key: cord-0865835-3sshkrb9
authors: Jenepha Mary, S.J.; Pradhan, Sayantan; James, C.
title: Molecular structure, NBO analysis of the hydrogen-bonded interactions, spectroscopic (FT–IR, FT–Raman), drug likeness and molecular docking of the novel anti COVID-2 molecule (2E)-N-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide (Dimer) - quantum chemical approach
date: 2021-04-15
journal: Spectrochim Acta A Mol Biomol Spectrosc
DOI: 10.1016/j.saa.2020.119388
sha: 7425654cbd617215c5646f7a79ddda1e9738d309
doc_id: 865835
cord_uid: 3sshkrb9

Prospective antiviral molecule (2E)-N-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide has been probed using Fourier transform infrared (FTIR), FT-Raman and quantum chemical computations. The geometry equilibrium and natural bond orbital analysis have been carried out with density functional theory employing Becke, 3-parameter, Lee-Yang-Parr method with the 6-311G++(d,p) basis set. The vibrational assignments pertaining to different modes of vibrations have been augmented by normal coordinate analysis, force constant and potential energy distributions. Drug likeness and oral activity have been carried out based on Lipinski's rule of five. The inhibiting potency of 2(2E)-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide has been investigated by docking simulation against SARS-CoV-2 protein. The optimized geometry shows a planar structure between the chromone and the side chain. Differences in the geometries due to the substitution of the electronegative atom and intermolecular contacts due to the chromone and hydrazinecarbothioamide were analyzed. NBO analysis confirms the presence of two strong stable hydrogen bonded N—H⋯O intermolecular interactions and two weak hydrogen bonded C—H⋯O interactions. The red shift in N—H stretching frequency exposed from IR substantiates the formation of N—H⋯O intermolecular hydrogen bond and the blue shift in C—H stretching frequency substantiates the formation of C—H⋯O intermolecular hydrogen bond. Drug likeness, absorption, distribution, metabolism, excretion and toxicity property gives an idea about the pharmacokinetic properties of the title molecule. The binding energy of the nonbonding interaction with Histidine 41 and Cysteine 145, present a clear view that 2(2E)-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide can irreversibly interact with SARS-CoV-2 protease.

Recently, the emergence of new viruses and the re-emergence of existing viruses have become a great threat to the global population due to the outbreak of infections such as severe acute respiratory syndrome-associated corona virus, which gained the attention of current researchers in the development of new compounds possessing antiviral activity. In search of promising compounds, the title molecule (2E)-N-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazine carbothioamide (MCMH) has been selected. In the present study, the prime focus is on the investigation of the molecular structure, charge transfer interactions, vibrational spectra, drug likeness and molecular docking of MCMH, with the anticipation that the results of the present investigation may be decisive in the prognosis of its mechanism of biological activity.

Chromones, compounds widely distributed in nature, especially in the plant kingdom play a prominent role in the field of medicine owing to its multifarious pharmacological activity against influenza virus [1] , hepatitis B virus [2] , human rhino virus(HRV) [1] and neuro degenarive diseases [3] . Chromones have been reported to show anti-bacterial, anti-fungal [4, 5] , anti-cancer [6] , antioxidant [7] , anti-HIV [8] and immune-stimulatory [9] activity. Also, 4-oxo-4H-chromen has been used to treat cystic fibrosis by activating the transmembrane conductance regulator [10] . The title compound, which has the chromone moiety, shows antimutagenic property [11] and the ability to inhibit electron transport through nicotinamide adenine dinucleotide (NAD) + hydrogen (H) [12, 13] . The NNS tridentate ligand system of thiosemicarbazone accounts for the anticancer activity molecule and has the capability to act against adenovirus, herpes virus rhinovirus and RNA tumor virus [14, 15] . In the title compound, the presence of the substituent in the 3-position of the chromone acts as hMAO-B inhibitors, which plays an essential role in the expression of toxicity of the Parkinsonism-producing neurotoxin [16] . Also, the attachment of the thiosemicarbazone to the heterocyclic ring has the ability to inhibit ribonucleotide reductase, in mammalian cells, which acts a key enzyme in the synthesis of DNA precursors [17] . The presence of the methyl group in the title molecule has the capability to lower plasma cholesterol levels [18] . The presence of hydrazine unit in thiosemicarbazide of MCMH has the capability to inhibit cholinesterase to treating Alzheimer's and Parkinson's disease [19, 20] .

