Synthesis, Antimicrobial Studies, and Molecular Docking Simulation of Novel Pyran, Pyrazole, and Pyranopyrazole Derivatives

Abdelatty, Mahmoud M.; Farag, Zeinab R.; El Hassane, Anouar; Moustapha, Moustapha E.; Makhlouf, Abdelmoneim A.; Yossef, Ayman M.

doi:https://doi.org/10.1155/2023/6623445

Journal of Chemistry

On this page

Abstract Introduction Results and Discussion Materials and Methods Conclusion Data Availability Conflicts of Interest Acknowledgments Supplementary Materials References Copyright Related Articles

Research Article | Open Access

Volume 2023 | Article ID 6623445 | https://doi.org/10.1155/2023/6623445

Synthesis, Antimicrobial Studies, and Molecular Docking Simulation of Novel Pyran, Pyrazole, and Pyranopyrazole Derivatives

Mahmoud M. Abdelatty,¹Zeinab R. Farag,¹Anouar El Hassane,²Moustapha E. Moustapha,²Abdelmoneim A. Makhlouf,¹and Ayman M. Yossef¹

Academic Editor: Mahmood Ahmed

Received03 Jul 2023

Revised13 Nov 2023

Accepted28 Nov 2023

Published07 Dec 2023

Abstract

A group of compounds containing pyran, pyrazole, and pyranopyrazole were synthesized (2–4) using a facile and convenient protocol. The structure of the synthesized compounds was elucidated by spectroscopic and elemental analysis. In vitro antimicrobial evaluation was also performed for all synthesized derivatives against human pathogenic bacterial strains such as Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus subtilis using chloramphenicol as a reference. It was depicted that compounds 3d, 4b displayed a high degree of inhibition against Bacillus subtilis and Staphylococcus aureus. Compounds 2d, 4f and 2d, 4e, 4f, and 4e had high inhibition effects against Escherichia coli and Pseudomonas aeruginosa, respectively. The molecular docking study was performed against S. aureus bacteria to rationalize the binding affinities and the feasible modes of interaction with the active site of tyrosyl-tRNA synthetase. It was found that the synthesized compounds were well fit into the binding site of tyrosyl-tRNA synthetase. The obtained results were in good accordance with the experimental data. The data obtained were promising candidates for further development of novel heterocyclic scaffolds as therapeutics with high efficacy biomedical precursors.

1. Introduction

Infectious diseases remain one of the main causes of death in the world today [1, 2]. Nowadays, one of the major challenges that researchers face is developing new compounds to control a vast majority of diseases. Heterocyclic chemistry plays a leading role in the construction of antimicrobial, anti-inflammatory, and analgesic therapeutic agents. Pyrazole nucleus is one of the major heterocycles, which exhibits a diverse array of biological properties due to its similarity to different basic building blocks of the body. The first pyrazole pharmaceutical discovered phenazone was proven to possess antipyretic properties. This gave impetus for diversification of pyrazole derivatives with considerable medicinal interests and biological and industrial applications (Figure 1) [3, 4]. There are several FDA-approved drugs containing the pyrazole scaffold [5, 6]. Recently, new synthetic protocols have been developed to synthesize structurally diverse pyrazole derivatives [7, 8].

On the other hand, pyran derivatives have been extensively employed as medicine intermediates due to their useful biological and pharmacological potential such as diuretic, antibacterial, anticoagulant, spasmolytic, anticancer, hypnotic, and insecticide [9–11]. Furthermore, pyranopyrazoles are privileged heterocyclic scaffolds, which exhibit various important biological properties. Many pyranopyrazoles derivatives have been reported [12–14] for their diverse pharmacological activities [14–16] such as antitumor [17], anticancer [18], antioxidant [19], and anti-inflammatory [20]. They also serve as potential inhibitors of human Chk1 kinase [21]. The innumerable applications of pyran, pyrazole, and pyranopyrazole analogs have stimulated researchers to develop new synthetic routes to prepare structurally diverse derivatives [8, 12, 15, 22, 23].

The approach of the present study combines the formation of substituted pyran and pyrazole rings with a variety of functional groups and a wide substrate scope. Meanwhile, the utilization of the synthesized derivatives for the construction of a series of new pyranopyrazole assemblies was performed, employing simple synthesis methods as well as the common one-pot multicomponent methodology [24].

2. Results and Discussion

2.1. Synthesis and Structure Elucidation

Compounds 3-oxo-N¹,N⁵-diarylpentanediamides (1a, b) [25] were synthesized, characterized, and utilized as a key intermediate to achieve the required derivatives cited in the present study (Section 3). Thus, the reaction of compounds (1a, b) with hydrazine hydrate or phenyl hydrazine afforded pyrazole derivatives (2a–d). These reactions were carried out under reflux conditions using absolute ethanol and glacial acetic acid as solvents (Scheme 1). The structure of the produced pyrazole derivatives was proved using elemental data and spectroscopic studies (Section 3).

In addition, the reaction of compounds 1a, b with 2-(4-chlorobenzylidene) malononitrile using piperidine afforded new pyran compounds 3a, b, while the replacement of piperidine by ammonium acetate or aniline in an analogous manner successfully produced pyridine derivatives 3c, d (Scheme 2). The microanalysis and spectroscopic data confirmed the structure of compounds 3a–d. The IR spectra of 3a–d revealed the disappearance of the characteristic ketonic carbonyl group, which was observed in the IR spectrum of 1a, b, with the appearance of new NH₂ absorption bands at 3210–3293 cm⁻¹ and sharp -CN absorption bands at 2202–2213 cm⁻¹. Furthermore, the ¹HNMR spectrum of compound 3a showed the existence of a singlet signal at δ_ppm 10.31 (1H, NH D₂O exchangeable), singlet at δ 10.13 (1H, NH D₂O exchangeable) along with a multiplet at δ 7.63–7.00 (14H, Ar-) due to the aromatic protons, singlet signal at δ 6.93 (2H, NH₂ D₂O exchangeable), singlet at δ 4.70 (1H, -CH), and doublet of doublet at δ 3.71–3.61 (J = 15.9, 15.9 Hz, 2H, -CH₂), which may be due to H-transfer and the formation of diastereomeric pairs [26].

Pyrazoles 2a–d were used as precursors to synthesize the fused pyranopyrazole derivatives 4a–f (Scheme 3). A green one-pot multicomponent protocol was adopted for the synthesis of pyranopyrazole derivatives 4a–d via the reaction of 2a–d with malononitrile and p-chlorobenzaldehyde in water containing a catalytic amount of glycine, whereas 4e, f were assembled by refluxing 2a, b with ethyl cyanoacetate in ethanol as a solvent. The structure of the isolated compounds was established on the basis of spectroscopic and elemental analyses. The IR spectrum of compound 4a as a representative example revealed the presence of a characteristic -CN absorption band at 2183 cm⁻¹, in addition to strong absorption bands at 3324, beside 3266 cm⁻¹ (NH₂), 3131 cm⁻¹ (NH), and 1646 cm⁻¹ (CONH). Its ¹HNMR spectrum showed the existence of a singlet signal at δ_ppm 12.33 (1H, NH D₂O exchangeable), a singlet at δ 9.85 (1H, NH, D₂O exchangeable), a multiplet at δ 7.46–7.05 (9H, Ar-) related to the aromatic protons, a singlet signal at δ 6.95 (2H, NH₂ D₂O exchangeable), singlet at δ 4.65 (1H, CH), and doublet of doublet at δ 3.45–3.20 (J = 16.7 Hz, 16.6 Hz, 2H, -CH₂) [26].

