key: cord-0893767-qp91tq07
authors: Moghimi, Parvin; Sabet-Sarvestani, Hossein; Kohandel, Omid; Shiri, Ali
title: Pyrido[1,2-e]purine: Design and Synthesis of Appropriate Inhibitory Candidates against the Main Protease of COVID-19
date: 2022-02-28
journal: J Org Chem
DOI: 10.1021/acs.joc.1c02237
sha: 963e24224bda5d4370fdf0958d3166424e625071
doc_id: 893767
cord_uid: qp91tq07

[Image: see text] A series of tricyclic and polycyclic pyrido[1,2-e]purine derivatives were designed and synthesized via a two-step, one-pot reaction of 2,4-dichloro-5-amino-6-methylpyrimidine with pyridine under reflux conditions. Various derivatives of pyrido[1,2-e]purine were also synthesized by substituting the chlorine atom with secondary amines. After careful physiochemical and pharmacokinetic predictions, the inhibitory effects of the synthesized compounds against the main protease of SARS-CoV-2 have been evaluated by molecular docking and molecular dynamics approaches. The in silico results revealed that among all of the studied compounds, the morpholine/piperidine-substituted pyrido[1,2-e]purine derivatives are the best candidates as effective inhibitors of SARS-CoV-2.

SARS-CoV-2, a single-stranded positive RNA, is a newly recognized member of the coronavirus family that causes a pandemic (COVID- 19) infectious disease that is a serious global health and economic threat. 1, 2 The genomic sequence of SARS-CoV-2 is 79% similar with the SARS-CoV genome. 3, 4 The main protease of SARS-CoV-2, the chymotrypsin-like cysteine protease (3CL pro ), is composed of two identical polypeptides and contains 300 amino acid residues. This enzyme plays a vital role in virus replication. In structural analysis, the 3CL pro enzyme consists of three domains: domain I (residues 8−101), domain II (residues 102−184), and domain III (residues 201−303). The chymotrypsin structure formed by the first two domains is known as a β-barrel, and the third domain consists of five αhelices. The active site of 3CL pro , located between domains I and II, includes Cys145 and His41 amino acid residues. These amino acids form a catalytic dyad that is responsible for viral genome replication. 5−7 Therefore, two separate diverse potent inhibitors of 3CL pro , including both peptidomimetic inhibitors and nonpeptidic inhibitors, have been reported to overcome the rapid spread of the COVID-19 pandemic. 8−12 Recently, studies have illustrated that N-heterocyclic compounds possess antiviral activity. Thus, they can be used as potential noncovalent inhibitors of 3CL pro of SARS-CoV-2. 13−16 Some of the most prominent nitrogen-containing heterocycles are the purine scaffolds, which have attracted medicinal interest due to their applications as drug candidates in cancer treatment and viral disorders. 17, 18 Also, there is a considerable tendency to study new heterocyclic fused imidazopyridine derivatives containing abundant biological activities, such as anticancer, 19 ,20 antiprotozoal agent, 21 antiviral, 22 anti-inflammatory, 23 and anti-Alzheimer's disease 24 activities. Recent investigations have revealed that the heterocyclic systems with additional fused rings display more effective pharmacological and physicochemical properties. Thus, purine-fused tricyclic and polycyclic derivatives have been classified as practical frameworks. 25−27 Moreover, pyrido-[1,2-e]purine derivatives have important biological activities such as selective inhibitory activity toward phosphodiesterase 5 (PDE5) (I), 28−30 anticancer activity (II and III), 31 and antitumor activity (IV) 32 (Figure 1 ).

With regard to the significant properties of pyrido[1,2e]purine, developing novel strategies for synthesizing different skeletons of these systems has attracted significant attention. It has been demonstrated in some classical methods that the functionalized imidazo[1,2-a]pyridine system can be employed as a practical substance in combination with various reagents to afford pyrido[1,2-e]purine scaffolds. 33, 34 The other synthetic routes using purine as the precursor include ring-closing metathesis followed by oxidation of 8,9-diallylpurines, 35 copper-catalyzed one-pot sequential allylic amination/cycloisomerization of the Boc-protected purine, 36 sequential Suzuki coupling of 9-(2-bromophenyl)purines with 2-bromophenylboronic acid followed by intramolecular C−H arylation, 37 and intramolecular cyclization reactions of 1,3-bis(4-methoxybenzyl)-5-(pyridin-2-ylamino)pyrimidine-2,4(1H,3H)-diones. 38 These methods have shown multistep reactions in the construction of pyrido[1,2-e]purine structures. As a continuation of our previous studies, 39−43 herein, we report a two-step, one-pot synthesis of pyrido[1,2-e]purine derivatives, and considering the physicochemical and pharmacokinetic predictions, their inhibitory activity against SARS-CoV-2 3CL pro is evaluated using molecular docking and molecular dynamics approaches.