Structural and spectral investigation of 2-((2-aminopyridin-3yl)methylene)-N-ethylhydrazinecarbothioamide responsible for the antitumour activity [21] , vibrational spectroscopic studies on ethylpyridine-4-carbothioamide and the NMR chemical shift has been reported [22] . FT-IR and FT-Raman studies pertaining to different modes of vibrations have been carried out on 9-methoxy-2 H-furo [3,2-g] chromen-2-one [23] . The hydrogen bonding profile in chromone-2-carboxylic acid and chromone-3-carboxylic acid have been carried out, by vibrational spectroscopy and theoretical approaches [24] . The red shift in stretching frequency of the C@O band due to hyper conjugative interactions responsible for the bioactivity of the chromone derivative has been reported [23] . The hydrophobic, hydrophilic, steric and electronic interactions in 3-(N,N-diethyldithiocarbamate)-2-(4-methoxyphenyl)-chro man-4-and its biological receptors have been reported [25] . The bonding of the aniviral molecule valacyclovir with the target protein through hydrogen bonded interaction has been reported [26] . Literature screening reveals the crystal structure of (2E)-Nmethyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbo thioamide [26] has been reported and no other studies has been reported so far on MCMH. MCMH has been probed using Density functional theory, vibrational spectroscopic techniques and docking simulation to elucidate the structure-activity relationship. Quantum chemical computations aided by density functional theory and vibrational spectroscopic methods have been used as an efficient method to determine the normal modes of vibration and the type of bonding in molecules. A detailed study of the intermolecular interactions has been done by NBO analysis. Drug likeness and the toxicity of the molecule have been done using ADMET (Adsorption, Distribution, Metabolism, Excretion and Toxicity) analysis. The antiviral potency of the title molecule has been probed by molecular docking simulations.

Synthesis of (2E)-N-methyl-2-[(4-oxo-4H-chromen-3-yl)methy lidene]-hydrazinecarbothioamide MCMH has been prepared by dissolving 1.05 g of N-methylhy drazinecarbothioamide in 20 ml of hot ethanol. To this 1.74 g of 4-oxo-4H-Chromene-3-carbaldehydein 10 ml of ethanol was added and stirred continuously for a period of 10 min. The reaction mixture was refluxed for 2 h and the completion of the reaction is monitored by thin layered chromatography (TLC). The resultant mixture was cooled, filtered, washed with ethanol and dried in vacuum. The compound has been recrystallized from hot ethanol yielding colourless block crystals [27] .

FT-IR spectrum of MCMH has been recorded using Perkin Elmer spectrum-I spectrometer in the spectral range of 4000-400 cm À1 with a resolution of 1 cm À1 and the FT-Raman spectrum of MCMH has been recorded using Bruker RFS27 Raman spectrometer in the spectral range of 4000-50 cm À1 . The neodymium doped yettrium aluminium (Nd:YAG) garnet acts as the laser source with an excitation of 1064 nm.

The equilibrium geometry and the geometric optimization has been carried out using Gaussian 09 W [28] at the B3LYP/6-311G+ +(d,p) level of theory. In order to understand the interactions that take place between the filled and vacant orbitals, natural bonding orbitals (NBO) calculations [29] have been carried out using NBO3.1 program as implemented in the Gaussian 09 package. The normal coordinate analysis (NCA) and the normal modes of vibrations have been performed using MOLVIB 7.0 program [30, 31] . The input required for the MOLVIB program has been employed as suggested by Pulay [32] . Molecular docking simulation has been carried out and the ligand-protein interactions have been studied using Auto Dock 4.2.6 software package [33] . The binding sites of the ligand-protein have been visualized using PYMOL graphic software [34] .

The optimized molecular structural parameters of the monomer and dimer form of MCMH have been performed using Gaussian 09 W program package and the optimized molecular structure has been visualized using Gauss View 5.0.9. The optimized monomer and dimer structure of the MCMH is depicted in Figs. 1(a) and 1(b).

The optimized bond length of MCMH involved in intermolecular hydrogen bonding is given in Table 1 . The optimized bond angle and dihedral angle of MCMH have been shown in supplementary  Table S2 and S3.