Compound 2a was further manipulated for the synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine-3-yl)-N-phenylacetamide (4g) through the reaction with 2-(4-chlorobenzylidene)malononitrile and ammonium acetate in ethanol (Scheme 3). Moreover, the treatment of pyranopyrazole 4b with p-anisidine in DMF under reflux afforded new pyridopyrazole compound (4h) (Scheme 4).

The structure of compound 4h was confirmed by elemental analysis and spectroscopic data (Section 3).

2.2. Antimicrobial Activity

The mentioned compounds were assessed against human pathogenic strains, and the results are represented in Table 1.

New derivatives of pyrazole, pyran, and pyranopyrazole were prepared and selected to screen their in vitro antimicrobial activity against Gram-positive bacteria such as Bacillus subtilis and Staphylococcus aureus and Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa. The organisms were assessed against the activity of 50 mg/mL solutions of each compound and using the diameter of the inhibition zone (IZ) in mm as the standard for the antimicrobial activity. The bactericide chloramphenicol was utilized as a reference to evaluate the efficacy of the tested compounds under the same conditions. The results in Table 1 depicted that compounds 3d, 4b displayed a high degree of inhibition against Bacillus subtilis and Staphylococcus aureus. Compounds 2d, 4f and 2d, 4e had high inhibition effects against Escherichia coli and Pseudomonas aeruginosa, respectively. Compounds 2a–d, 3a, b, d, 4a, c, d, e, f, g, h and 2a–d, 3a–c, 4a, c, d, e, f, g, h also exhibited moderate inhibition effects against Bacillus subtilis and Staphylococcus aureus, respectively. Compounds 2a–c, 3a–d, 4a–e, g, h and 2c, 3a–d, 4b–d, f–h showed mild inhibition effects against Escherichia coli and Pseudomonas aeruginosa, respectively. Compounds 3a–b, 4a were reflecting the lack of growth inhibition against Pseudomonas aeruginosa.

2.3. Molecular Docking Results

The molecular docking study indicated that these compounds may have moderate to high activity against S. aureus bacteria (Table 2). This activity may be strongly related to the interactions of the amino acids of S. aureus tyrosyl-tRNA synthetase in the binding site with these compounds. To explain the observed antibacterial activities of the prepared compounds, a molecular docking study was performed to determine their binding affinities into the binding site by calculating their estimated free binding energies, the number of the intermolecular hydrogen bonds along with the number, and the type of interactions that may be formed with the amino acids of tyrosyl-tRNA synthetase into its binding site (Table 2).

The synthesized compounds fit well into the binding site of tyrosyl-tRNA synthetase. The resulting complexes were found stable and showed negative binding energies in the range of −5 to −11 kcal/mol (Table 2). The negative binding energies indicated that the inhibition of tyrosyl-tRNA synthetase by these compounds was thermodynamically favorable. The synthesized compounds formed subsets. In the first subset, each compound was derived from another by the chlorine substation of the aromatic ring. The first subset was 2b/2d, 2a/2c, 4b/4d, 3a/3b, and 4a/4c. In the second subset, the amine was substituted by the phenyl/methoxyphenyl moieties. The second subset was 3c/3d, 4e/4f, and 4g/4h. For the first subset, it was observed that the chlorine substitution increased the antibacterial activity. For instance, the difference between 4a and 4c is the presence of chlorine substitution (Figure 2). The substituted chlorine atom interacted with ASP A195, which increased the stability of 4c-tyrosyl-tRNA synthetase compared with that of 4a-tyrosyl-tRNA. Thus, the increased antimicrobial activity of 4c compared to that of 4a is represented in Figure 2. For the second subsets, the amine substitution increased the antibacterial activity and led to the stability of the formed complex into the binding site of tyrosyl-tRNA synthetase. For instance, 3d incorporated an aromatic group on imine functionality compared with 3c (Figure 2). The aromatic ring interacted with LEU A70 and THR A75 through π-alkyl and π-donor hydrogen bonds, which increased the stability of the 3d-tyrosyl-tRNA synthetase complex compared to that of the 3c-tyrosyl-tRNA synthetase complex. Furthermore, in the 3d-tyrosyl-tRNA synthetase complex, the number of intermolecular interactions between 3d and the active amino acids of tyrosyl-tRNA synthetase increased significantly, which may be due to the change in its geometry (Figure 2).

3. Materials and Methods

The melting points were determined with an electrothermal melting point device and were uncorrected. Pye-Unicam IR spectrophotometer SP 2000 was used to record the IR (KBr) spectra (Faculty of Science, Fayoum University). At the Regional Center for Mycology and Biotechnology (RCMB), Al-Azhar University, Nasr City, Cairo, mass spectroscopy was performed on a Direct Inlet part to mass analyzer in Thermo Scientific GCMS model ISQ. The purity of the compounds was verified using mass spectrometry, which was also utilized to investigate the distinctive fragmentation and the anticipated molecular weight. Mass spectroscopy was performed in electron impact mode. Nuclear magnetic resonance (NMR) spectra were measured in DMSO-d₆ (TMS, ¹H δ = 0; DMSO-d₆, ¹H δ = 2.50, ¹³C δ = 39.52) on a BRUKER AVANCE III (¹H at 400-MHz, ¹³C at 100 MHz) magnetic resonance spectrometer at NMR unit, Faculty of Pharmacy, Beni-Suef University, Egypt. Chemical shifts (δ) and coupling constants (J) were recorded in parts per million (ppm) and Hertz (Hz), respectively.

The charts of ¹HNMR, IR, etc., from which we analyzed the synthesized compounds are available as a supplementary data file. The values were presented in the manuscript, and the charts were added for comparing the numbers and data in the manuscript with the analysis charts.

3.1. Synthesis

3.1.1. Synthesis of 3-Oxo-N¹,N⁵-diphenylpentanediamide (1a)

Diethyl-3-oxopentanedioate (20.2 mL, 0.1 mol) was refluxed with aniline (9.12 mL, 0.1 mol) in 30 mL pyridine for 4 h. The reaction mixture was cooled and poured over ice/HCl solution. The solid precipitate was filtered out, dried, and recrystallized from ethanol to give 1a [25].

Compound 1a: off-white crystals; mp 138–140°C (Lit. [25] mp = 155°C); yield (23.68 mg, 80%).

3.1.2. Synthesis of N¹,N⁵-bis(2-chlorophenyl)-3-oxopentanediamide (1b)

Diethyl-3-oxopentanedioate (18.15 mL, 0.1 mol) was refluxed with 2-chloroaniline (10.54 mL, 0.1 mol) in 30 mL pyridine for 4 h. The reaction mixture was cooled and poured over ice/HCl solution. The solid precipitate was filtered out, dried, and recrystallized from ethanol to give 1b.

