key: cord-1016702-4kdxepj0
authors: Rajamanickam, Ramachandran; Mannangatty, Rani; Sampathkumar, Jayanthi; Senthamaraikannan, Kabilan; Diravidamani, Barathi
title: Synthesis, crystal structure, DFT and molecular docking studies of N-acetyl-2,4-[diaryl-3-azabicyclo[3.3.1]nonan-9-yl]-9-spiro-4′-acetyl-2′-(acetylamino)-4′,9-dihydro-[1′,3′,4′]-thiadiazoles: A potential SARS-nCoV-2 Mpro (COVID-19) inhibitor
date: 2022-03-02
journal: J Mol Struct
DOI: 10.1016/j.molstruc.2022.132747
sha: 6cdb3b9f77ea140716a0bde5d027828de3ee3661
doc_id: 1016702
cord_uid: 4kdxepj0

In this paper, we describe the synthesis and crystal structure analysis of N-acetyl-2,4-[diphenyl-3-azabicyclo[3.3.1]nonan-9-yl]-9-spiro-4′-acetyl-2′-(acetylamino)-4′,9-dihydro-[1′,3′,4′]-thiadiazole (3a) and N-acetyl- 2,4-[bis(p-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-yl]-9-spiro-4′-acetyl-2′-(acetylamino)-4′,9-dihydro-[1′,3′,4′]-thiadiazole (3b). The title compounds 3a and 3b were characterized by 1D NMR and single crystal x-ray diffraction analysis. Non-covalent interactions in a molecule were identified by Hirshfeld surface (d(norm) contacts and 2D fingerprint plot) analysis. In addition, the existence of chalcogen bond (S•••O bond) in the molecular structures (3a and 3b) were described with NCI-RDG and QTAIM analysis. NBO analysis is employed to describe the orbital interactions and electron transfer between sulfur and oxygen atoms. Molecular docking is carried out for compounds 3a and 3b with COVID-19 viral protein SARS-nCoV-2 M(pro) (PDB ID: 6LU7).

Spiro heterocyclic structure is a unique feature of a several natural and synthetic products that possess remarkable biological activities [1, 2] . The potential use of spiro heterocycles in medicinal chemistry has been well documented owing to their prominent pharmacological properties [3] . The thiadiazole moiety is associated with a broad spectrum of biological activities such as antifungal [4] , antioxidant [5] , anticonvulsant, antiviral [4] , plant growth regulatory [6] , CNS depressant [7] , and anticancer [8] activitiy.

Methazolamide is a thiadiazole based drug being used to treat reduction of high pressure inside the eyes, prevents blindness, nerve damage, and vision loss and glaucoma [9] .

Similarly, acetazolamide is an another thiadiazole drug candidate being used as drug for the treatment of epileptic seizure, and periodic paralysis [10] .

1,3,4-thiadiazole core has been reported as an electron-deficient nature, electronaccepting ability and good thermal as well as chemical stability [11] . Thus, thiadiazole derivatives are often used to create liquid crystals due to charge-transporting ability, photoconductivity, photoluminescence and mesomorphism [12] . Therefore, development of new spiro-heterocycles having thiadiazole ring is worthwhile from the perspective of medicinal and material chemistry [13, 14] .

Piperidine is an another heterocyclic compound that found naturally in alkaloids, and its derivatives have good biological and pharmacological properties [15] . On the other hand, the six membered piperidine ring undergoes several conformational changes when introducing electron donating or withdrawing substituents at the nitrogen site. For example, the piperidine ring adopts chair conformation with electron donating substituent (CH 3 , CH 2 Ph) whereas the electron withdrawing group (heteroatom group, COR, NO) on the same site adopts boat conformation [16] . Recently, several piperidine derivatives along with the incorporation of hetero conjugate groups at the nitrogen atom of piperidine ring have been well explored by spectroscopic and X-ray analysis [17] [18] [19] . Earlier reports disclosed that the blocking of secondary nitrogen atom in the piperidine ring by electron donating or withdrawing groups, abrupt changes were observed in the ring conformations. As a result, the molecule displays different conformation such as chair, boat or twist-boat forms.