In the beginning, 2,4-dichloro-5-amino-6-methylpyrimidine (2) was synthesized, according to our previous published procedure. 44 2,4-Dichloro-5-amino-6-methylpyrimidine (2) can react with pyridine used as both a solvent and a substrate under the reflux conditions to generate 2-chloro-4methylpyrido[1,2-e]purine (3) (Scheme 1).

Although numerous synthetic methods have been developed to construct the C−N bonds, there is still great demand for milder and cheaper methodologies. The S N Ar and C−H aminations are examples of general approaches implemented to form the C−N bonds of aromatic compounds. 45−47 Significantly, few reports are recorded to construct pyridopurine skeletons from unsubstituted pyridines in one step, 48, 49 and most similar structures have exploited at least two steps to obtain the desired products. Figure 2 depicts the singlecrystal X-ray diffraction analysis of the structure of 3. Crystallographic data for the structure reported here have been deposited with the Cambridge Crystallographic Data Center (CCDC 2109260).

On the basis of the results, the proposed mechanism has been suggested as a two-step, one-pot pathway, including the formation of a C(sp 2 )−N bond through the S N Ar amination of 2,4-dichloro-5-amino-6-methylpyrimidine (2) with pyridine followed by direct intramolecular C−H amination. First, the chlorine atom at the C-4 position of compound 2 is replaced with the pyridine ring nitrogen as the nucleophile to afford pyridinium product A. Then, the amino group of intermediate A attacks the C α atom of pyridinium, which acts as a highly electrophilic center to furnish intermediate B. Finally, removing the hydrogen in the presence of pyridine leads to the corresponding tricyclic structure of 3. 50, 51 The driving force of this phenomenon is the aromatization of the resulting fused tricyclic ring. A plausible reaction mechanism for the synthesis of pyrido[1,2-e]purine is depicted in Scheme 2.

In compound 3, the chlorine atom at the C-2 position can be directly replaced with various secondary amines in ethanol under reflux conditions through the S N Ar reaction to afford the corresponding products (4a−f) in 84−92% yields ( Table 1) .

The treatment of compound 3 with hydrazine hydrate in ethanol under reflux conditions gave 2-hydrazinyl-4methylpyrido[1,2-e]purine (5) in 68% yield. Also, the reaction of compound 5 with triethylorthoesters was carried out in various solvents such as ethanol, acetonitrile, chloroform, and acetic acid under reflux conditions to test the effects of the solvents. The results revealed that the reaction in acetic acid has a shorter reaction time and better yields. 52, 53 Then, compound 5 was cyclized with various triethylorthoesters in boiling acetic acid to give pyrido[1,2-e] [1, 2, 4] triazolo [3,4-b] purine derivatives 6a−c (Table 2) . Moreover, conducting the reaction of compound 5 with acetic acid as an example of aliphatic acid under reflux conditions did not lead to the formation of 3-alkylpyrido[1,2-e] [1, 2, 4] triazolo [3,4-b] purine even after 24 h.

Due to the regioselectivity of the cyclization reaction of compound 5 with triethylorthoesters, two-dimensional nuclear Overhauser effect spectroscopy (NOESY) is applied to determine which nitrogen atom on the pyrimidine core is cyclized with triethylorthoesters to form the corresponding triazole ring. The NOESY spectrum of compound 6c reveals that there is no correlation between the hydrogens of the methyl group on the pyrimidine core (δ = 3.27 ppm) and the hydrogens of the methylene moiety on the triazole ring (δ = 3.06 ppm). As a result, the true regioisomer is the structure of 6a−c ( Figure 3 ).

On the contrary, the treatment of compound 5 with carbon disulfide in pyridine under reflux conditions afforded 5methylpyrido [1,2-e] [1, 2, 4] triazolo [3,4-b] purine-1(2H)-thione (7) in 63% yield. Consequently, the reaction of different alkyl halides with compound 7 in DMF at room temperature produced the corresponding S-alkylated products 8a−g in 68− 80% yields (Table 3) . Furthermore, the two-dimensional NOESY spectrum for compound 8b as an example has been implemented to determine the regioselectivity of the cyclization reaction with carbon disulfide. The obtained result indicates no interaction between the hydrogens of the methylene moiety of SEt and the hydrogens of the methyl group on the pyrimidine ring (see the Supporting Information).