The crystallographic information of MCMH [C12H11N3O2S] has been taken from Cambridge Crystallographic Data Center (CCDC 1027156). The molecular structure of MCMH has been visualised as consisting of a 4H-chromen-4-one ring and a methyl hydrazinecarbothioamide moiety substituted in the 3-position of the chromone ring. The calculated geometric parameters are in good agreement with the experimental data with small discrepancies. From the optimized geometry the global minimum energy of MCMH monomer and dimer are found to be À1176 Hartree and À2353.64 Hartree with the dipole moment of 0 Debye and 7.7226 Debye. The substitution of the carbonyl at the C5 position leads to an elongation in the C5AC6 bond angle by 0.004 Å and C5AC6AC11 bond angle by 1°. A considerable increase in the C22AS23 bond length by 0.007 Å is noticed. Also, there is an increase in the N20AC22AS23 bond angle by 1°. This is due to the presence of the electronegative nitrogen atom on either side of the C22 carbon atom. The attachment of the oxygen atom in the chromone ring causes a distortion from the regular hexagon structure. This is well reflected by the decrease in the C6AC11AC12 endoangle by 5°[ Table S1 ]. MCMH on dimerization leads to the formation of two NAHÁ Á ÁO hydrogen bonded intermolecular interactions and two CAHÁ Á ÁO hydrogen bonded inter- molecular interactions, adding stability to the system. The formation of four hydrogen bonded interactions results in substantial changes which leads to an increase in the C11AO15 bond length by 0.009 Å, decrease in C46AH47 and C17AH18 bond lengths by 0.005 Å and an increase in N20AH21 and N49AH50 bond lengths by 0.007 Å. Owing to the formation of intermolecular hydrogen bonded interactions the NAHÁ Á ÁO and CAHÁ Á ÁO bond angles have been twisted by 22°and 39°with respect to the chromone plane. The elongation and contraction in bond length is due to the orbital interactions and charge distributions that take place within the molecule [35] .

NBO analysis is proved to be an efficient method to elucidate the most possible natural Lewis structure picture of orbitals. MCMH has been subjected to NBO analysis to elucidate the intra and intermolecular interactions between the filled and vacant orbital, which is a measure of hyperconjugation or intramolecular delocalization. Intermolecular interactions arises due to the hyperconjugation and electron density transfer (EDT) from filed lone pair electrons of the n(Y) of the ''Lewis base" Y into the unfilled antibond r*(XAY) of the ''Lewis acid" in XAHÁ Á ÁY have been recorded [36] .The calculated stabilization energy E(2) associated with the interaction between the filled orbital i and the vacant orbital j have been tabulated in (Table 2 ).

In MCMH, significant interactions have been noticed due to the interaction of lone pair electrons with the antibonding orbitals n2 (O14) ? p*(C1AC6), n2(O14) ? p*(C12AC13), n1(O15) ? r*(C6 AC11), n2(O15) ? r*(C11AC12), n1(N20) ? p*(C17AN19) and n2(S23) ? r*(C22AN24) with the stabilization energy of 27.48 kcal/mol, 34.880 kcal/mol, 17.11 kcal/mol,19.230,31.03 kca l/mol and 11.16 kcal/mol respectively. The second order perturbation energies associated with the hyperconjugative interactions in NBO basis confirms the presence of intermolecular interactions. Bonding orbital analysis of MCMH monomer and dimer manifests the formation of four hydrogen bonded intermolecular interactions, of which two are CAHÁ Á ÁO, observed between the oxygen lone pair electrons n1(O15) ? r*(C46AH47) and n1(O44) ? r*(C17AH18) with the stabilization energy of 1.860 kcal/mol interactions and 1.8 kcal/mol. As a consequence, the length of the CAH bond involved in intermolecular interaction is shortened by 0.005 Ǻ. The CAHÁ Á ÁO interaction energies are found to vary from 0.5 and 2 kcal/mol [37] , which are weaker than conventional hydrogen bonds play a prominent role in molecular and protein conformation.

The other two NAHÁ Á ÁO hydrogen bonded interactions are observed between the oxygen lone pair electrons n1(O15) ? r*(N49AH50) and n1(O44) ? r*(N20AH21) with the stabilization energy of 7.810 kcal/mol and 7.810 kcal/mol respectively. As a result, the NAH bond involved in intermolecular interactions shows an elongation in the NAH bond length by 0.007 Ǻ. The occupancies and their corresponding energies of the interacting bonding orbitals have been represented in Table 3 .

