processes and discover of new drugs [43] .

In this context we were interested to prepare a new series of sulfamide containing the oxazolidinone moiety.

The synthetic route for the preparation of sulfamoyloxy-oxazolidinones (1-10)C is outlined in scheme 1.

The synthesis was carried out in two steps [44] . First, carbamoylation under anhydrous conditions of commercial chlorosulfonyl isocyanate with the corresponding oxazolidinones The structures of the prepared compounds C(1-10) are confirmed by spectroscopic methods ppm confirm the formation of the sulfamoyloxy-oxazolidinones.

Structural resolution revealed that the asymmetric unit consists of one molecule of (S)-4benzyl-2-oxo-N-((4-phenylpiperazin-1-yl)sulfonyl)oxazolidine-3-carboxamide (6C), which crystallizes in the orthorhombic crystal system with P2 1 2 1 2 1 space group (Table 2) . The ORTEP diagram of this compound is shown in (Figure 2 ). The dihedral angle between the mean planes of the two phenyl rings is 73.37(1)°.

The crystal packing can be described as alternating double layers parallel to (001) Table 3 ). Based on the connectivity of these interactions, we have formation of chains and rings, respectively, with C 1 1 (8), C 2 2 (17), R 4 4 (25) and R 6 6 (41) graph-set motifs, leading a three-dimensional molecular structure .The crystal structure is also supported by intermolecular interactions of C-H... π (Table 3) .

In these layers, the arrangement of each molecule induces a π-π staking intramolecular interactions. The distance centroid-centroid is 4.9476 (7)Å between phenyl rings not in the same asymmetric unit (with translation of 1+x,-1+y,z) [45, 31] . Table 3 . Distances (Å) and angles (°) of hydrogen bond for 6C. 

In order to understand the interactions between protein and ligand, molecular docking study was performed to explore the binding mode of the prepared sulfamoyloxy-oxazolidinones to the SARS-CoV-2 main protease, we have performed our studies using Schrodinger suite (version 11.8) and UCSF Chimera (version 1.13.1) programs, and the Methyl 4sulfamoylbenzoate was taken as reference ligand to investigate the binding mode of the studied synthesized derivatives C(1-10).

Accuracy of docking protocol was examined by re-docking of Methyl 4-sulfamoylbenzoate in the active site of SARS-CoV-2 main protease. Figure 4 shows Compounds 1C, 2C, 3C, 4C, 5Cand 6C gave a better glide score in the range (-7.807 to -6.646 kcal/mol) when compared with the reference compound, with binding score of -6.551 kcal/mol. Met49, Met165, Leu167, Pro168, Cys44,

We have noticed that the stable compounds form a hydrogen bond with the Glu166 residue as the binding of the reference ligand; these compounds also form other important hydrogen bonds with the residues Gln192, Gln189, Gly143, Asn142.

Compound 1C, which has the least docking score (-7.807 kcal/mol) is most favorable, with the most interesting interaction inside the pocket. This compound formed 4 hydrogen bonds, the first one between the doublet of oxygen atom of oxazolidinone and Glu166 residue, the second between the doublet of oxygen atom of sulfamide group and Gly143 residue, the third and the last hydrogen bonds formed between Asn42 residue and the sulfamoyloxy group.

Moreover, it developed electrostatic attraction forces and two aromatic π-π stacking interactions with Hip41 and His 41, which explains its great value of glide score and binding energy. (Figure 5 ). 

The molecular geometry of synthesized sulfamoyloxy-oxazolidinones and the nature of their substituents are often correlated with their stability and their reactivity. In order to specify the relationship between the results of the molecular docking with the structure of the molecules and to evaluate this relationship, DFT study were carried out by Gaussian 09. This study gives some important and necessary information on the structure and reactivity of sulfamoyloxyoxazolidinones.

The Most of the studied compounds show a significant lipophilicity (Log p) in the range of [1.99-2.90 ] except the derivatives 3C, 9C and 7C which presents the lowest value of Log p= -0.12.

The compound 1C has the highest energy gap ΔEgap=6.4371, it is the most stable of all studied compounds ; this value confirms the results obtained by the molecular docking. The gap energy (ΔEgap) of other compounds is in the range of [5.8409-4.5865 ].

The results show that the gap energy ΔEgap is strictly proportional to the total energy (Table   6 ). 

It is necessary to study the pharmacokinetic properties such as absorption, distribution, metabolism, excretion and toxicity (ADMET) of any molecule classified as drug candidate, before proceeding to in vivo testing. The drug-likeness of synthesized compounds were predicted using ADME properties calculated from Swiss ADME. These fundamental parameters determine the resemblance to the drug as well as the activity inside the body of the studied substance [46] .

The pharmacokinetic process of a drug answers whether a drug is able to get to the site of action. The pharmacodynamic process provides the answer of whether or not a drug is able to produce the required pharmacological effect.

The pharmacokinetic properties such as gastrointestinal absorption (GI), water soluble capability (Log S), lipophilicity (LogPo/W), CYP1A2 inhibitor and Blood Brain Barrier (BBB) are very important for any compound to be considered as a drug candidate [47] .

Based on Lipinski's rule on orally active drug has a total number of hydrogen bond donors ≤ 5, hydrogen bond acceptors ≤ 10, logP ≤ 5, and molecular weight < 500da [48] .

Analysis of table 7 have revealed that all the studied compounds C(1-10) showed good gastrointestinal absorption (GI), they have consensus lipophilicity (LogPo/W) value in the range 0.74-2.88 and blood brain barrier (BBB) penetration properties, also their molecular weights are less of 500 da. Table 7 and Figure 9 show the in silico physicochemical properties, druglikeness, and pharmacokinetics of SOO compared with Beclabuvir as antiviral drug. As shown in Figure 9 , all multifunctional sulfamoyloxyoxazolidinone had physicochemical profiles that makes them suitable for oral administration. All compounds had FLEX and POLAR (or TPSA) values that were inside the desired range for enhanced bioavailability (see shaded regions in Figure 9 ). Figure 9 shows physicochemical property of possible oral drug candidates according to five different rules determined by the Lipinski, Ghose, Veber, Egan, and Muegge [49] [50] [51] [52] . 

In the current study, 10 derivatives of novel sulfamoyloxy-oxazolidinones were designed and 

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