The novel coronavirus 2019 (nCoV, also called as COVID- 19) , is a new strain and highly contagious viral disease. The coronavirus causes a severe acute respiratory syndrome (SARS-nCoV-2), has showed to be the most deadly global health crisis since the 1918 influenza pandemic [20] . The novel virus (SARS-nCoV-2) has proven to be a worldwide unprecedented disaster that affects billions of lives across the world in many ways. Currently, there are no specific treatment options for SARS-CoV-2. Thus, it has been classified that COVID-19 is a very rare disease with a limited number of treatment options [21] . Molecular docking is the preliminary study in the drug designing, which help us to find the possible binding site between lead molecule and protein structure. For Covid-19, several docking studies have been reported to find potential antiviral drugs and vaccines [22] [23] [24] [25] [26] .

In this paper, we have selected bicyclic ring system that contains both heterocyclic (piperidine) and non-heterocyclic (cyclohexane) rings based on spiro derivatives viz. N-acetyl-2,4-[diaryl-3-azabicyclo[3.3.1]nonan-9-yl]-9-spiro-4-acetyl-2-(acetylamino)-4,9-dihydro-[1,3,4]-thiadiazoles (3a and 3b) to describe the spectral characterization and single crystal structure analysis. Also, the DFT studies have been employed to explore the electronic properties of molecules 3a and 3b. In addition, the molecular docking is carried out to extend the scope of molecular structure with novel coronavirus causing protein.

1 H and 13 C NMR spectra of 3a and 3b were obtained from BRUKER AMX 500

MHz FT-NMR spectrometer using CDCl 3 as the NMR solvent, whereas TMS was used as an internal reference. The NMR chemical shift (δ) and coupling constants values were measured in ppm and coupling constants in Hz, respectively.

The title compounds 3a and 3b were synthesized according to the Scheme 1.

Initially, 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one thiosemicarbazones (2a and 2b) were synthesized according to the literature precedent [27] . The title compounds 3a and 3b

were synthesized by modification of our earlier reports [28] . A mixture of 2,4-diaryl-3azabicyclo[3.3.1]nonan-9-one thiosemicarbazone (2a or 2b, 0.5 g) and 20 mL of distilled acetic anhydride were heated at 60˚C on water bath for 6 h. After completion of the reaction, as confirmed by TLC, the reaction mixture was kept in the freezer at overnight and the separated solid was filtered off, dried and purified by column chromatography.

The pure crystals of 3a and 3b for X-ray diffraction analysis were grown by slow evaporation technique using distilled ethanol. group at the phenyl group).

Colorless rectangular crystals (0.25, 0.20, 0.20 mm for 3a and 0.20, 0.20, 0.25 mm for 3b) were used for the data collections. The single crystal X-ray diffraction data were recorded using a CCD area detector at room temperature (273 K). The data reduction and cell refinement were carried out using SAINT/XPREP (Bruker), and APEX2/SAINT, respectively. The crystal structures (3a and 3b) were solved by direct methods using SHELX-97 [29] . All the non-hydrogen atoms were treated anisotropically by the full-matrix least squares method, whereas hydrogen atom bound to the carbon atoms were constrained isotropically. However, the hydrogen atoms bound to the nitrogen atoms refined freely. Graphical molecular illustrations were done with ORTEP 3

for Windows [30] . The Crystallographic information files (CIFs) were deposited in the Cambridge Crystallographic Data Centre. The CCDC number for 3a and 3b are 796611 and 793237, respectively. CIF data of 3a and 3b can be obtained free of charge from www.ccdc.cam.ac.uk/data_request/cif.

The Crystal Explorer 21.5 program was used to generate Hirshfeld surfaces (HS) mapped over d norm , shape-index and curvedness plots [31] , as previously studied in reference [32] . The structural input files of 3a and 3b were obtained from CIF data. The normalized intermolecular contact distance was denoted as d norm using the following relation.

where d e and d i define the distance from the Hirshfeld surface to nearest outside and inside the nucleus surfaces, respectively, r e vdw / r i vdw define the van der Waals radii of outside and inside the atoms, respectively. The value of intermolecular contacts (d norm )

such as hydrogen bonding, van der Waals radii and steric interaction are distinguished by tricolor code; red-white-blue-colors, respectively. The bright red spots on the Hirshfeld surface show the intermolecular contacts less than their van der Waals radii, whereas the blue region on the HS demonstrates intermolecular contacts longer than their van der Waals radii. However, the white spot on the HS indicates the sum of their van der Waals radii. Further, the π-π interaction between asymmetric units can be detected through the shape index mapped surface as they exhibit adjacent red-blue triangle concave.