The quantity of charge transferred from lone pairs of n(O15) ?

r* (N49AH50) and n(O44) ? r* (N20AH21) of the hydrogen Similarly upon dimerization, the amount of charge transferred from lone pairs of n(O15) ? r* (C46AH47) and n(O44) ? r*(C1 7AH18) of the hydrogen bonded atoms into the antibonds have been increased by 0.0031 with the stabilization energy of 1.860 kcal/mol and 1.800 kcal/mol. The observed low energy (<3 kcal/mol) shows the presence of improper hydrogen bonding [38] . Therefore rehybridization plays an important role in CAH bond. From Table 4 it has been seen that the s-character of the C17AH18 hybrid orbitals increases (0.97%) from sp 2.04 to sp 1.96 that leads to the strengthening of C17AH18 bond and its contraction. This has been well reflected in the geometry as bond C17AH18 contracts by 0.005 with respect to monomer. The contraction and elongation of CAH is due to the effect of rehybridization and hyperconjugation. However, rehybridization dominates and overshadows the hyperconjugative interaction resulting in the contraction of CAH bond (0.005Ǻ) and a concomitant blue shift (~50) in stretching frequency. In case of N-Hintermolecular hydrogen bonding the hyperconjugative effect dominates rehybridization resulting in the elongation of NAH bond (0.007Ǻ) and a concomitant red shift (~55) in stretching frequency

MCMH dimer consists of 58 atoms and hence there are 168 modes of vibrations. The fundamental modes of vibration have been carried out using normal coordinate analysis following force field calculation with the ab initio method. The scaling has been carried out using multiple scaling factors. The calculated and the experimental wavenumbers of MCMH with their normal modes of vibrations along with their corresponding potential energy distribution (PED) are represented in Table 5 . Experimental spectra and simulated spectra of MCMH have been depicted in Fig. 2 and Fig. 3. 

The normal nodes of vibrations of the substituted phenyl rings have been assigned according to Wilson's numbering convention [39, 40] . Generally the allowed CAH stretching modes for phenyl ring are 2, 7b, 20a and 20b are expected in the range 3120-3010 cm À1 [39] . The CAH stretching mode of the phenyl ring is observed at 3052 cm À1 in IR spectra with week intensity and in Raman it is observed at 3057 cm À1 with medium intensity. The five CAC stretching vibrational modes are 8a, 8b, 19a, 19b, and 14, which depend more on the substituent. The degenerate mode 8a of di-substituted ring is expected to be in the range 1609-1565 cm À1 and 8b extends from 1625 to 1586 cm À1 , with 8a smaller than 8b. The vibrational mode 8b of phenyl ring is observed as a very strong band in the Raman spectrum at 1592 cm À1 and as a medium band at 1610 cm À1 in the IR spectrum. The bands observed at 1318 cm À1 with medium intensity in IR and at 1314 cm À1 in Raman spectra have been has been assigned to normal mode 14. The normal mode 19a has been observed in the Raman spectrum at 1566 cm À1 . The enhanced intensity clearly shows the conjugation in the phenyl ring. Also, the bands observed at 1538 cm À1 and 1537 cm À1 in IR and Raman spectra have been assigned to mode 19a of the pyran ring. Due to the hyperconjugative interaction between the lone pair n1(O15) ? r*(C6AC11) predicted by the NBO analysis is well reflected in IR spectra at 1314 cm À1 and in Raman spectra at 1318 cm À1 showing a red shift in CAC stretching frequency.

The CAH in-plane bending modes are 3, 9a, 15, 18a, and 18b for the mono-substituted ring and modes 3, 15, 18b, and 9b for the disubstituted phenyl ring. The band observed at 1253 cm À1 in IR spectra with medium intensity and a week band observed at 1260 cm À1 in Raman spectra have been assigned to CAH in-plane bending mode 3 of phenyl ring. Mode 15 coupled with oxygen shows enhanced intensity in IR spectrum at 1163 cm À1 . The vibrational modes are 11, 5, 17a, and 17b, which are usually observed in the region 1000-675 cm À1 have been assigned to CAH out-plane bending vibrations. These modes have been identified as medium IR band at 953 cm À1 (5), weak IR band at 904 cm À1 (17b), weak IR band at 847 cm À1 (10a), and the weak bands observed at 849 cm À1 (10a) and 757 cm À1 (11) in Raman spectra have been assigned to C-H out-of-plane bending vibration. In flavone derivatives, the CAC stretching vibrations are expected around 1619 cm À1 [41] [42] [43] . In the IR spectra, an intense band has been observed at 1628 cm À1 are predominantly localised on the C12AC13 atom of the chromone part, which is coupled with carbonyl stretching.