Computational Analyses. The roles of computational approaches in drug discovery and evaluation of therapeutic behaviors of novel synthesized compounds are considerable. Computational tools do not have the limitation of animal models in investigating the synthesized compounds as safe drug candidates. 54 Also, an in silico molecular docking technique is used to study the biological activities by evaluating the interactions of the synthesized compounds with the corresponding active site. During a drug discovery process, pharmacokinetic problems have direct relations with the consumed costs and times. To overcome these issues, in silico physicochemical and pharmacokinetic investigations are necessary. Table 4 shows the calculated parameters by the SwissADME server, 55 including the number of the hydrogen-bond donors, the number of the hydrogen-bond acceptors, molecular weights, molar refractivities, logarithms of octanol/water partition coefficients (logP), and topological polar surface areas (TPSAs). Also, the results of PAINS (pan-assay interference compounds) analysis, applied to determine the possibility of a molecule being toxic, are reported in Table 4 . Zero values of PAINS structural alerts signify a nontoxic nature for a typical compound. 56 The analyses are performed on the basis of the bioavailability applied during the procedure of drug design and discovery. Different rules have been provided to determine the bioavailability of the molecules.

However, Lipinski's rule of five is one of the best approaches for assessing appropriate membrane permeability, good oral bioavailability, and effective gastrointestinal absorption in the Scheme 2. A Plausible Mechanism for Pyrido [1,2-e] 58 As shown in Table 4 , the synthesized compounds do not show any violation of Lipinski's rule of five. Moreover, all compounds do not violate other rules, which illustrate their druglike potential. One of the most applicable computer-assisted drug design methods is molecular docking implemented to discover the preferred orientation of ligands into protein active sites. 59 The purpose of the docking study is to understand the proper orientation of the pyrido[1,2-e]purine derivatives in the active site of the main protease of COVID-19. Yang and co-workers 60 reported the three-dimensional (3D) crystal structure of the main protease of SARS-CoV-2, and its complex with an inhibitor N3 has been deposited as RCSB Protein Data Bank entry 6LU7. After the inhibitor and water molecules had been removed, missing atoms were corrected with Chimera and Notepad++. 61 The improved 3D crystal structure of the main protease was subjected to a molecular docking investigation and molecular simulations. The amino acids in the binding site of the enzyme were determined by Cavityplus. 62 The specified amino acids were applied to determine a grid box in molecular docking investigations by AutoDock-Vina software. All synthesized molecules were optimized using Gaussian 09 63 Table 5 . The outcomes of the molecular docking revealed that compounds 4a and 4c have the lowest binding energy. Figure 4 illustrates the binding modes of compounds 4a and 4c and the interactions of amino acids.

Molecular Dynamics Simulation. After extraction of the final mode from the docking analyses for compounds 4a and 4c, the final models were simulated by the AMBER99SB-ILDN force field in Gromacs2020. 64 The docked complex was solvated in a cubic box with simple point charge (SPC) waters, and Na + or Cl − counterions were added to the system to achieve overall electrostatic neutrality. Long-range electrostatic interactions were evaluated by the particle mesh Ewald (PME) method, in which the cutoff distance was considered 1.2 Å for the longrange van der Waals (VDW) energy. During the simulation, the temperature was readjusted by using V-rescale. First, energy minimization of the whole system was performed without any restraints for 50000 interaction steps using the steepest descent algorithm. Then, the systems were equilibrated via two separate simulation steps. In the first step, the systems were equilibrated via a constant number of particles, volume, and temperature. The NVT ensemble protocol was used for the 200 ps simulation at 310 K, in which the Verlet scheme was utilized to control the temperature. In the same simulation time, the second phase of equilibration was carried out using a constant number of particles, pressure, and temperature (the NPT ensemble protocol) at 300 K, in which the Berendsen barostat and Verlet scheme were used to control the pressure (constant to 1 bar) and temperature, respectively. The LINCS algorithm was applied to covalent-bond restrictions in the equilibration steps. The ultimate production step was performed for 50000 ps of MD simulation at a constant temperature of 300 K, in which trajectories were saved every 1 fs. Figure 5 depicts the root-mean-square deviations (RMSDs) of the protein for compounds 4a and 4c as the criteria for structural stability of the complexes during the simulation. RMSD values show the stability and conformational changes of the protein during the simulation. As shown in Figure 5 , RMSD plots show that the main protease reached equilibrium after simulation for 3 ns and are stable up to 35000 ps. However, from 35000 to 45000 ps, the RMSD values increase and again decrease until 50000 ps. Both compounds 4a and 4c inhibit the increase in the RMSD values between 35000 and 45000 ps. The average RMSD values of the enzyme for complexes 4a and 4c are 0.23 and 0.21 nm, respectively. One can conclude that 4a and 4c compounds have remarkable effects on the stability of the enzyme. Also, the complex form of 4c is more stable during the time of the simulation.