All quantum chemical calculations were carried out by using Gaussian 09 software with DFT method at B3LYP/6-311G (d,p) level [33] . Gauss view 5.0.9 was used to prepare and inspect the input and output files. Quantum theory of atoms in a molecule (QTAIM) was done with AIMALL software [34] whereas non-covalent interaction and radiant density gradient (NCI-RDG) were executed with Multiwin and VMD molecular visualization programmes [35] . The docking study was carried out using AutoDockTools 1.5.7 [36] . 

NMR signals were assigned based on the signal position, multiplicity and integral values [38] . as that of our earlier study on N-chloroactyl-2,6-diarylpiperidin-4-ones [17] . Contrary to this, sharp signal appeared due to perpendicular orientation of acetyl group [39] .

Further, a collection of signals were observed in the upfield region from 1.24-2.73 ppm are due to signals of methylene protons of cyclohexane ring, as shown in Fig   S1 -S2. It is seen that, three multiplets appeared at 1.70, 1.66 and 1.30 ppm (for 3a) and

1.72, 1.60 and 1.28 ppm (for 3b). It is worth to mention that due to the anisotropy effect of C-C bond, the equatorial proton in methylene carbon of cyclohexane ring is more deshielded than its axial proton. Based on this, the deshielded multiplets at 1.70 ppm (3a), and 1.72 ppm (3b) is attributed to H-6e/H-8e protons whereas the signal at 1.66 (3a), and 1.60 ppm (3b) should be due to H-6a/H-8a protons. However, the signal 1.30 ppm (3a), 1.28 ppm (3b) with one proton integral value is due to H-7e proton. Similarly, a multiplet at 2.61 with one proton value is due to another H-7 proton. The chemical shift value of cyclohexane methylene proton of 3a and 3b are in good agreement with the earlier report on parent compounds reported by us [27, 40] . In addition, two singlets were resonated at 2.20, 1.90 (3a) and 2.19 and 2.20 (3b) ppm with six proton integral value should be due to acetyl methyl protons, whereas the signal at the deshielded region 9.67 (3a) and 9.73 ppm (3b) with one proton integral value is ascribed to N-H proton in the side chain acetylamino group. 13 C NMR spectra of compounds 3a and 3b are depicted in Fig. S3 

The molecular structures with atom-numbering schemes of 3a and 3b are shown in Fig. 1a and Fig. 1b , respectively. The structure refinements and selected geometrical parameters are enumerated in Table 1 and Table 2 , respectively. The compounds 3a and 3b were crystallized into a monoclinic lattice with P21/c symmetry. Further, all the C-C and C -H bond lengths in the benzene rings were found to be in the normal range and bond angles were found to be approximately 120º. The C-C-C bond angles and C-C-C-C torsion angles of piperidine and cyclohexane rings are greatly deviated from the parent crystal structures [27] . As a result, significant changes are observed in the conformation of saturated cyclic rings.

To describe the conformation of piperidine and cyclohexane rings, the puckering parameters were derived for compound 3b using X-ray data. Based on the data, one of the six membered (piperidine) ring adopts boat conformation with the puckering parameters being q 2 and q 3 are 0.045 Å and 0.5773 Å, respectively. The total puckering amplitude Q T and θ were calculated as 0.5791 Å and 4.46° respectively. However, the cyclohexane ring is preferably adopts normal chair conformation with the puckering parameters of q 2 and q 3 were predicted to be 0.136 Å and 0.559 Å, respectively and Q T and θ were calculated to be 0.575 (2) Å, and 13.73° respectively [41] . Further, the saturated piperidine ring adopts boat conformation as suggested by the torsion angles around the bonds involving the ring atoms N1-C1-C2-C3 and N1-C5-C4-C3 were found as 22.05 and -39.9 • (for 3a) and 41.6 and -24.6 • (for 3b), respectively. These torsion angles suggest that the piperidine ring N1-C1-C2-C3-C4-C5 deviated significantly from the ideal value of 56˚ reported for the chair conformation of cyclohexane [16] . Therefore, the piperidine preferred to adopt boat conformation. On the other hand, the cyclohexane ring adopts chair conformation as they shows torsion angle of C3-C4-C20-C19 and C3-C2-C18-C19, were found to be -61.71 and 52.4 • (for 3a) and 62.17 and -53.7 • (for 3b),