The most characteristic bands of the IR and Raman spectra are the carbonyl bands [44, 45] . The intensity of C@O stretching frequency increases due to conjugation or due to the formation of hydrogen bonds, which leads to the intensification of Raman and IR bands [46] . In MCMH, the C@O bond is in conjugation with the pyrone ring. The carbonyl stretching frequency of flavones is observed in the range 1712-1675 cm À1 [41] . The C@O stretching vibrations give raise to the characteristics in IR and Raman spectra, and the intensity of these bands may increase owing to the formation of hydrogen bonds [47] . The intense band observed at 1628 cm À1 in the IR spectrum and the band at 1624 cm À1 in Raman have been assigned to the C@O stretching mode. This decrease in stretching frequency is due to an increase in the p-conjugation between the ring and pyrone part. Also, the constraints induced by the intermolecular interactions results in a stronger p-electron delocalisation [48, 49] resulting in the lowering of the carbonyl stretching mode, which is justified by DFT calculations. In case of pyran ring the CAO stretching frequency is expected to be in the region of 1200 cm À1 . From the IR spectra, the bands observed at 1218 cm À1 and 1193 cm À1 have been assigned to CAO stretching.

In MCMH, the skeletal vibrations have been defined by CAH vibrations, C@N vibration, NAN vibrations, NAH vibrations, thioamide group vibrations and methyl group vibrations. 

In methylidene molecules, the most interesting and informative parameter is the CAH stretching frequency. In general, the CAH stretching modes are expected to occur in the range 3120-3010 cm À1 [39] . The CAH stretching frequency in methylidene is found to be higher than the normal CAH stretching frequencies. The bands with weak intensity observed at 3146 cm À1 in IR spectra and at 3130 cm À1 in Raman spectra have been assigned to CAH stretching mode. The blue shift in wavenumber (~35 cm À1 ) shows the spectral evidence about the intermolecular interactions that takes place between n1 (O44) ? r* (C17AH18) [54] . In MCMH, the C@N stretching frequencies coupled with CAC bands have been observed at 1538 cm À1 in IR spectra and at 1566 cm À1 in Raman with medium intensity. A significant shift in frequency is pronounced due to the phase sensitivity of the C@N group due to hydrogen-bond interactions of the neighbouring atom [55] .

In compounds containing NAN bond, the NAN stretching frequency is expected to occur as a very strong polarized band in Raman at 1111 cm À1 [56] .In MCMH, the band observed with medium intensity at 1090 cm À1 in Raman spectra has been assigned to NAN stretching mode. The in-plane and out-plane bending vibrations associated with NAN have been observed in the IR spectra at 557 cm À1 with medium intensity and in Raman spectra at 559 cm À1 with very weak intensity. These modes are found to be coupled with other modes.

The NAH stretching frequency is expected to occur in the region 3320-3280 cm À1 [45] .

In the IR spectra of MCMH, a broadened band has been observed at 3225 cm À1 with medium intensity. This widened band with medium intensity has been assigned to N20AH21 stretching mode. A red shift in stretching frequency (~55 cm À1 ) has been observed, which proves the spectral evidence of the formation of NAHÁ Á ÁO intermolecular interactions. This shift has been evinced from the results obtained from the optimized geometry by an increase in N20AH21 bond length by 0.007 Å over the isolated molecule. Also, the redshift in stretching frequency have been evinced by the intermolecular charge transfer interactions between n1(O15) ? r* (N49AH50) and n1(O44) ? r* (N20AH21) in NBO basis with the stabilization energy of 7.810 kcal/mol.