The radius of gyration (R g ) is a criterion for studying the compactness of the ligand−protein complex throughout the time of the molecular simulation. This factor evaluates the changes in distance between the center of mass of the protein atoms and its terminus. Generally, when the R g of the ligand− protein complex is lower, the compactness of the complex becomes higher, which leads to stronger interactions between the ligand and protein. Also, the R g value of a stable complex varies relatively less, which is a criterion of dynamic stability. Figure 6 depicts the variation of R g of the ligand−protein complex versus the time of the simulation. The maximum values of R g for 4a and 4c complexes occur at approximately 2.28 and 2.25 nm, respectively. However, after the maximum point, R g values decrease during the simulation for both complexes. R g values show that the binding of the compounds to the active site The Journal of Organic Chemistry pubs.acs.org/joc Article atom of the morpholine ring in 4a, the average H-bond number in the corresponding complex is higher than that of 4c.

To obtain a quantitative viewpoint, the study of free energy is helpful in the evaluation of the binding energy of the synthesized compounds in complexes with the enzyme. The molecular mechanics/Poisson−Boltzmann surface area (MMPBSA) method was used to determine the binding energies. 65, 66 Different components of binding energies for the complexes of 4a and 4c were calculated by the g_mmpbsa application. The binding energy is composed of the average of three energetic parameters such as the binding free energy in a vacuum, polar solvation energy, and nonpolar solvation energy. In this study, snapshots taken every 1 ps between 45 and 50 ns were collected, and the MMPBSA method was carried out to evaluate the binding energy.

The results of MMPBSA studies (Table 6) show that the binding energy for complex 4a is lower than that of complex 4c. The energy of the solvent accessible surface area (SASA) and polar solvation energy have no remarkable effects on the total binding energy. However, the effects of van der Waals and electrostatic energies are more significant. Finally, one can conclude that the inhibitory effects of compound 4a are more remarkable than those of compound 4c.

In summary, a diverse library of pyrido[1,2-e]purine derivatives were prepared by a new two-step, one-pot pathway, including the reaction between pyridine and 2,4-dichloro-5-amino-6methylpyrimidine under reflux conditions. The chlorine atom at the C-2 position can be directly replaced with various secondary amines as well as hydrazine hydrate, followed by cyclization with different triethylorthoesters and carbon disulfide to afford the desired products 4a−f, 6a−c, and 8a−g. Different rules have been provided to distinguish the bioavailability of the prepared molecules, illustrating that the synthesized compounds do not show any toxicity or violation of Lipinski's rule of five. Due to these results, molecular docking and molecular dynamics simulation have been implemented to evaluate the inhibitory activity of the synthesized products against the main protease of COVID-19. On the basis of the molecular docking results, compounds 4a and 4c exhibited the highest binding affinities (−7.5 and −7.7 kcal/mol, respectively), which represent the favorable orientation in the active site of the chymotrypsin-like cysteine protease (3CL pro ). After molecular docking, molecular dynamics simulations have been used to obtain more details about the ligand−protein complexes. The outcome of the MD simulation shows that the binding energy of complex 4a is lower than that of complex 4c, illustrating the inhibitory effects of compound 4a are more significant than those of compound 4c. Finally, the obtained results reveal that they can be used as The Journal of Organic Chemistry pubs.acs.org/joc Article suitable promising inhibitors of the main protease of SARS-CoV-2.