Compound 1b: white crystals; mp 194–196°C; yield (27.36 mg, 75%); IR (KBr) ν/cm⁻¹: 3282 (2 NH), 1731 (C=O), 1658 (CONH); ¹HNMR (DMSO-d₆): δ 9.94 (s, 2H, 2 NH D₂O exchangeable), 7.39–6.88 (m, 8H, Ar-), 3.51 (s, 4H, 2CH₂); ¹³C-NMR (DMSO-d₆): δ 197.40, 169.12, 136.70, 129.55, 128.54, 127.21, 126.18, 121.18, 48.89. Ms m/z (%): 365 (M⁺, 24.20), 128 (55.50), 77 (100). Anal. Calcd. For C₁₇H₁₆N₂O₃: (C, 55.91; H, 3.86; Cl, 19.41; N, 7.67%). Found (C, 55.70; H, 3.56; Cl, 19.12; N, 7.45%).

3.1.3. Synthesis of 2-(5-hydroxy-1H-pyrazol-3-yl)-N-phenylacetamide (2a)

Hydrazine hydrate (0.5 mL, 0.01 mol) was added to a solution of 3-oxo-N¹,N⁵-phenylpentanediamide (1a) (2.96 gm, 0.01 mol) in 20 mL ethanol, and the mixture was refluxed for 2 h. The solid product was filtered off, washed with cold ethanol, and recrystallized from ethanol to give 2a [25]. Compound 2a: white crystals; mp 240–242°C (Lit. [25] mp = 246°C); yield (2 gm, 95%).

3.1.4. Synthesis of 2-(5-hydroxy-1-phenyl-1H-pyrazol-3-yl)-N-phenylacetamide (2b)

A solution of 3-oxo-N¹,N⁵-diphenylpentanediamide (1a) (2.96 gm, 0.01 mol) in 20 mL of glacial acetic acid was refluxed with phenylhydrazine (0.98 mL, 0.01 mol) for 3 h. The mixture was diluted with water and left overnight; the obtained solid was separated by filtration, washed with cold ethanol, and crystallized from ethanol to yield 2b [25].

3.1.5. Another Method for the Synthesis of Compound 2b

Compound 3-Oxo-N¹,N⁵-diphenylpentanediamide (1a) (2.96 gm, 0.01 mol) and phenylhydrazine (0.98 mL, 0.01 mol) were taken in an agate mortar, and 2 mL of acetic acid was added. The mixture was vigorously ground by using a pestle until a pasty mass was obtained (30 min). The reaction mixture was triturated with ethanol and recrystallized from ethanol to yield 2b.

Compound 2b: orange crystals; mp 184–186°C (Lit. [25] mp = 192°C); yield (2.63 gm, 90%).

3.1.6. Synthesis of N-(2-chlorophenyl)-2-(5-hydroxy-1H-pyrazol-3-yl)acetamide (2c)

Hydrazine hydrate (0.5 mL, 0.01 mol) was added to a solution of N¹,N⁵-bis(2-chlorophenyl)-3-oxopentanediamide (1b) (3.65 gm, 0.01 mol) in 20 mL ethanol and refluxed for 2 h. The resulting solid was filtered off, washed with cold ethanol, and recrystallized from ethanol to give 2c. Compound 2c: white crystals; mp 270–272°C; yield (2.08 gm, 83%); IR (KBr) ν/cm⁻¹: 3247 (NH), 3104 (NH), 1658 (2CO); ¹HNMR (DMSO-d₆): δ 11.40 (s, 1H, OH D₂O exchangeable), 10.08 (s, 1H, NH D₂O exchangeable), 9.45 (s, 1H, NH D₂O exchangeable), 7.59–7.01 (m, 4H, Ar-), 5.38 (s, 1H, CH), 3.54 (s, 2H, CH₂). Anal. Calcd. For C₁₁H₁₀ClN₃O₂: (C, 52.50; H, 4.01; Cl, 14.09; N, 16.70%). Found (C, 52.36; H, 3.87; Cl, 13.90; N, 16.45%).

3.1.7. Synthesis of N-(2-chlorophenyl)-2-(5-hydroxy-1-phenyl-1H-pyrazol-3-yl)acetamide (2d)

A solution of N¹,N⁵-bis(2-chlorophenyl)-3-oxopentanediamide (1b) (3.65 gm, 0.01 mol) in 20 mL glacial acetic acid was refluxed with phenylhydrazine (0.98 mL, 0.01 mol) for 3 h. The mixture was diluted with water and left overnight; the obtained solid was separated by filtration, washed with cold ethanol, and crystallized from ethanol to yield 2d.

Compound 2d: yellow crystals; mp 218–220°C; yield (2.87 gm, 88%); IR (KBr) ν/cm⁻¹: 3243 (NH), 1658 (2CO); ¹HNMR (DMSO-d₆): δ 11.64 (s, 1H, OH D₂O exchangeable), 10.29 (s, 1H, NH D₂O exchangeable), 7.76 - 7.24 (m, 9H, Ar-), 5.55 (s, 1H, CH), 3.57 (s, 2H, CH₂); ¹³C-NMR (DMSO-d₆): δ 170.76, 168.68, 149.90, 138.55, 133.97, 128.54, 127.69, 127.21, 126.57, 126.18, 125.61, 121.18, 120.25, 46.18, 43.18. Anal. Calcd. For C₁₇H₁₄ClN₃O₂: (C, 62.30; H, 4.31; Cl, 10.82; N, 12.82%). Found (C, 62.15; H, 4.20; Cl, 10.56; N, 12.62%).

3.1.8. Synthesis of 6-Amino-4-(4-chlorophenyl)-5-cyano-2-(2-oxo-2-(phenylamino)ethyl)-N-phenyl-4H-pyran-3-carboxamide (3a)

Compound 3-Oxo-N¹,N⁵-diphenylpentanediamide (1a) (2.96 gm, 0.01 mol) was dissolved in 50 mL of absolute ethanol; later, 2-(4-chlorobenzylidene) malononitrile (1.9 gm, 0.01 mol) was added with a few droplets of piperidine. The reaction mixture was refluxed for 1 h. The obtained solid was precipitated, filtered out after cooling, washed with cold ethanol, dried, and recrystallized from acetic acid to yield 3a.

Compound 3a: white crystals; mp 248–250°C; yield (4.11 gm, 85%); IR (KBr) ν/cm⁻¹: 3471 (NH₂), 3293 (NH), 3189 (NH), 2202 (CN), 1693 (CO); ¹HNMR (DMSO-d₆): δ 10.31 (s, 1H, NH D₂O exchangeable), 10.13 (s, 1H, NH D₂O exchangeable), 7.63–7.00 (m, 14H, Ar-), 6.93 (s, 2H, NH_2, D₂O exchangeable), 4.70 (s, 1H, -CH), 3.71–3.61 (dd, J = 15.9, 15.9 Hz, 2H, -CH₂); ¹³C-NMR (DMSO-d₆): δ 169.12, 165.13, 157.90, 155.47, 142.39, 139.91, 138.55, 131.14, 129.55, 128.54, 128.07, 127.21, 123.33, 122.47, 120.48, 120.25, 118.95, 103.89, 53.55, 46.05, 43.18. Ms m/z (%): 484 (M⁺, 20.42), 365 (20.47), 81 (100). Anal. Calcd. For C₂₇H₂₁ClN₄O₃: (C, 66.87; H, 4.37; Cl, 7.31; N, 11.55). Found (C, 66.46; H, 4.23; Cl, 7.11; N, 11.23).