Amides have gained interest owing to their conjugation between lone pair electrons in the Nitrogen and the carbonyl bond results in distinct physical and chemical properties. Secondary amides are important as they are the backbone of every protein molecule [57] . Secondary amide contains only one NAH stretching band in the infrared spectrum. This band appears between 3350 and 3500 cm À1 [58] . From the IR spectra, the band noticed at 3352 cm À1 has been assigned to N24AH25 stretching mode. In compounds containing thioamides, the noncyclic ANHA (C@S) exhibits C@S stretching, CANAS bending vibrations and NAH stretching. The assignment of the band due to the CAS stretching vibration varies in compounds and is difficult to identify [59] .The CAS stretching mode is usually exhibited as a strong band in Raman spectra in the region of 750-500 cm À1 [60] . In the title molecule, the delocalization of the CAS bond and the vibrational coupling effect caused by the attachment of the adjacent nitrogen atom leads to the band with medium intensity at 745 cm À1 in Raman spectra, which has been assigned to CAS stretching vibration. The out-plane CANAS bending (CNS wagging) and the inplane bending mode(CNS rocking) coupled with other modes have been observed as a weak band at 563 cm À1 in Raman spectra and as an intense band at 558 cm À1 in IR spectra has been assigned to these modes respectively.

The asymmetric stretching and symmetric stretching modes of methyl group attached nitrogen atom are usually downshifted due to electronic effects and are expected near 2820 cm À1 and 2810 cm À1 for asymmetric and symmetric stretching vibrations. Also, the low force constant of the methyl group attached with amine nitrogen leads to the lowering of CAH stretching frequency in methyl group [44] . The other normal modes of the methyl group appear to be coupled with other modes are expected near 1554-1502 cm À1 . The symmetric deformations, at about 1510 cm À1 coupled with rocking modes have been observed. The asymmetric deformations, at about 1459 cm À1 coupled with rocking modes have been observed in IR spectra as a sharp intense band.

In recent years, the development of assays and computer-based (in silico) models to assess absorption, distribution, metabolism, excretion and toxicity (ADMET) properties has greatly abridged drug development time. The ability to predict these properties quickly and reliably facilitate the exclusion of compounds with potential ADMET problems, and hence help investigators prioritizes which compounds to synthesize and evaluate. There is an overall of 26 constraints in ADMET statistics, which has been taken from the full text of peer-reviewed scientific journals through weekly PubMed and Google Scholar searches from 2002 to 2018 [61] . ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) results show that MCMH (+) in human intestinal absorption and blood-brain barrier permeability, which suggests that the molecule is well absorbed in the human body (Table 7) . Inhibition and initiation of P-glycoprotein have been described as the causes of drug-drug interactions. [62] . It has been observed that MCMH has P-glycoprotein non-inhibitor, which shows the non interacting activity of MCMH with other drugs. ADMET data show MCMH is in permissible limit [63, 64] . Organic cation transporters are accountable for drug absorption and disposition in the kidney, liver, and intestine [63] . ADMET result of MCMH shows that it has been a non-inhibitor of renal organic cation transporter. The human cytochromes P450 (CYPs) are responsible for about 90% oxidative metabolic reactions. Inhibition of CYP enzymes will lead to inductive or inhibitory failure of drug metabolism [65] . A non-inhibitor and non-substrate property of MCMH supports the fact it is safe to the human liver. The Ames test is employed to test the mutagenic activity of chemical compounds. It is usually carried out to test bacteria and viruses to whether a given chemical can cause cancer [66, 67] . ADMET result of MCMH is shown in Table 6 ADMET property analysis result shows MCMH has been nonames toxic and non-carcinogenic. Human Ether-à-go-go-Related Gene (hERG) is a gene delicate to drug binding [68] . ADMET results shows MCMH have been weak inhibitor and non-inhibitor of hERG inhibition (predictor I and II). That means the MCMH molecules will well bind with SARS-CoV-2 main protease [69] . Analyzing the ADMET properties, together with their attributes and prediction, has given an idea about the pharmacokinetic properties of MCMH. 

According to the rule of thumb, orally absorbed drugs should have the tendency to obey Lipinski's rule of five. The rule was derived from an analysis of compounds from the World Drugs Index database aimed at identifying features that have been important in making a drug orally active. It has been found that the factors concerned involved numbers that are multiples of five: a molecular weight less than 500; no more than 5 hydrogen bond donor (HBD) groups; no more than 10 hydrogen bond acceptor groups; a calculated log P value less than + 5 [70] [71] [72] [73] [74] [75] . MCMH has been passed through Lipinski's rule of five (Table 7) to overcome drug-likeness filter.

