key: cord-1007144-q7km2dl6
authors: Missioui, Mohcine; Said, Musa A.; Demirtaş, Güneş; Mague, Joel T.; Al-Sulami, Ahlam; Al-Kaff, Nadia S.; Ramli, Youssef
title: A possible Potential COVID-19 Drug Candidate: Diethyl 2-(2-(2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetyl)hydrazono)malonate: Docking of Disordered Independent Molecules of a Novel Crystal Structure, HSA/DFT/XRD and cytotoxicity
date: 2021-11-28
journal: Arab J Chem
DOI: 10.1016/j.arabjc.2021.103595
sha: 333645997f38332b5bc3ea796a626ef18e31d434
doc_id: 1007144
cord_uid: q7km2dl6

This study reports the synthesis, characterization and importance of a novel diethyl 2-(2-(2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetyl)hydrazono)malonate (MQOAHM). Two independent molecular structures of the disordered MQOAHM have been established by XRD‑single‑crystal analysis in a ratio of 0.596(3)/0.404(3), MQOAHM (a) and MQOAHM (b), respectively. MQOAHM was characterized by means of various spectroscopic tools ESI-MS, IR, 1H &13C NMR analyses. Density Functional Theory (DFT) method, B3LYP, 6-311++G(d,p) basis set was used to optimize MQOAHM molecule. The obtained theoretical structure and experimental structure were superimposed on each other, and the correlation between them was calculated. The Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) were created, and the energy gap between these orbitals was calculated. For analyzing intermolecular interactions, Molecular Electrostatic Potential (MEP) and Hirshfeld Surface Analysis were studied. For a fair comparative study, the two forms of the title compound were docked together with 18 approved drugs and N3 under precisely the same conditions. The disordered molecule structure's binding scores against 7BQY were -7.0 and -6.9 kcal/mol-1 for MQOAHM (a) and MQOAHM (b), respectively. Both the forms show almost identical superimposed structures and scores indicating that the disorder of the molecule, in this study, has no obvious effect. The high binding score of the molecule was attributed to the multi-hydrogen bond and hydrophobic interactions between the ligand and the receptor's active amino acid residues. Worth pointing out here that the aim of using the free energy in Silico molecular docking approach is to rank the title molecule compared to the wide range of approved drugs and a well-established ligand N3. The binding scores of all the molecules used in this study are ranged from -9.9 to -4.5 kcal/mol-1. These results and the supporting statistical analyses suggest that this malonate-based ligand merits further research in the context of possible therapeutic agents for COVID-19. Cheap computational techniques, PASS, Way2drug and ADMET, online software tools, were used in this study to uncover the title compound's potential biological activities and cytotoxicity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 [1] . However, several reports proposed agents to treat COVID-19 include direct antivirals [2] , baricitinib [3] , hydroxychloroquine [4] , glucocorticoids [5] and anakinra [6, 7] . Researchers have made great progress in the development of potential medical treatments in response to the COVID-19 pandemic. Currently, several molecules are being tested for their efficiency on COVID-19 disease, some of which have reached clinical trials, while others are still in the preclinical phase [8] [9] [10] [11] [12] . Quinoxaline as a wonder nucleus in the fused systems of nitrogen-containing heterocycles, is important nitrogenous hetero compound due to their extensive properties, [13] [14] [15] [16] [17] [18] and shows a variety of activities in the medical field, including analgesic [19] , antiinflammatory [20] anti-tubercular [21] , anti-bacterial [22] , bacteriocides [23] , anti-HIV [24] , anti-diabetic [25] , antioxydant [26] and anti-cancer [27, 28] agents. Malonate-based compounds have aroused increasing attention because of their important pharmacological activities, such as decreased blood glucose [29] anti-HIV [30] anticancer [31] anti-inflammatory [32] antioxidative [33] and antiviral [34] activities. Moreover, malonates are traditionally regarded as important materials for synthesizing the key intermediates of numerous active substances [35] [36] [37] [38] . 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. Based on the above findings and our interest in developing novel and promising pharmacological agents [39] [40] [41] [42] [43] [44] , including anti COVID-19 drug [45, 46] , a malonate-based derivative containing oxoquinoxalin-1(2H)yl)acetohydrazide moiety MQOAHM was synthesized and characterized. In addition, the molecular structure was confirmed by single-crystal X-ray diffraction studies. The theoretical molecular geometry of this compound was found by DFT calculation, and the obtained structure was compared with the experimental structure. FOMs and MEP graphics were plotted, and the energy gap between HOMO and LUMO was calculated. For analyzing the intermolecular hydrogen bonds, Hirshfeld surface analysis was studied.