3.1.9. Synthesis of 6-Amino-N-(2-chlorophenyl)-4-(4-chlorophenyl)-2-(2-((2-chlorophenyl)amino)-2-oxoethyl)-5-cyano-4H-pyran-3-carboxamide (3b)

N¹,N⁵-bis(2-chlorophenyl)-3-oxopentanediamide (1b) (3.65 gm, 0.01 mol) was dissolved in 50 mL of absolute ethanol; later, 2-(4-chlorobenzylidene) malononitrile (1.9 gm, 0.01 mol) was added with a few droplets of piperidine. The reaction mixture was refluxed for 1 h; the solid precipitate was filtered out after cooling, washed with cold ethanol, dried, and recrystallized from acetic acid to yield 3b.

Compound 3b: brown crystals; mp 120–122°C; yield (4.42 gm, 80%); IR (KBr) ν/cm⁻¹: 3266 (NH₂), 3193 (NH), 3124 (NH), 2183 (CN), 1658 (CO); ¹HNMR (DMSO-d₆): δ 10.08 (s, 1H, NH D₂O exchangeable), 9.09 (s, 1H, NH D₂O exchangeable), 7.63–7.00 (m, 12H, Ar-), 6.93 (s, 2H, NH₂ D₂O exchangeable), 4.91 (s, 1H, CH), 3.71–3.61 (dd, J = 15.9 Hz, 2H, CH₂). Anal. Calcd. For C₂₇H₁₉Cl₃N₄O₃: (C, 58.56; H, 3.46; Cl, 19.20; N, 10.12). Found (C, 58.32; H, 3.24; Cl, 19.01; N, 9.91).

3.1.10. Synthesis of 6-Amino-4-(4-chlorophenyl)-5-cyano-2-(2-oxo-2-(phenylamino)ethyl)-N-phenyl-1,4-dihydropyridine-3-carboxamide (3c)

To an alcoholic solution of 3-oxo-N¹,N⁵-diphenylpentanediamide (1a) (2.96 gm, 0.01 mol) and 2-(4-chlorobenzylidene) malononitrile (1.9 gm, 0.01 mol), ammonium acetate (2.31 gm, 0.03 mol) was added. The reaction mixture was refluxed for 6 h, cooled, and added to ice/HCl. The precipitate product was filtered off, washed with water, dried, and recrystallized with an appropriate solvent.

Compound 3c: orange crystals; mp 184–186°C (ethanol); yield (2.94 gm, 61%); IR (KBr) ν/cm⁻¹: 3259 (NH₂), 3197 (NH), 3135 (NH), 2198 (CN), 1662 (CO); ¹HNMR (DMSO-d₆): δ 10.31 (s, 1H, NH D₂O exchangeable), 10.13 (s, 1H, NH D₂O exchangeable), 9.46 (s, 1H, NH D₂O exchangeable), 7.63–7.00 (m, 14H, Ar-), 6.56 (s, 2H, NH₂ D₂O exchangeable), 4.70 (s, 1H, CH), 3.71–3.61 (dd, J = 15.9 Hz, 2H, CH₂); ¹³C-NMR (DMSO-d₆): δ 168.68, 165.36, 153.81, 148.52, 141.33, 139.58, 137.81, 131.14, 129.55, 128.07, 127.21, 124.35, 123.33, 120.25, 119.41, 118.95, 96.51, 57.20, 36.09, 33.92. Anal. Calcd. For C₂₇H₂₂ClN₅O₂: (C, 67.01; H, 4.58; Cl, 7.33; N, 14.47). Found (C, 66.86; H, 4.34; Cl, 7.09; N, 14.12).

3.1.11. Synthesis of 6-Amino-4-(4-chlorophenyl)-5-cyano-2-(2-oxo-2-(phenylamino)ethyl)-N,1-diphenyl-1,4-dihydropyridine-3-carboxamide (3d)

To an alcoholic solution of 3-oxo-N¹,N⁵-diphenylpentanediamide (1a) (2.96 gm, 0.01 mol) and 2-(4-chlorobenzylidene) malononitrile (1.9 gm, 0.01 mol), aniline (3.72 mL, 0.01 mol) was added. The reaction mixture was refluxed for 6 h, cooled, and added to ice/HCl. The precipitate product was filtered off, washed with water, dried, and recrystallized with an appropriate solvent.

Compound 3d: yellow crystals; mp 260–262°C (acetic acid); yield (2.96 gm, 53%); IR (KBr) ν/cm⁻¹: 3309 (NH₂), 3193 (NH), 2213 (CN), 1658 (CO); ¹HNMR (DMSO-d₆): δ 10.47 (s, 1H, NH D₂O exchangeable), 9.57 (s, 1H, NH D₂O exchangeable), 7.81–7.04 (m, 19H, Ar-), 6.44 (s, 2H, NH₂ D₂O exchangeable), 5.36 (s, 1H, CH), 4.09–3.90 (dd, J = 15.6 Hz, 2H, CH₂). Anal. Calcd. For C₃₃H₂₆ClN₅O₂: (C, 70.77; H, 4.68; Cl, 6.33; N, 12.51). Found (C, 70.56; H, 4.46; Cl, 6.12; N, 12.23).

3.1.12. Synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-2,4-dihydropyrano[2,3-c]pyrazol-3-yl)-N-phenylacetamide (4a)

Compound 2-(5-oxo-4,5-dihydro-1H-pyrazol-3-yl)-N-phenylacetamide (2a) (2.17 gm, 0.01 mol) was added to a mixture of malononitrile (0.66 gm, 0.01 mol), 4-chlorobenzaldehyde (1.41 gm, 0.01 mol), and (2 mol%) glycine in 25 mL of water [27]. The reaction mixture was stirred vigorously for 30 min at 25°C. The solid obtained was separated by filtration, washed with cold ethanol, dried, and recrystallized with a suitable solvent.

Compound 4a: white crystals; mp 240–242°C (DMF/water); yield (3.64 gm, 90%); IR (KBr) ν/cm⁻¹: 3324 (NH₂), 3266 (NH), 3131 (NH), 2183 (CN), 1646 (CO); ¹HNMR (DMSO-d₆): δ 12.33 (s, 1H, NH D₂O exchangeable), 9.85 (s, 1H, NH D₂O exchangeable), 7.46–7.05 (m, 9H, Ar-), 6.95 (s, 2H, NH₂D₂O exchangeable), 4.65 (s, 1H, -CH), 3.45 - 3.20 (dd, J = 16.7 Hz, 16.6 Hz, 2H, -CH₂); ¹³C-NMR (DMSO-d₆): δ 172.40, 162.63, 151.87, 139.58, 138.55, 134.84, 131.14, 128.54, 127.69, 127.21, 123.80, 121.18, 120.25, 105.32, 62.66, 36.48, 33.92. Ms m/z (%): 405 (M⁺, 22.42), 285 (19.47), 195 (100). Anal. Calcd. For C₂₁H₁₆ClN₅O₂: (C, 62.15; H, 3.97; Cl, 8.73; N, 17.26). Found (C, 61.79; H, 3.43; Cl, 8.41; N, 16.88).