respectively. In both the crystal structures, the phenyl rings C2 and C4 occupy equatorial The nature and strength of intramolecular S⋅⋅⋅O chalcogen bonds play a key role in biological activity and in supramolecular recognition due to presence of sigma hole in the sulfur atom [43, 44] . In both crystal structures 3a and 3b, the chalcogen interaction geometry is created 5 2 motifs, which shows the S-O interaction distances of 2.710 Å with ∠C3-S1-O3 angle of 160.46˚ for 3a, whereas for 3b, the S-O distance and ∠C3-S1-O3

were found to be 2.798 Å and 156.84˚ respectively. Further, it was noted that the, the S-O interaction distance was found to be within the vander Waals radii of sum of the S and O atoms [45] . Therefore, we suggest that there is a charge transfer component to this chalcogen interaction. The bond lengths and bond angles of thiadiazole ring is similar to other previously reported crystal structures [46] .

3D Hirshfeld surface and 2D fingerprint plots of compounds 3a and 3b were obtained from Crystal Explorer 21.5 to describe the contacts of molecular surface, which have been highlighted with conventional mapping of d norm , as shown in Fig. 2 weak contact was also observed by C-H…O, as shown in weak red spot on the Hirshfeld surface (Fig. 3) . In addition, a weak π-π stacking interactions was detected as shown the red-blue triangle concave in shape index (Fig. S5 ).

2D-fingerprint plot analysis was executed to determine the percentage contribution of intermolecular contacts of 3a and 3b with the d i and d e distances scales on the graph axes for the total contacts in the range of 0.6-2.6 Å, as shown in Fig. 4 and Fig.   5 , respectively. For compound 3a (Fig. 4) (3a and 3b) , the existence of highest percentage contribution of H···H interaction by 2D-fingerprint plots analysis is in good agreement with the single crystal X-ray analysis. and 3b respectively, Table 4 ). The accumulation of electron density ρ in the interaction region and the ∇ 2 ρ values at the S···O chalcogen bond for compound 3a and 3b were found to be quite similar to the results from experimental charge density and quantum chemical studies on sulfa-drugs [45] . Further, the crystal structure analysis of compounds 3a and 3b show a short S···O interaction of 2.710 and 2.798 Å with a linear C21-S1-O3

angle of 73.44 and 72.77°, respectively. However, the sum of the Van der Waals radii of sulfur and oxygen atoms are significantly shorter than S···O interaction. Further, the linearity of the chalcogen bond angle is linked to the nature of n→σ* interactions.

In addition, other contacts such as C18-H…O17 and C13-H…O17 was observed with 0.0122 and 0.04 (for 3a) and 0.024 and 0.093 (for 3b) electron density ρ, and positive Laplacian ∇ 2 ρ respectively (Table 4 ).

Non-covalent interactions-reduced density gradient (NCI-RDG) method was used to explore the various attractive and repulsive forces in a molecule such as H-bond, van der Waals and steric forces. Recently, the classical chalcogen bonding interaction in a molecule has been explored widely using NCI-RDG method [47] . The scatter graph of RDG against sin(λ 2 )ρ exploring the type of attractive or repulsive forces that exist in the molecular structure by tri-color scheme (blue-green-red). Blue and green scattering graph at the negative sign indicates attractive forces (hydrogen and chalcogen bonding and van der Waals forces) whereas red spot on the positive sign express the repulsive forces, which mostly occurred in the rings. The following relation can be used for the detection of NCI isosurfaces in RDG using this technique. and 3b. Jindani et al. [48] examined the NCI-RDG analysis for thiazole molecular structure, which showed the electron density (λ 2 ) value which is similar to the electron density of title compounds 3a and 3b.