Additionally, for a comparative study and ranking the title compound to the approved drugs, the title compound was docked together with 18 approved drugs and N3 under the same conditions. This study aimed to rank the title compound, MQOAHM with respect to a wide range of approved drugs and the well-established inhibitor, N3.

Moreover, the biological and cytotoxicity activities prediction of this novel compound was carried out. Finally, in silico ADMET screening was also performed.

All commercial chemicals were purchased from Sigma-Aldrich and used as received. TLC follow-up of the reaction to check the compound's purity was made out on silica gel-precoated aluminium sheets (Fluorescent indicator 254 nm, Fluka, Germany). The spots were detected by exposure to UV lamp at λ 254/366 nm for a few seconds. The melting point was obtained on a Büchi Melting Point SMP-20 apparatus and is uncorrected. The 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance 300 NMR Spectrometer in DMSO-6. The chemical shifts δ were reported in parts per million (ppm); the IR spectrum was obtained using the Bruker-VERTEX 70 device and the associated software OPUS, an ATR (attenuated total reflectance) mode. Mass spectra were recorded on an API 3200 LC/MS/MS mass spectrometer using electrospray ionization (ESI) in positive polarity.

Following a procedure similar to that of Hinsberg [13] , we have successfully synthesized 3-methyl-1H-quinoxalin-2-one with a yield of 91% by condensation of O-phenylenediamine (10 mmol) with ethyl pyruvate (15 mmol) in HCl 4N aqueous solution for 30 minutes at room temperature, Scheme 1.

To a solution of 3-methylquinoxalin-2(1H)-one (3 g, 18.7 mmol) in N,N-dimethylformamide (15 mL) were added ethyl 2-bromoacetate (4.7 mL, 28.5 mmol), potassium carbonate (3.6 g, 28.5 mmol) and a catalytic quantity of tetranbutylammonium bromide. The reaction mixture was stirred at room temperature for 24 h. The solution was filtered, and the solvent was removed under reduced pressure. The solid obtained was recrystallized from ethanol solution to afford a white powder, ethyl 2-(3-methyl-2-oxoquinoxalin-1 (2H)-yl) acetate ( EMQOA ), with a yield of 72%.

To the formed residue ( EMQOA ) (1g, 4 mmol) taken in ethanol (20 mL) was added hydrazine hydrate (0.3mL, 6 mmol), then left stir for 24 hours at room temperature. The target compound, 2-(3-methyl-2-oxoquinoxalin-1(2H)yl)acetohydrazide ( MQOAH ) precipitate and recrystallized from ethanol, the yield is around 77%, Scheme 1.

In ethanol (15 mL) , to this quinoxaline(0.5g, 2.1 mmol) was added (0.7ml, 4.2 mmol) of diethyl 2-oxomalonate, stirred for 2h under reflux at 80°C. The mixture then was filtered and the solvent evaporated under reduced pressure, and the residue was crystallized from its ethanol solution. The reaction yield is 65%. Scheme 1. The compound was dissolved in ethanol and left for slow evaporation to afford a colourless plate-like crystal, Fig. 1 

A colourless plate-like specimen of C 18 H 20 N 4 O 6 , approximate dimensions 0.032 mm x 0.230 mm x 0.303 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured on a Bruker Smart APEX CCD system equipped with a fine-focus sealed tube (Mo-Kα, λ = 0.71073 Å) and a graphite monochromator. The complete sphere of data was processed using SAINT [47] . The structure (Fig. 2) was solved by direct methods and refined by the full-matrix least-squares method on F2 using SHELXT and SHELXL programs [48, 49] . The molecular and packing diagrams were generated using DIAMOND [50] . Crystal and refinement details are presented in Table 1 . 