3.1.13. Synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-2-phenyl-2,4-dihydropyrano[2,3-c]pyrazol-3-yl)-N-phenylacetamide (4b)

Compound 2-(5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-N-phenylacetamide (2b) (2.93 gm, 0.01 mol) was added to a mixture of malononitrile (0.66 gm, 0.01 mol), 4-chlorobenzaldehyde (1.41 gm, 0.01 mol), and (2 mol%) glycine in 25 mL water. The reaction mixture was stirred vigorously for 30 min at 25°C. The obtained solid was separated by filtration, washed with cold ethanol, dried, and recrystallized with a suitable solvent.

Compound 4b: yellow crystals; mp 182–184°C (ethanol); yield (4.09 gm, 85%); IR (KBr) ν/cm⁻¹: 3328 (NH₂), 3193 (NH), 2194 (CN), 1654 (CO); ¹HNMR (DMSO-d₆): δ 9.93 (s, 1H, NH D₂O exchangeable), 7.84–7.01 (m, 14H, Ar-), 6.58 (s, 2H, NH₂ D₂O exchangeable), 4.76 (s, 1H, -CH), 3.67–3.56 (dd, J = 16.5 Hz, 13.2 Hz, 2H, -CH₂); ¹³C-NMR (DMSO-d₆): δ 171.43, 162.31, 151.87, 139.91, 138.55, 138.23, 136.70, 132.01, 129.55, 128.54, 128.07, 127.21, 126.18, 122.47, 121.81, 121.18, 120.25, 108.72, 61.76, 38.14, 35.02. Anal. Calcd. For C₂₇H₂₀ClN₅O₂: (C, 67.29; H, 4.18; Cl, 7.36; N, 14.53). Found (C, 66.86; H, 3.92; Cl, 7.12; N, 14.18).

3.1.14. Synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-2,4-dihydropyrano[2,3-c]pyrazol-3-yl)-N-(2-chlorophenyl)acetamide (4c)

A mixture of N-(2-chlorophenyl)-2-(5-oxo-4,5-dihydro-1H-pyrazol-3-yl)acetamide (2c) (2.52 gm, 0.01 mol), malononitrile (0.66 gm, 0.01 mol), 4-chlorobenzaldehyde (1.41 gm, 0.01 mol), and (2 mol%) glycine in 25 mL water was vigorously stirred for 30 min at 25°C. The produced solid was filtered out, washed with cold ethanol, dried, and purified by crystallization.

Compound 4c: orange crystals; mp 186–188°C (DMF/water); yield (3.62 gm, 82%); IR (KBr) ν/cm⁻¹: 3459 (NH₂), 3320 (NH), 3205 (NH), 2183 (CN), 1677 (CO); ¹HNMR (DMSO-d₆) δ 12.23 (s, 1H, NH D₂O exchangeable), 9.75 (s, 1H, NH D₂O exchangeable), 7.36–6.95 (m, 8H, Ar-), 6.72 (s, 2H, NH₂ D₂O exchangeable), 4.55 (s, 1H, CH), 3.35–3.10 (dd, J = 16.7 Hz, 16.6 Hz, 2H, CH₂); ¹³C-NMR (DMSO-d₆): δ 170.76, 161.31, 152.44, 139.58, 136.01, 134.84, 131.14, 128.54, 128.07, 127.21, 127.12, 126.18, 125.61, 122.47, 120.25, 103.89, 61.76, 37.59, 35.02. Anal. Calcd. For C₂₁H₁₅Cl₂N₅O₂: (C, 57.29; H, 3.43; Cl, 16.10; N, 15.91%). Found (C, 57.05; H, 3.21; Cl, 15.89; N, 15.73%).

3.1.15. Synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-2-phenyl-2,4-dihydropyrano[2,3-c]pyrazol-3-yl)-N-(2-chlorophenyl)acetamide (4d)

A mixture of 2-(5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-N-phenylacetamide (2d) (3.28 gm, 0.01 mol), malononitrile (0.66 gm, 0.01 mol), 4-chlorobenzaldehyde (1.41 gm, 0.01 mol), and (2 mol%) glycine in 25 mL water was vigorously stirred for 30 min at 25°C. The produced solid was filtered out, washed with cold ethanol, dried, and purified by crystallization.

Compound 4d: yellow crystals; mp 210–212°C (ethanol); yield (4.09 gm, 79%); IR (KBr) ν/cm⁻¹: 3320 (NH₂), 3197 (NH), 2202 (CN), 1662 (CO); ¹HNMR (DMSO-d₆): δ 9.83 (s, 1H, NH D₂O exchangeable), 7.71–6.91 (m, 13H, Ar-), 6.48 (s, 2H, NH₂ D₂O exchangeable), 4.66 (s, 1H, CH), 3.57–3.46 (dd, J = 16.5 Hz, 13.2 Hz, 2H, CH₂); ¹³C-NMR (DMSO-d₆): δ 172.66, 161.31, 150.94, 138.23, 137.61, 136.28, 136.01, 132.01, 128.07, 128.05, 127.21, 126.57, 126.18, 124.35, 123.33, 122.98, 121.81, 121.18, 119.41, 108.72, 62.30, 37.59, 36.48. Anal. Calcd. For C₂₇H₁₉Cl₂N₅O₂: (C, 62.80; H, 3.71; Cl, 13.73; N, 13.56%). Found (C, 62.56; H, 3.43; Cl, 13.65; N, 13.34%).

3.1.16. Synthesis of Ethyl 4-(4-chlorophenyl)-5-cyano-3-(2-oxo-2-(phenylamino)ethyl)-2,4-dihydropyrano[2,3-c]pyrazole-6-carboxylate (4e)

Compound 4e was yielded by refluxing 2-(5-oxo-4,5-dihydro-1H-pyrazol-3-yl)-N-phenylacetamide (2a) (2.17 gm, 0.01 mol), ethyl cyanoacetate (1.1 mL, 0.01 mol), and 4-chlorobenzaldehyde (1.41 gm, 0.01 mol) in 15 mL absolute ethanol for 2 h. The formed precipitate was filtered off, washed with water, dried, and recrystallized from ethanol.

Compound 4e: pale gray crystals; mp 268–270°C; yield (3.7 gm, 80%); IR (KBr) ν/cm⁻¹: 3320 (NH), 3209 (NH), 2244 (CN), 1747 (CO ester), 1666 (CO amide); ¹HNMR (DMSO-d₆): δ 12.33 (s, 1H, NH D₂O exchangeable), 9.85 (s, 1H, NH D₂O exchangeable), 7.49–7.00 (m, 9H, Ar-), 4.65 (s, 1H, CH), 4.03 (q, J = 16.9 Hz, 2H, CH₂), 3.45–3.20 (dd, J = 16.7 Hz, 16.6Hz, 2H, CH₂), 1.31 (t, J = 21.3 Hz, 3H, CH₃); ¹³C-NMR (DMSO-d₆): δ 171.76, 163.02, 156.77, 149.18, 139.58, 138.55, 134.84, 133.04, 130.04, 129.55, 128.07, 123.33, 120.25, 116.35, 106.22, 103.94, 67.22, 36.48, 35.94, 17.85. Anal. Calcd. For C₂₄H₁₉ClN₄O₄: (C, 62.27; H, 4.14; Cl, 7.66; N, 12.10). Found (C, 62.02; H, 3.87; Cl, 7.45; N, 11.90).