Melting points were recorded using an Electrothermal-type 9200 melting point apparatus. The IR spectra were recorded using an Avatar 370 FT-IR Thermo Nicolet instrument, and only outstanding absorptions were listed. The 1 H NMR (300 MHz) and 13 C NMR (75 MHz) spectra were recorded using a Bruker Avance DRX-300 Fourier transform spectrometer. Chemical shifts were reported in parts per million downfield from tetramethylsilane (TMS) as an internal standard. The mass spectra were scanned using a Varian Mat CH-7 instrument at 70 eV. Synthesis of 2-Chloro-4-methylpyrido[1,2-e]purine (3). 2,4-Dichloro-5-amino-6-methylpyrimidine (2) (1.78 g, 10 mmol) in pyridine (8 mL) was heated under reflux for 24 h. The progress of the reaction was monitored by TLC using a chloroform/methanol solvent (20:1). After the completion of the reaction, the solvent was evaporated under reduced pressure, and then water (10 mL) was added. The organic layer was extracted with CHCl 3 (3 × 15 mL) and dried over Na 2 SO 4 . The organic layer was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (3:2 ethyl acetate/n-hexane eluent) to give the pure product: yellow solid (0.09 g, 44%); mp 195−198°C; 1 (3) (0.65 g, 3 mmol) in ethanol (10 mL) was added hydrazine hydrate (3 mL), and the mixture was refluxed for 4 h. The progress of the reaction was monitored by TLC using a 10:1 chloroform/methanol eluent. After the completion of the reaction, the yellow precipitate was filtered off and washed with water (5 mL) and cold ethanol (5 mL). The residue was recrystallized from ethanol to afford the desired product: pale yellow solid (0.14 g, 68%); mp 236− 238°C; 1 General Procedure for the Synthesis of 6a−c. A mixture of 2hydrazinyl-4-methylpyrido[1,2-e]purine (5) (0.21 g, 1 mmol, 1 equiv) and triethylorthoformate/acetate/propionate (2 mmol, 2 equiv) in glacial acetic acid (1 mL) was heated under reflux conditions for 5 h. After the completion of the reaction was monitored by TLC using a 20:1 chloroform/methanol eluent, the solvent was evaporated, and water (5 mL) was added. The pH was adjusted to ∼7 with a saturated NaHCO 3 solution, and the resulting precipitate was filtered off and recrystallized from ethanol. 

27 (s, 3H), 3.06 (q, 2H

13 C{ 1 H} NMR (CDCl 3 , 75 MHz)

H 5 ), 197 (M + − C 3 H 5 N). Anal. Calcd for C 13 H 12 N 6 : C

To a suspension of 2-hydrazinyl-4-methylpyrido[1,2-e]purine (5) (0.21 g, 1 mmol) in pyridine (3 mL) was added carbon disulfide (1 mL). The mixture was refluxed in an oil bath for 4 h. The reaction progress was monitored by TLC using a 10:1 chloroform/methanol eluent

MS (m/z) 256 (M + ), 223 (M + − SH), 197 (M + − CHNS). Anal

General Procedure for the Synthesis of 8a−g. To a solution of 5-methylpyrido

After the completion of the reaction monitored by TLC using a 30:1 chloroform/methanol solvent, cold water (5 mL) was added. The mixture was neutralized with 5% HCl, and the precipitate was filtered, washed with water (5 mL), and recrystallized from ethanol. 5-Methyl-1-(methylthio)

MHz) δ 8.59 (d, 1H, J = 9 Hz), 7.44−7.57 (m, 2H)

17 (s, 3H), 2.72 (s, 3H); 13 C{ 1 H} NMR (CDCl 3 , 75 MHz)

IR (KBr discs, cm −1 ) 3082, 2926

MS (m/z) 270 (M + ), 223 (M + − SMe), 197 (M + − C 2 H 3 NS). Anal

H, 3.64; N, 30

MHz) δ 8.66 (d, 1H, J = 6 Hz), 7.51−7.63 (m, 2H), 6.91 (t

37 (q, 2H, J = 6 Hz), 3.23 (s, 3H), 1.52 (t, 3H

1305; MS (m/z) 284 (M + ), 223 (M + − C 2 H 5 S), 197 (M + − C 3 H 5 NS). Anal

MHz) δ 8.63 (d, 1H

08 (t, 3H, J = 6 Hz); 13 C{ 1 H} NMR (CDCl 3 , 75 MHz) δ 168.9

37 (t, 2H, J = 6 Hz), 3.23 (s, 3H), 1.79−1.89 (m, 2H), 1.47−1.59 (m, 2H), 0.97 (t, 3H

S, 10.17. 1-(Benzylthio)-5-methylpyrido

02 (t, 1H, J = 6 Hz), 4.63 (s, 2H), 3.29 (s, 3H); 13 C{ 1 H} NMR (CDCl 3 , 75 MHz)

Anal. Calcd for C 18 H 14 N 6 S: C, 62

Green solid (0.28 g, 74%)

Yellow solid (0.26 g, 68%); mp 278−280°C; 1 H NMR (CDCl 3 , 300 MHz) δ 8.68 (d, 1H, J = 9 Hz), 8.16 (d, 2H, J = 9 Hz), 7.72 (d, 2H

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