HAS and the related 2D-fingerprint plots were calculated for diethyl-2-(2-(2-(3-methyl-2-oxoquinoxalin-1(2H)yl)acetyl)hydrazono)malonate MQOAHM (a), using Crystal Explorer, Version 17, which reads CIF format as an Xray input file [52] . The cut-off for the hydrophobic interactions between the amino acid residues and the ligands is 3.9 Å [53].

Geometric optimization of the molecule was executed with Gaussian 09 W package program [54] and was calculated by using Density Functional Theory (DFT) method by B3LYP (Becke's three-parameter hybrid functional using the LYP correlation functional) with 6-311++G(d,p) basis set. For modeling, initial values were obtained Xray diffraction. Molecular electrostatic potential map and molecular orbitals were plotted with Gauss-View 5 molecular visualization program [55] .

Docking calculations of MQOAHM (a) and 20 approved drugs were accomplished using the Autodock Vina wizard in PyRx 0.8 [56] . PyMOL molecular viewer was used to present the output [58] . Schematic diagrams of protein-ligand interactions were generated using the LIGPLOT program [59] . 

(MQOAHM) 3-Methyl-1H-quinoxalin-2-one (MQO) Yield 91%,

Yield 77%, color: white, mp=183.5-182.3°C, FT-IR (ATR, υ, cm -1 ) 1168 υ (N-C amide ), 1600 υ (C=C arom ), 1645 υ 

Yield The synthesis of the compound MQOAHM is depicted in Scheme1. The starting material, 3-methylquinoxalin-2(1H)-one was prepared through treatment of o-phenylenediamine with sodium pyruvate in acetic acid [60] . This heteroycle was proven to be a good synthon for different highly biologically active compounds. 

The quinoxaline moiety, except N2, is planar to within 0.0169 (15) Å (rms deviation = 0.0098). N2 is displaced by 0.0307(18) Å from the mean plane. The attached substituent to N2 is nearly perpendicular to the mean plane defined above as indicated by the dihedral angle of 83.34 (6) ° between this plane and that defined by N2/C11/C12/O2. The intramolecular N3-H3A···O5 hydrogen bond ( Table 2 ) orients, the two ester groups to be close to coplanarity with the N2/C11/C12/O2 unit (Fig. 3) . Bond distances and interbond angles appear as expected for the given formulation.

In the crystal, slipped π-stacking interactions between C1···C6 and C1/C6/N1/C7/C8/N2 rings (centroid···centroid = 3.6768 (11) Å, dihedral angle = 0.89 (9)°, slippage = 1.53 Å), together with C2-H2···O2 and C10-H10B···O1 hydrogen bonds plus C9-H9A···Cg1 interactions ( Table 2 ) form oblique stacks of molecules extending along the a-axis direction (Fig. 2) . These stacks are connected in pairs by inversion-related C17-H17B···O2 hydrogen bonds ( Table 2 and Fig. 4 ). Bond distances and bond angles in both X-ray results and theoretical results are given in Table 3 and Table 4, respectively. Linear correlations for all bond distances and all bond angles are shown in Fig.6 

HSA is a successful tool in showing the inter-and intra-molecular interactions in the crystal structure. The mesh

drawing generated using Crystal Explorer shows the electron density around all of the molecule atoms and displays the short contacts, within 3.8 A o in red dashed lines, Fig. 8(A) , [56] . Many types of these interactions were detected surface shows the presence of π-π stacking, which corresponds to the phenyl-phenyl interaction. All 2D-finger plots and the percentage contributions of many interactions are shown in Fig. 9 . is related to ionization potential, and Lowest Unoccupied Molecular Orbital (LUMO) is related to electron affinity.