3.1.17. Synthesis of Ethyl 4-(4-chlorophenyl)-5-cyano-3-(2-oxo-2-(phenylamino)ethyl)-2-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-6-carboxylate (4f)

Compound 4f was yielded by refluxing 2-(5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-N-phenylacetamide (2b) (2.93 gm, 0.01 mol), ethyl cyanoacetate (1.1 mL, 0.01 mol), and 4-chlorobenzaldehyde (1.41 gm, 0.01 mol) in 15 mL absolute ethanol for 2 h. The formed precipitate was filtered off, washed with water, dried, and recrystallized from ethanol.

Compound 4f: pale yellow crystals; mp 282–284°C; yield (4.09 gm, 76%); IR (KBr) ν/cm⁻¹: 3320 (NH), 2256 (CN), 1743 (CO ester), 1666 (CO amidic); ¹HNMR (DMSO-d6) δ 9.93 (s, 1H, NH D₂O exchangeable), 7.84–7.01 (m, 14H, Ar-), 4.76 (s, 1H, CH), 3.93 (q, J = 13.5 Hz, 2H, CH₂), 3.40–3.16 (dd, J = 15.8 Hz, 16.3Hz, 2H, CH₂), 1.06 (t, J = 7.0 Hz, 3H, CH₃); ¹³C-NMR (DMSO-d₆): δ 172.00, 162.63, 160.45, 150.45, 139.91, 138.55, 138.23, 136.70, 132.01, 128.54, 128.19, 128.07, 127.21, 126.18, 123.33, 122.98, 120.25, 117.86, 108.72, 107.49, 61.76, 36.09, 35.02, 16.47. Anal. Calcd. For C₃₀H₂₃ClN₄O₄: (C, 66.85; H, 4.30; Cl, 6.58; N, 10.40). Found (C, 66.56; H, 4.17; Cl, 6.25; N, 10.16).

3.1.18. Synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-(2-phenyl) 4,7-dihydro-2H-pyrazolo[3,4-b]pyridin-3-yl)-N-phenylacetamide (4g)

Compound 2a (2.17 gm, 0.01 mol) and 2-(4-chlorobenzylidene) malononitrile (1.89 gm, 0.01 mol) were refluxed in 30 mL of absolute ethanol for 10–12 h in the presence of ammonium acetate (2.31 gm, 0.03 mol). The reaction mixture was left to cool. The obtained solid was filtered off, dried, and recrystallized from ethanol to give 4g. Compound 4g: pale orange crystals; mp 120–122°C; yield (2.46 gm, 61%); IR (KBr) ν/cm⁻¹: 3282 (NH₂), 3143 (NH), 2121 (CN), 1650 (CO); ¹HNMR (DMSO-d6) δ 12.33 (s, 1H, NH D₂O exchangeable), 9.85 (s, 1H, NH D₂O exchangeable), 7.96 (s, 1H, NH D₂O exchangeable), 7.49–7.00 (m, 9H, Ar-), 5.97 (s, 2H, NH₂), 4.65 (s, 1H, CH), 3.45–3.20 (dd, J = 16.7 Hz, 16.6 Hz, 2H, CH₂); ¹³C-NMR (DMSO-d₆): δ 170.76, 153.90, 144.16, 139.91, 138.55, 134.84, 132.01, 129.55, 128.54, 128.07, 123.33, 121.18, 120.25, 105.32, 59.06, 36.09, 34.06. Anal. Calcd. For C₂₁H₁₇ClN₆O: (C, 62.41; H, 4.36; Cl, 7.67; N, 15.16). Found (C, 62.16; H, 4.22; Cl, 7.34; N, 15.02).

3.1.19. Synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-7-(4-methoxyphenyl)-2-phenyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridin-3-yl)-N-phenylacetamide (4h)

Compound 2-(6-amino-4-(4-chlorophenyl)-5-cyano-2-phenyl-2,4-dihydropyrano[2,3-c]pyrazol-3-yl)-N-phenylacetamide (4b) (4.81 gm, 0.01 mol) was added to a solution of p-anisidine (1.15 mL, 0.01 mol) in 30 mL dimethylformamide and refluxed for 5 h. The reaction mixture was cooled and added to ice/H₂O. The produced solid precipitate was filtered out, washed with water, dried, and recrystallized from acetic acid to afford 4h. Compound 4h: dark brown crystals; mp 148–150°C; yield (4.39 gm, 75%); IR (KBr) ν/cm⁻¹: 3216 (NH₂), 3135 (NH), 2206 (CN), 1662 (CO); ¹HNMR (DMSO-d₆) δ 10.47 (s, 1H, NH D₂O exchangeable), 7.82–7.05 (m, 18H, Ar-), 6.15 (s, 2H, NH₂ D₂O exchangeable), 4.99 (s, 1H, CH), 4.09–3.90 (dd, J = 15.6 Hz, 2H, CH₂), 3.49 (s, 3H, CH₃); ¹³C-NMR (DMSO-d₆): δ 171.43, 154.97, 149.18, 147.38, 142.39, 139.58, 138.55, 134.84, 132.01, 129.55, 128.54, 127.12, 126.18, 122.98, 122.75, 121.18, 120.10, 114.33, 105.32, 63.28, 54.85, 41.74, 35.02. Anal. Calcd. For C₃₄H₂₇ClN₆O₂: (C, 69.56; H, 4.64; Cl, 6.04; N, 14.32). Found (C, 69.24; H, 4.43; Cl, 5.83; N, 14.15).

3.2. Antimicrobial Test

The semiquantitative disk diffusion procedure was used to evaluate the antimicrobial activity of the prepared compounds. The diameter of the inhibition zone around each disk was estimated in millimeters. All the procedures were performed according to the standard protocol of the NCCLS disk diffusion susceptibility method [28]. All the above tests were conducted in triplicates.

3.3. Molecular Docking Study

To further understand the experimental antimicrobial activity of the synthesized compounds against S. aureus, the molecular docking study was performed, and their binding affinities into S. aureus tyrosyl-tRNA synthetase were determined. The target tyrosyl-tRNA synthetase was downloaded from the RCSB website (PDB code 1JIJ) [29]. The intermolecular interactions of the prepared compounds into the binding site of tyrosyl-tRNA synthetase have been explored using the AutoDock package [30].

4. Conclusion

In the present study, a series of pyran, pyrazole, and pyranopyrazole derivatives were synthesized and their structure was elucidated. The synthesized compounds were then screened for their antimicrobial activity against some human pathogenic bacterial strains such as Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa using chloramphenicol as a reference. Compounds 3c, 4b and 3d, 4b exhibited a high degree of inhibition against Bacillus subtilis and Staphylococcus aureus, respectively. Compounds 2d, 4f and 2d, 4e had a high inhibition effect against Escherichia coli and Pseudomonas aeruginosa, respectively. The docking studies of the prepared compounds 4a, c indicated that the substituted chlorine atom in 4c interacted with ASP A195, which increased the stability of 4c-tyrosyl-tRNA synthetase compared with that of 4a-tyrosyl-tRNA. Thus, 4c had a higher antibacterial activity than 4a. The data obtained from the theoretical calculations were promising candidates for further development as therapeutic precursors with high efficacy.

Data Availability

The data used to support the findings of this study can be made available upon reasonable request to the corresponding author.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This study was supported via funding from Prince Sattam Bin Abdulaziz University project number (PSAU/2023/R/1445).

Supplementary Materials

The supplementary file containing the original analysis charts (FTIR, ¹HNMR, ¹³C-NMR, and mass spectra) is available. (Supplementary Materials)

References

webmd, “COPD (chronic obstructive pulmonary disease),” 2006, https://www.webmd.com/lung/copd/news/20060525/top-10-causes-death-worldwide.
View at: Google Scholar
weforum, “COVID-19,” 2020, https://www.weforum.org/agenda/2020/09/covid-19-deaths-global-killers-comparison.
View at: Google Scholar
S. Sharma, D. Kumar, G. Singh, V. Monga, and B. Kumar, “Recent advancements in the development of heterocyclic anti-inflammatory agents,” European Journal of Medicinal Chemistry, vol. 200, Article ID 112438, 2020.
View at: Publisher Site | Google Scholar
A. T. Taher, M. T. Mostafa Sarg, N. R. El-Sayed Ali, and N. Hilmy Elnagdi, “Design, synthesis, modeling studies and biological screening of novel pyrazole derivatives as potential analgesic and anti-inflammatory agents,” Bioorganic Chemistry, vol. 89, Article ID 103023, 2019.
View at: Publisher Site | Google Scholar
K. Karrouchi, S. Radi, Y. Ramli et al., “Synthesis and pharmacological activities of pyrazole derivatives: a review Molecules,” Molecules, vol. 23, no. 1, p. 134, 2018.
View at: Publisher Site | Google Scholar
O. Alam, M. Naim, F. Nawaz, M. J. Alam, and P. Alam, “Current status of pyrazole and its biological activities,” Journal of Pharmacy and BioAllied Sciences, vol. 8, no. 1, p. 2, 2016.
View at: Publisher Site | Google Scholar
S. Maddila, S. B. Jonnalagadda, K. K. Gangu, and S. N. Maddila, “Recent advances in the synthesis of pyrazole derivatives using multicomponent reactions,” Current Organic Synthesis, vol. 14, no. 5, pp. 634–653, 2017.
View at: Publisher Site | Google Scholar
M. Sadeghpour and A. Olyaei, “Recent advances in the synthesis of bis(pyrazolyl)methanes and their applications Research on Chemical Intermediates,” Research on Chemical Intermediates, vol. 47, no. 11, pp. 4399–4441, 2021.
View at: Publisher Site | Google Scholar
S. Anthal, G. Brahmachari, S. Laskar, B. Banerjee, R. Kant, and V. K. Gupta, “2-Amino-7, 7-dimethyl-5-oxo-4-(p-tolyl)-5, 6, 7, 8-tetrahydro-4H-chromene-3-carbonitrile,” Acta Crystallographica, Section E: Structure Reports Online, vol. 68, no. 8, pp. o2592–o2593, 2012.
View at: Publisher Site | Google Scholar
L. Bonsignore, G. Loy, D. Secci, and A. Calignano, “Synthesis and pharmacological activity of 2-oxo-(2H) 1-benzopyran-3-carboxamide derivatives,” European Journal of Medicinal Chemistry, vol. 28, no. 6, pp. 517–520, 1993.
View at: Publisher Site | Google Scholar
X. S. Wang, Z. S. Zeng, D. Q. Shi, S. J. Tu, X. Y. Wei, and Z. M. Zong, “The crystal structure and unclassical pyran conformation of 2-amino-7-methyl-4-(3-nitrophenyl)-5-oxo-4H, 5H-pyran [4, 3-b] pyran-3-carbonitrile,” Journal of Chemical Research, vol. 2005, no. 12, pp. 775–777, 2005.
View at: Publisher Site | Google Scholar
S. K. Biswas and D. Das, “One-pot synthesis of pyrano [2, 3-c] pyrazole derivatives via multicomponent reactions (MCRs) and their applications in medicinal chemistry,” Mini-Reviews in Organic Chemistry, vol. 19, no. 5, pp. 552–568, 2022.
View at: Publisher Site | Google Scholar
R. K. Ganta, N. Kerru, S. Maddila, and S. B. Jonnalagadda, “Advances in pyranopyrazole scaffolds’ syntheses using sustainable catalysts—a review,” Advances in Pyranopyrazole Scaffolds’ Syntheses Using Sustainable Catalysts—A Review Molecules, vol. 26, no. 11, p. 3270, 2021.
View at: Publisher Site | Google Scholar
H. T. Nguyen, M.-N. H. Truong, T. V. Le, N. T. Vo, H. D. Nguyen, and P. H. Tran, “A new pathway for the preparation of pyrano[2,3-c]pyrazoles and molecular docking as inhibitors of p38 MAP kinase,” ACS Omega, vol. 7, no. 20, pp. 17432–17443, 2022.
View at: Publisher Site | Google Scholar
H. Emtiazi, A. S. Sharif, and M. Ardestani, “Synthesis, biological screening and docking study of some novel pyrazolopyrano[ 2,3-B]quinolin derivatives as potent antibacterial agents,” Current Bioactive Compounds, vol. 18, no. 5, pp. 58–65, 2022.
View at: Publisher Site | Google Scholar
A. Musa, S. K. Ihmaid, D. L. Hughes et al., “The anticancer and EGFR-TK/CDK-9 dual inhibitory potentials of new synthetic pyranopyrazole and pyrazolone derivatives: X-ray crystallography, in vitro, and in silico mechanistic investigations,” Journal of Biomolecular Structure and Dynamics, vol. 41, no. 21, pp. 12411–12425, 2023.
View at: Publisher Site | Google Scholar
A. A. Al-Amiery, R. I. Al-Bayati, F. M. Saed, W. B. Ali, A. A. H. Kadhum, and A. B. Mohamad, “Novel pyranopyrazoles: synthesis and theoretical studies Molecules,” Molecules, vol. 17, no. 9, pp. 10377–10389, 2012.
View at: Publisher Site | Google Scholar
J.-L. Wang, D. Liu, Z. J. Zhang et al., “Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells,” Proceedings of the National Academy of Sciences, vol. 97, no. 13, pp. 7124–7129, 2000.
View at: Publisher Site | Google Scholar
R. S. Aliabadi and N. O. Mahmoodi, “Green and efficient synthesis of pyranopyrazoles using [bmim] [OH⁻] as an ionic liquid catalyst in water under microwave irradiation and investigation of their antioxidant activity,” RSC Advances, vol. 6, no. 89, pp. 85877–85884, 2016.
View at: Publisher Site | Google Scholar
M. E. A. Zaki, H. A. Soliman, O. A. Hiekal, and A. E. Rashad, “Pyrazolopyranopyrimidines as a Class of Anti-inflammatory Agents61,” Zeitschrift Fur Naturforschung C, vol. 61, no. 1-2, pp. 1–5, 2006.
View at: Publisher Site | Google Scholar
N. Foloppe, L. M. Fisher, R. Howes, A. Potter, A. G. S. Robertson, and A. E. Surgenor, “Identification of chemically diverse Chk1 inhibitors by receptor-based virtual screening,” Bioorganic & Medicinal Chemistry, vol. 14, no. 14, pp. 4792–4802, 2006.
View at: Publisher Site | Google Scholar
A. A. Bekhit, S. N. Nasralla, E. J. El-Agroudy et al., “Investigation of the anti-inflammatory and analgesic activities of promising pyrazole derivative,” European Journal of Pharmaceutical Sciences, vol. 168, Article ID 106080, 2022.
View at: Publisher Site | Google Scholar
S. Chakraborty, B. Paul, U. C. De, R. Natarajan, and S. Majumdar, “Water-SDS-[BMIm] Br composite system for one-pot multicomponent synthesis of pyrano [2, 3-c] pyrazole derivatives and their structural assessment by NMR, X-ray, and DFT studies,” RSC Advances, vol. 13, no. 10, pp. 6747–6759, 2023.
View at: Publisher Site | Google Scholar
S. Farooq and Z. Ngaini, “Chalcone derived pyrazole synthesis via one-pot and two-pot strategies current organic chemistry,” Current Organic Chemistry, vol. 24, no. 13, pp. 1491–1506, 2020.
View at: Publisher Site | Google Scholar
M. I. Ali and M. M. S. El-Morsy, “Reactions with acetonedicarboxylic dianilides. I. Reactions at the carbonyl group,” Journal für Praktische Chemie, vol. 321, no. 6, pp. 1047–1052, 1979.
View at: Publisher Site | Google Scholar
V. A. Mamedov, L. P. Sysoeva, A. M. Murtazina et al., “Fused polycyclic nitrogen-containing heterocycles 24. Three-component condensation of diethyl 2,4,6-trioxoheptanedicarboxylate with salicylaldehydes and ammonium acetate as a new method for the synthesis of 7- and 9-substituted benzo[e]pyrano[4,3-b]pyridines Russian Chemical Bulletin,” Russian Chemical Bulletin, vol. 58, no. 7, pp. 1452–1464, 2009.
View at: Publisher Site | Google Scholar
M. B. M. Reddy, V. P. Jayashankara, and M. A. Pasha, “Glycine-catalyzed efficient synthesis of pyranopyrazoles via one-pot multicomponent reaction,” Synthetic Communications, vol. 40, no. 19, pp. 2930–2934, 2010.
View at: Publisher Site | Google Scholar
O. Olajuyigbe and A. Ashafa, “Chemical composition and antibacterial activity of essential oil of Cosmos bipinnatus Cav. leaves from South Africa,” Iranian Journal of Pharmaceutical Research, vol. 13, no. 4, pp. 1417–1423, 2014, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232809/.
View at: Google Scholar
X. Qiu, C. A. Janson, W. W. Smith et al., “Crystal structure of Staphylococcus aureus tyrosyl‐tRNA synthetase in complex with a class of potent and specific inhibitors Protein Science,” Protein Science, vol. 10, no. 10, pp. 2008–2016, 2001.
View at: Publisher Site | Google Scholar
G. M. Morris, R. Huey, W. Lindstrom et al., “AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility,” Journal of Computational Chemistry, vol. 30, no. 16, pp. 2785–2791, 2009.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2023 Mahmoud M. Abdelatty et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

330

Downloads

247

Citations

Journal of Chemistry

Synthesis, Antimicrobial Studies, and Molecular Docking Simulation of Novel Pyran, Pyrazole, and Pyranopyrazole Derivatives

Abstract

1. Introduction

2. Results and Discussion

2.1. Synthesis and Structure Elucidation

2.2. Antimicrobial Activity

2.3. Molecular Docking Results

3. Materials and Methods

3.1. Synthesis

3.1.1. Synthesis of 3-Oxo-N1,N5-diphenylpentanediamide (1a)

3.1.2. Synthesis of N1,N5-bis(2-chlorophenyl)-3-oxopentanediamide (1b)

3.1.3. Synthesis of 2-(5-hydroxy-1H-pyrazol-3-yl)-N-phenylacetamide (2a)

3.1.4. Synthesis of 2-(5-hydroxy-1-phenyl-1H-pyrazol-3-yl)-N-phenylacetamide (2b)

3.1.5. Another Method for the Synthesis of Compound 2b

3.1.6. Synthesis of N-(2-chlorophenyl)-2-(5-hydroxy-1H-pyrazol-3-yl)acetamide (2c)

3.1.7. Synthesis of N-(2-chlorophenyl)-2-(5-hydroxy-1-phenyl-1H-pyrazol-3-yl)acetamide (2d)

3.1.8. Synthesis of 6-Amino-4-(4-chlorophenyl)-5-cyano-2-(2-oxo-2-(phenylamino)ethyl)-N-phenyl-4H-pyran-3-carboxamide (3a)

3.1.9. Synthesis of 6-Amino-N-(2-chlorophenyl)-4-(4-chlorophenyl)-2-(2-((2-chlorophenyl)amino)-2-oxoethyl)-5-cyano-4H-pyran-3-carboxamide (3b)

3.1.10. Synthesis of 6-Amino-4-(4-chlorophenyl)-5-cyano-2-(2-oxo-2-(phenylamino)ethyl)-N-phenyl-1,4-dihydropyridine-3-carboxamide (3c)

3.1.11. Synthesis of 6-Amino-4-(4-chlorophenyl)-5-cyano-2-(2-oxo-2-(phenylamino)ethyl)-N,1-diphenyl-1,4-dihydropyridine-3-carboxamide (3d)

3.1.12. Synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-2,4-dihydropyrano[2,3-c]pyrazol-3-yl)-N-phenylacetamide (4a)

3.1.13. Synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-2-phenyl-2,4-dihydropyrano[2,3-c]pyrazol-3-yl)-N-phenylacetamide (4b)

3.1.14. Synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-2,4-dihydropyrano[2,3-c]pyrazol-3-yl)-N-(2-chlorophenyl)acetamide (4c)

3.1.15. Synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-2-phenyl-2,4-dihydropyrano[2,3-c]pyrazol-3-yl)-N-(2-chlorophenyl)acetamide (4d)

3.1.16. Synthesis of Ethyl 4-(4-chlorophenyl)-5-cyano-3-(2-oxo-2-(phenylamino)ethyl)-2,4-dihydropyrano[2,3-c]pyrazole-6-carboxylate (4e)

3.1.17. Synthesis of Ethyl 4-(4-chlorophenyl)-5-cyano-3-(2-oxo-2-(phenylamino)ethyl)-2-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-6-carboxylate (4f)

3.1.18. Synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-(2-phenyl) 4,7-dihydro-2H-pyrazolo[3,4-b]pyridin-3-yl)-N-phenylacetamide (4g)

3.1.19. Synthesis of 2-(6-amino-4-(4-chlorophenyl)-5-cyano-7-(4-methoxyphenyl)-2-phenyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridin-3-yl)-N-phenylacetamide (4h)

3.2. Antimicrobial Test

3.3. Molecular Docking Study

4. Conclusion

Data Availability

Conflicts of Interest

Acknowledgments

Supplementary Materials

References

Copyright

3.1.1. Synthesis of 3-Oxo-N¹,N⁵-diphenylpentanediamide (1a)

3.1.2. Synthesis of N¹,N⁵-bis(2-chlorophenyl)-3-oxopentanediamide (1b)