In silico calculation Molecular docking has been used to acquire binding modes and binding affinities of the title molecule. Binding mode and affinity to SARS-CoV-2 main protease (Mpro) are essential for insilco drug design [76, 77] . The protein structure of SARS-COV-2 has been retrieved from protein data bank (PDB id: 5r80), which has 1.93 Å resolution. Mpro was co-crystallized with methyl 4sulfamoylbenzoate inhibitor. The docking study has been performed by AutoDock Vina [33] , which uses a Lamarckian genetic algorithm (GA) in combination with grid-based energy estimation, to check the docking accuracy of software we have performed redocking to the co-crystal bound ligand. To find the effective inhibitors for Mpro, the 3D structure of MCMH from the Cambridge Crystallographic Data Centre (CCDC) database. The protein (Mpro) and ligand (MCMH) structures have been modified by Autodock Tools [78] . The chains of the main protease have been modified by removing water and bound ligand. Missing amino acids have been checked, and polar hydrogen has been added to the protein structure. Centre Grid box x:5.108, y:18.9177, z:-18.1863 and number of points in x,y,z dimensions are considered as 30x30x30 Å3 respectively and grid spacing has been taken as 0.3750 Å. Ligand has been prepared by adding Gasteiger charges, detecting root and choosing torsions from the torsion tree of Autodock Tools panel [79] . Docking procedure has been performed by using the Lamarckian genetic algorithm [80] and the results have been tabulated in Table 8 .

MCMH bound to the active site of Mpro with good complementarity (Fig. 4) and formed three hydrogen bonds and four hydrophobic bonds with the Mpro. The binding energy of the nonbonding interaction is À8.8 kcal/mol. MCMH has been bound to the Cysteine-Histidinecatalytic dyad (Cys-145 and His-41) by pi-sulphur interaction as well as significant interactions with the other amino acids, and the docking score (À8.8 kcal/mol) was relatively higher than most of the other inhibitor drugs targeting Mpro [81] and hence proves its ability to bind with the SARS-CoV-2 main protease. The pi-sulphur interaction taken place pi-electron cloud of aromatic ring of amino acid histidine 41, Cysteine145 acts as the aromatic pi-motif and interacted with lone pair of the electron cloud of Sulphur atom of MCMH (Fig. 4) . The pi-sulphur interaction has been probed in biological and model systems and it has been estimated to contribute between 0.5 and 2 kcal/mol to binding stability [82] . All these results present a clear view that MCMH can irreversibly interact with Mpro. The catalytic dyad composed of Histidine 41 and Cysteine 145 is a set of amino acids that can be found in the active site of most SARS-CoV-2 main proteases, plays an essential role in drug binding [83] . MCMH bound both to Histidine 41 and Cysteine 145 ( Fig. 4 and Table 8 ) claims to be an excellent antiviral drug.

The compound MCMH has been characterized by FT-IR, FT-Raman spectroscopic techniques at B3LYP/6-311++G(d,p) level using DFT calculations and the complete vibrational analysis has been carried out. The presence of the intermolecular and intramolecular hydrogen bonds has been analyzed using NBO analysis. The transfer of electrons from the lone pair oxygen to the antibonding orbital of NAH and CAH bond evinces the formation of two hydrogen bonds that brings about most interesting biological properties. The occurrence of NAHÁ Á ÁO intermolecular interactions and the conspicuous red shifting in the wavenumber have been authenticated by the increase in NAH bond length and an increase in the electron density in the antibonding orbitals. Also, the presence of CAHÁ Á ÁO intermolecular interactions and the blue shifting in the wavenumber have been authenticated by the decrease in CAH bond length and the occupancy of the interacting NBOs. The existence of NAHÁ Á ÁO and CAHÁ Á ÁO intermolecular hydrogen bonding plays an important role in imparting stability to protein structure. Drug likeness predicts the oral activity and ADMET property analysis gives an idea about the pharmacokinetic properties of the title molecule. The binding energy of À8.8 kcal/mol and the binding affinity of MCMH with Histidine 41 and Cysteine 145 with nonbonding interactions present a clear view that MCMH can irreversibly interact with SARS-CoV-2 protease and claims to be an excellent antiviral inhibitor.

CRediT authorship contribution statement S.J. Jenepha Mary: Conceptualization, Data curation, Investigation, Software, Validation. Sayantan Pradhan: Data curation. C. James: Supervision.

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.

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Synthesis, crystal and molecular structure, and characterization of 2-((2-aminopyridin-3-yl)methylene)-N-ethylhydrazinecarbothioamide using spectroscopic (1H and 13C NMR, FT-IR, FT-Raman, UVeVis) and DFT methods and evaluation of its anticancer activity

Uma maheswari, Vibrational spectroscopic investigation on the structure of 2-ethylpyridine-4-carbothioamide

Molecular structure analysis and spectroscopic characterization of 9-methoxy-2H-furo[3,2-g] chromen-2-one with experimental (FT-IR and FT-Raman) techniques and quantum chemical calculations

Conformational behaviour of antioxidant chromones. A vibrational spectroscopy study

Quantum chemical study of a derivative of 3-substituted dithiocarbamic flavanone

Molecular docking studies, charge transfer excitation and wave function analyses(ESP,ELF,LOL)on valacyclovir: A potential antiviral drug

Crystal structure of (2E)-N-methyl-2

NBO Version 3.1, TCI

Scaling of ab initio force fields by MOLVIB

Molvib -a flexible program for force field calculations

Combination of theoretical ab initio and experimental information to obtain reliable harmonic force constants

Automated docking using a lamarckian genetic algorithm and empirical bindingfree energy function

The PYMOL Molecular Graphics System, LLC, Schrodinger

NBO Version 3.1

Vibrations Spectra of Benzene Derivatives

Infrared Characteristic Group of Frequencies

Structural conformations and vibrational spectral study of chloroflavone with density functional theoretical simulations

FT-IRspectral and DFT studies on 6, 8-Dichloroflavone and 6, 8-Dibromoflavone

FT-Raman and FT-IR spectral and quantum chemical studies on some Flavonoid derivatives: Baicalein and Naringenin

Infrared Spectral Interpretation: A Systematic Approach

Characteristic Raman Frequencies of Organic Compounds

Introduction to Infrared and Raman Spectroscopy

Molecular structure, normal coordinate analysis, harmonic vibrational frequencies, NBO, HOMO-LUMO analysis and detonation properties of (S)-2-(2-oxopyrrolidin-1-yl) butanamide by density functional methods

Semi-empirical and vibrational studies of flavone and some deuterated analogues

Electronic structure of chromone and its hydroxylated derivatives on positions 2 and 3

Magnitude and mechanism of charge enhancement of CHÁ Á ÁO hydrogen bonds

Cation-cation pairing by N-C-HÁÁO hydrogen bonds

Conservation and functional importance of carbon-oxygen hydrogen bonding in AdoMet-dependent methyltransferases

Magnitudes and chemical consequences of R3N+-C-HÁ Á ÁO=C hydrogen bonding

Vibrational assignments and electronic structure calculations for 6-thioguanine

Vibrational assignments and electronic structure calculations for 6-thioguanine

The C=S stretching frequency and the ''ÀNÀC=S bands" in the infrared

admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties

Use of amino acid composition to predict ligand-binding sites

Potential of biopartitioning micellar chromatography as an in vitro technique for predicting drug penetration across the blood-brain barrier

Role of organic cation transporters in drug absorption and elimination

Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib

Ames, the Ames test, and the causes of cancer

The Ames Salmonella/ microsome mutagenicity assay

Tristani-Firouzi, hERG potassium channels and cardiac arrhythmia

Structurebaseddesign of antiviral drug candidates targeting the SARS-CoV-2 main protease

Lead-and drug-like compounds: the rule-of-five revolution

Prediction of drug-likeness

Computational methods for the prediction of druglikeness

The application of in silico druglikeness predictionsin pharmaceutical research

Understanding drug-likeness

Guiding molecules towards druglikeness

Molecular Modeling of Proteins

Molecular recognition and docking algorithms

Lead discovery using molecular docking

Development and validation of a genetic algorithm for flexible docking

A review of protein-small molecule docking methods

AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility

Iterative partial equalization of orbital electronegativity-arapid access to atomic charges

Automated docking using a Lamarckian genetic algorithm and an empirical bindingfree energy function

Supplementary data to this article can be found online at https://doi.org/10.1016/j.saa.2020.119388.