Density functional theory (DFT) method was employed to inspect the structural geometry (bond lengths and bond angles) and electronic parameters (E HOMO and E LUMO ).

To describe these, molecular structures 3a and 3b were optimized at B3LYP/6-311g(d,p) level, which are depicted in Fig. S7 and S8, respectively. The selected geometrical parameters are presented in Table S1 . It can be seen from the Table S1 that the optimized bond lengths and bond angles by theoretical analysis were found to be well replicated with the experimental XRD results, as indicated by the correlation coefficient analysis, Fig . S9 [49] . However, the minor deviations were observed between theoretical and experimental results due to the differences in the molecular environment.

In the DFT method of 3a and 3b, the C11-S1 bond distance was calculated as 1.90 Å whereas the XRD value found to be 1.86 Å. This should be due to stronger interaction between sulfur and oxygen atoms in the gas phase. However, the non-bonded distance between the sulfur and oxygen in the optimized structures (3a and 3b) were which is used to describe the stability of molecules. For compounds 3a and 3b, E HOMO and E LUMO values were obtained by the DFT method using B3LYP/6-311 g(d,p) level and the 3D molecular orbital energies of the compounds 3a and 3b are depicted in Fig. 7 .

From the Fig. 7 , the band gap energy (ΔE) between HOMO and LUMO orbitals were found to be 5.0 and 4.65 eV, respectively for 3a and 3b. It can be further discussed that 3b shows about 0.5 eV less compared to 3a due to the presence of electron donating methoxy substituent in the phenyl group, which further increase the electron delocalization.

Further using the energy of HOMO-LUMO orbitals, global chemical reactivity descriptor (GCRD) such as electron affinity (EA), ionization potential (IP), Electronegativity (χ), hardness (η), softness (S) potential (μ), and electrophilicity index (ω) were calculated. The calculated GCRD parameters are presented in Table 5 . It is seen that the chemical hardness and softness were calculated to be 0.20 and 0.21 eV for 3a and 3b, respectively. Therefore, the molecule 3a and 3b have good chemical stability and strength. However, the electronegativity (χ), and chemical potential (μ), were estimated as -3.73 / -3.05 eV; and 3.73 / 3.05 eV, respectively for 3a / 3b. From the Table 5 , it can be concluded that the GCRD parameters of molecule 3b is significantly lower due presence of methoxy group at the phenyl substituent.

The molecular electrostatic potential (MEP) of an organic molecule can be defined in terms of total charge distribution of the molecule. 3D MEP surface encompassing different color scheme between blue to red, are depicted in Fig. 8a (for 3a) and Fig. 8b (for 3b) , generated from the optimized structure at B3LYP/6-311 g(d,p) level.

It is seen that red, blue and green are the three major color scheme, which define the electrostatic potential value. Further, the color scheme expands in the order of blue > green > yellow > orange > red. Out of which, the blue regions on the surface signify the positive potential corresponds to the electron deficient site and favor for nucleophilic attack, whereas the red surface region with negative potential, corresponds to electron rich regions and favor for electrophilic reactivity. The green color on the MEP surface indicates zero potential. In addition, the pale blue and yellow colors on the surface map denote the slightly electron deficient and electron rich areas, respectively. For 3a, (Fig. 8a) the red and yellow region are corresponds to the negative electrostatic potential which associated with electron rich regions (high electron density) such as electronegative groups, and targeted by electrophiles whereas the blue region indicates the positive electrostatic potential (low electron density) which found mostly on the alkyl groups and associated with nucleophilic attack. For compounds 3b, (Fig. 8b) , the negative potential is dominated over the carbonyl group whereas the positive potential exists only on the N-H group.

As the presence of sulfur and oxygen atoms are close in the molecular structure (3a and 3b), we sought to evaluate the strength of S···O (chalcogen bonding) interaction.

To do this, NBO analysis was performed to get better understanding of inter and intra molecular charge transfer and electron delocalization between filled Lewis type orbital (bonding) and empty non-Lewis type orbital (anti-bonding) of 3a and 3b using DFT method at B3LYP/6-311g(d,p) level. The 2 nd order perturbation energies of 3a and 3b

were used to predict the strength and type of interaction between donor and acceptor orbitals, and the interacting stabilization energy. Further, the stabilization energy E(2) is used to define the hyper conjugative interactions and charge transfers in a molecule.

Larger stabilization energy provides a stronger interaction between donor and acceptor atoms. Therefore, it is concluded that the stabilization energy E(2) is closely associated with each donor and acceptor NBO orbitals which are denoted as (i) and (j), respectively.

The energy delocalization between each donor NBO (i) and acceptor NBO (j) can be predicted using the given equation:

The electron delocalization and its stabilization energies E(2) of 3a and 3b are presented in Table S2 . Based on the results presented in Table S2 -S3, a number of σ-σ * , π→π * , n→π * , and n→σ * , intramolecular charge transfer processes observed for compounds 3a and 3b. Also, the results revealed that the showed significant orbital interaction between the oxygen lone pair (donor-bonding) and sulfur-carbon antibonding (acceptor) orbital (S−C σ* orbital), in 3a and 3b were calculated as 2.01 kcal/mol (O4 LP → S1-C11 σ* orbital) and 1.99 kcal/mol (O4 LP → S1-C17 σ* orbital, respectively.

Theoretical NLO study was explored for spiro thiadiazole compounds 3a and 3b

by quantum chemical calculation to estimate the NLO efficiency. The relationship between NLO property and molecular structure was studied theoretically with the aid of dipole moment, polarizability and hyperpolarizability, which have been calculated using B3LYP/6-311g(d,p) level and the results are summarized in Table 6 . Based on the data presented in Table 6 , the dipole moment (μ), polarizability and hyperpolarizability values were predicted to be 4.34 Debye, 8.18 x 10 -24 e.s.u and 2.136 x 10 -30 e.s.u. (for 3a); 3.47

Debye, 33 .05 x 10 -24 e.s.u and 9.145 x 10 -29 e.s.u. (for 3b) , respectively. The calculated first order hyperpolarizability value is significantly higher than that of urea, which has been used as the reference value for many organic compounds [26] . Therefore, the high values of first order hyperpolarizability reveal that the synthesized spiro compounds 3a

and 3b have efficient NLO behavior.

It should be mentioned that the NLO of organic material originates from delocalized electron density of the substituents. In this case, both 3a and 3b were found to be polar in nature and have non zero dipole moment components. However, out of 3a and 3b, compound 3b contains electron donating p-methoxy phenyl group which further increase the electron delocalization. Therefore, 3b exhibits greater (βo) values than their unsubstituted phenyl group based spiro thiadiazole 3a.

Molecular docking has proven to be highly efficient method for screening potential drug candidates against specific disease by using computer aided design [51] . Further, these catalytic dyads of M pro are the major protease activity [54] . It was disclosed that inhibition M pro catalytic dyad was found to be potential and attractive target for designing and screening of anti-coronavirus drug [55] . Also, it was reported that no specific therapeutic agents or vaccines yet to be identified to treat the infection caused by COVID-19. However, only few clinically trial antiviral drugs such as antimalarial, and anti HIV have been used as the supportive measures to treat COVID-19 infections [55, 56] . Virtual screening of molecular docking provides an alternative approach to screen the potential drug candidates for the specific illness at relatively short time.

Studies have been reported various therapeutic options against the COVID-19 causing protein (SARS-CoV-2) through molecular docking studies [57, 58] . The docking studies have been applied on compounds 3a and 3b with "6LU7" protein which was taken from protein data bank (PDB ID: 6LU7). To examine the protein-ligand binding affinity, 6LU7

and lead compounds (3a and 3b) were fitted to interact with the active site of amino acid residue by using autodock tools. The obtained binding interactions are shown in Fig. 9a and Fig. 9b of 3a and 3b respectively. The docking results showed that the lead compounds 3a and 3b are formed various binding interactions including H-bond, πcation, and π-sulfur interactions. Also, this Fig. 9 presents the best docked poses of our ligand in 6LU7. It can be seen from Fig. 9a , Compound 3a showed significant binding affinity with His41, Met49, Ser144, Cys145, and His163 residues, whereas lead compound 3b (Fig. 9b) showed interactions with His41, Met49, Pro52, Phe140, Asn142, Cys145, Glu166, and Arg188 residues of 3CL pro . Among these, His41, Ser144, Cys145, and His163 (for 3a) and Phe140, Cys145, and Glu166 (for 3b) displays conventional hydrogen bonding, whereas Met49 forms π-cation, and π-sulfur interactions with compounds 3a and 3b. "Further, it can be seen in Fig. 9 , the carbonyl group of acetyl function in 3a exhibits conventional hydrogen bonding with His41, Ser144, Cys145, and

His163 residues (Compound 3a). Unlike 3a, in compound 3b, sulphur atom in thiadiazole ring and amino group of acetylamino function show hydrogen bond with Phe140, and Glu166 residues. The interacting amino acid residues were compared with earlier [25, 26, 59] , which showed that the residues His41 and Cys145 are the major catalytic active residues in 6LU7. Interestingly, lead compounds 3a and 3b exhibit similar binding affinity with His41 and Cys145 amino acid residues. Also, binding energies of 3a and 3b

were calculated to be -7.90 and -7.85 kcal/mol, (Table S4 ) [60] . As clearly seen from this Table S4 , the existence of methoxy function in the phenyl group was found to be insignificant contribution towards the binding affinity". Also, In conclusion, the above docking results proved that the ligands 3a and 3b could be the potential lead molecule for antiviral drug against SARS-nCoV-2 M pro .

Thiazole based spiro derivatives 3a and 3b were synthesized and characterized by spectroscopic and single crystal X-ray diffraction techniques. Both the NMR and XRD results proved that the bicyclic rings adopt chair and boat conformation of cyclohexane and piperdine rings, respectively. The asymmetric unit of crystal structures 3a and 3b are stabilized mainly due to chalcogen bond, whereas as the crystal packing is stabilized due 

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General definition of ring puckering coordinates

Synthesis, characterization and stereochemistry of N-acyl-r-2,c-4-bis(4-methoxyphenyl)-3-azabicyclo[3.3.1]nonanes

Chalcogen Bonds Involving Selenium in Protein Structures

Chalcogen-Bonding Supramolecular Polymers

Guru Row, S⋯O chalcogen bonding in sulfa drugs: insights from multipole charge density and X-ray wavefunction of acetazolamide

Spectral characterization and crystal structure of 5-spiro-(3-methyl-2,6-diphenyltetrahydropyran-4-yl)-4,5-dihydro

Telb, σ-Hole and Lone-Pair Hole Interactions in Chalcogen-Containing Complexes: A Comparative Study

Exploiting the role of stereoelectronic effects to design the antagonists of the human complement C3a receptor

Structural, spectroscopic, quantum chemical, and molecular docking investigation of (E)-N'-(2,5-dimethoxybenzylidene)picolinohydrazide

The influence of alkoxy side chains on the conformational flexibility of oligo-and polythiophenes

Molecular docking study and antiviral evaluation of 2-thioxo-benzo[g]quinazolin-4(3H)-one derivatives

Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

Structures of Two Coronavirus Main Proteases: Implications for Substrate Binding and Antiviral Drug Design

Design of Wide-Spectrum Inhibitors Targeting Coronavirus Main Proteases

Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Why Are Lopinavir and Ritonavir Effective against the Newly Emerged Coronavirus 2019? Atomistic Insights into the Inhibitory Mechanisms

Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2

Fragment Molecular Orbital Based Interaction Analyses on COVID-19 Main Protease − Inhibitor N3 Complex (PDB ID: 6LU7)

Inhibitory activity of quercetin, its metabolite, and standard antiviral drugs towards enzymes essential for SARS-CoV-2: the role of acid-base equilibria

Non-covalent interactions (NCIs) and reduced density gradient (RDG) Interactions: (a) Compound 3a ; b) Compound 3b

C3 C2 C1

N1-C5-C4-C3 -39.9 -24.6 S1-C3-N2-N3

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.