The energy gap between HOMO and LUMO is related to charge transfer in molecules [64] and identifies the chemical stabilities of molecules [65] . Furthermore, a low energy gap indicates high biological activity due to transferring electrons efficiently from HOMO [66] . Additionally, average energy values for HOMO and LUMO are connected to electronegativity [63] . HOMO and LUMO of the molecule were plotted using the same level theory.

These Frontier Molecular Orbitals (FMOs) and the energy gap between HOMO and LUMO can be seen in Fig. 10 .

While HOMO orbital is mainly localized on 3-methylquinoxalin-2(1H)-one molecule group, LUMO orbital is mainly localized on diethyl 2-(2-acetylhydrazono)malonate group. The energy gap between HOMO and LUMO is 3.6842 eV. 

The whole world is experiencing a tough time at many economic and social levels because of Covid-19. Hence, we have been motivated to study how a malonate ligand might behave in the main protease's active site for Covid-19

(M Pro , PDB 7BQY). Worth mentioning that previous docking studies have used the main protease, M pro , Table 5 , with different resolutions [67] . In this study, we preferred to use the 7BQY because it has been docked against the well-known inhibitor N3 that appeared recently in Nature journal and has a good resolution value (1.70 Å) [68] . All the collected proteases in Table 5 can be used in docking as they are around 2 Å in resolution (https://www.rcsb.org/). Table 5 . Likewise, MQOAHM (a) was superposed on 18 approved drugs [70] , N3 [71] and MQOAHM (b) to reveal a highly interestingly wider range of displays of the compounds bound to the protein cavity of 7BQY compared to MQOAHM (a). All molecules are colour-coded throughout the study, Fig. 12 . The reason for choosing these approved drugs is that they are active against different viral diseases ( Ebola virus, HI, Herpes, Hepatitis, Influenza, Cytomegalovirus, Small Pox and more) [70, 72] . The result revealed that the studied malonate-based ligand MQOAHM (a) has a similar layout and binding affinity, against the main protease (PDB code 7BQY), to the 18 approved drugs and N3 inhibitor, Fig. 12 . It is essential to mention that all the docked molecules against the target enzyme COVID-19 are ranked according to their binding energy, shown in ascending order and colour-coded molecules (Fig. 13) . The binding affinity was attributed to many hydrogen bonds and hydrophobic interactions between the MQOAHM (a) and the receptor's active amino acid residues, as shown in the Schematic 2D LIGPLOT, Fig. 11 (F) . A similar full Schematic 2D

LIGPLOT for Oseltamivir was presented for comparison, Fig. 11 (E) . It could be seen that Arg188 and only H-bonds in (F). A key to the symbols is given in our recent report [69] . Schematic 2D LIGPLOT representations of all molecules are available in the SI. The binding affinity to the protein target is usually considered in selecting a possible drug candidate. All docking poses demonstrated a good fit inside the substrate pocket. Therefore, the lowest-energy docking poses of all compounds were considered for the superposition in Figure 12 . Analysis results for all the nine poses of each molecule docked to 7BQY are presented in Table 6 to assess the predicted binding poses' reasonability. Statistical analysis, using a statistical model (Minitab Statistical Software (Version 19) 2020. Available from: www.minitab.com), showed no significant differences between the nine-poses for each compound used, Table   5 -SI. However, a highly significant variation between the nine-poses and compounds' binding affinity means at pvalue = 0.00, Table 6 . The Pairwise comparison, Tukey, showed that Telaprevir with a mean of -9.20±0.36 is the strongest significant binding affinity. The following medicines have no significant differences in their M pro binding affinity; Faldaprevir (-9.06± 0.38), Indinavir (-8.94±0.29), Remdesivir (-8.80±0.39) and Telaprevir (-9.20±0.36 ) , Table 7 [74] and Way2drug (Provides more information about the biological potential of new compounds, Way2Drug URL, http://way2drug.com) [75] are online software tools that predict various types of biological activities as shown in Table 7 . They were both used at Pa>Pi (Pa represents the probability of being active, and Pi means inactive). The aim mainly was to predict the cytotoxicity of our malonate-based ligand MQOAHM (a) against human tumours and non-tumours. The first predicted biological activity for MQOAHM (a)

was Antieczematic, ranging from 0.079 to 0.616. Whereas, the second predicated activity was antiviral against a single-stranded RNA Picornavirus. This virus is considered a simple and positive-sense RNA vertebrate virus group.

It comprises many small RNA viruses that cause significant pathogens in both humans and livestock [76] . The activity predicated, by PASS, was in the range of 0.041-0.524. The Picornaviruses (PV) and coronaviruses (Cov), to which COVID-19 belongs, are positive-stranded RNA viruses that infect humans worldwide. Around 6800 small molecules were tested to discover a novel inhibitor against viral protease for both viruses. Results showed a protease that inhibits SARS-CoV 3CL pro and 3C pro from PV and CoV, respectively [77] . Therefore, in this study, MQOAHM predicated by PASS as Platelet aggregation and ATPase, Table 7 . Side negative effect was also predicted, such as In silico assessment of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties were also used. It is a fast method to screen compounds for their pharmacokinetics and pharmacodynamics properties. The toxicity risks and bioavailability of MQOAHM were predicted based on ADMET profile (Table 11) . Results showed a good human intestinal absorption probability, a good Blood-Brain Barrier crossing and a high plasma protein binding percentage. In addition, it has a good excretion and optimal toxicity except for drug-induced liver injury. The prediction results also showed that no carcinogenic effects and no AMES toxicity were found. Additionally, the energy gap is 3.6842 eV. A comparative study of the two forms of the title compound was docked together with a wide range of approved drugs and the ligand N3, against 7BQY, under the same conditions. The binding scores -7.0 and -6.9 kcal/mol -1 for MQOAHM (a) and MQOAHM (b), respectively suggesting almost no difference. Also, both the forms show almost identical lay down of the structures, after docking, indicating that the disorder of the molecule, in this study, has no clear-cut effect. However, the multi-hydrogen bond and hydrophobic interactions between the ligand and the receptor's active amino acid residues merits further research in the context of possible therapeutic agents for COVID-19. The binding scores of all the molecules used in this study ranged from -9.9 to -4.5 kcal/mol -1 . Preliminary toxicity properties of MQOAHM were predicated for its possible potential use as an inhibitory drug against COVID-19 using energy-free methods.

The authors of this manuscript 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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ARABJC) the right to publish and distribute the manuscript in part or in its entirety. The Author's name will always be included with the publication of the manuscript. The Author has the following nonexclusive rights: (1) to use the manuscript in the Author's teaching activities; (2) to publish the manuscript, or permit its publication, as part of any book the Author may write; (3) to include the manuscript in the Author's own personal or departmental (but not institutional) database or on-line site; and (4) to license reprints of the manuscript to third persons for educational photocopying. The Author also agrees to properly credit the Arabian Journal of Chemistry (ARABJC) as the original place of publication. The Author hereby grants the Arabian Journal of Chemistry (ARABJC) full and exclusive rights to the manuscript, all revisions, and the full copyright. The Arabian Journal of Chemistry (ARABJC) rights include but are not limited to the following: (1) to reproduce, publish, sell, and distribute copies of the manuscript, selections of the manuscript, and translations and other derivative works based upon the manuscript, in print, audiovisual, electronic, or by any and all media now or hereafter known or devised

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The authors are grateful to Mohammed V University and Ondokuz Mayıs University Research Fund for financial support for this study. The support of NSF-MRI Grant #1228232 for purchasing the diffractometer and Tulane University for support of the Tulane Crystallography Laboratory is gratefully acknowledged. Thanks go to the reviewers of this article for their comments.

Date : 21 September 2021 Editor in Chief: AbdulRahman Al-Warthan Date:

☒ 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.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: