Abstract
Two series of s-triazine derivatives were synthesized by copper-catalyzed Ullmann reaction. Facile route was adopted to achieve amination of s-triazines for the first time. The C-N coupling reactions were conducted in water under ligand-free and oxygen-free conditions. The synthesized compounds were screened for their in vitro antibacterial and antifungal activity. Compounds were further subjected to in vitro antitubercular screening against the H37Rv strain. Compared with standard drugs, compound 5b was found to be the most active antimicrobial and antitubercular agent that inhibits Staphylococcus aureus and H37Rv strain with minimum inhibitory concentration of 1.56 and 6.25 μg/mL, respectively.
Introduction
During the past few decades, the growing human population has been affected by significant increase in the frequency of severe infectious diseases because of the increasing number of multi-drug-resistant (MDR) microbial pathogens [1–3]. These organisms multiply with the ability to resist the available antimicrobial drugs, and this uncontrolled rise in resistant pathogens may affect the immunocompromised individuals, patients with malignancies, and transplant recipients [4, 5]. In particular, tuberculosis (TB) has emerged as one of the most complicated infectious diseases worldwide. MDR and extensively drug-resistant TB are major two types of TB caused by some mycobacteria of the Mycobacterium tuberculosis complex that commonly affect the lungs [6–8]. According to World Health Organization (WHO) reports, about 8.6 million of people were infected with TB in 2013 [9, 10]. When a patient adopts bacterial resistance to the first-line drugs such as isoniazid, rifampicin, ethambutol, and pyrazinamide [11], health-threatening problems in the chemotherapy of TB arise, which seriously reduces the progress in anti-TB medical care.
In continuation of our research to design and synthesize bioactive heterocycles [12, 13], we have recently published the review on pharmacological potential of s-triazines [14], showing their important therapeutic applications as antibacterial [15], antifungal [16], antimycobacterial [17], anti-HIV [18], anticancer [19], and antiviral [20] agents. Compounds structurally related to s-triazine are also bioactive [21, 22].
In the present work, copper-catalyzed C-N coupling was introduced by using the Ullmann reaction approach [23, 24]. In the known successful C-N cross-coupling reactions [25, 26], palladium [27], nickel [28], and copper [23] catalysts have been used. To date, various modifications were attempted to develop improved conditions for C-N coupling [29–32]. The air-sensitive, toxic, and expensive reagents have been used in a Buchwald-Hartwig reaction [33–36], and one report describes a reaction conducted in water under ligand-free conditions [37]. Some mechanistic studies on copper-catalyzed arylation of a nucleophile have also been reported for C-N coupling reactions [38, 39]. In this work, we focused on the synthesis of copper-catalyzed trisubstituted triazine derivatives. The products were then screened for antimicrobial and antimycobacterial activities.
Results and discussion
Chemistry
The desired compounds 4a–j and 5a–j were synthesized by a series of reactions as shown in Scheme 1. The characteristic displacement of the first chloro atom of cyanuric chloride by 4-aminobenzonitrile has been reported in literature [20]. In this work, cyanuric chloride and 4-aminobenzonitrile in presence of K2CO3 were allowed to react in dry THF to yield 4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]benzonitrile (1). The intermediate 4-[(4-chloro-6-(cyclopropylamino)-1,3,5-triazin-2-yl)amino]benzonitrile (2) was synthesized by stirring 1 with cyclopropylamine and K2CO3 in dry DMF at 40–45°C for 4–5 h. The resulting compound 2 was further reacted to 4-chloroaniline in the presence of K2CO3 at reflux temperature to yield product 3. The chlorophenyl moiety of 3 was coupled to various substituted amines and piperazines via Ullmann coupling reaction. The Cu-catalyzed C-N coupling was carried out in water under oxygen-free conditions under reflux to furnish the desired compounds 4a–j and 5 a–j. The structures of all intermediate and final products are fully consistent with the results of elemental analysis and analysis of spectral data.
Synthetic route to compounds 4a–j and 5a–j.
Biological evaluation
Selected s-triazine derivatives 4 and 5 were examined for their in vitro antimicrobial activity against two Gram-positive bacterial strains (Staphylococcus aureus MTCC 96 and Bacillus cereus MTCC 430), two Gram-negative bacterial strains (Escherichia coli MTCC 741 and Salmonella typhi MTCC 109), and two fungal strains (Aspergillus niger MTCC 1323 and Aspergillus clavatus MTCC 183) using agar dilution method [40]. Ciprofloxacin and streptomycin were used as standard control drugs for antibacterial activity, whereas griseofulvin was used as the standard control drug for antifungal activity. In vitro antitubercular activity was also performed for title compounds against the M. tuberculosis H37Rv strain by BACTEC MGIT method [41] using isoniazid, rifampicin, ethambutol, and pyrazinamide as standard control drugs. Some of the synthesized products were found to be potent against specific microbial strains.
In vitro antibacterial activity
Table 1 shows that several s-triazines exhibit good to moderate activity against several microbial strains. It can be seen that compound 5b bearing N-methyl piperazine moiety is the most potent analog that shows a 32-mm zone of inhibition and MIC of 1.56 μg/mL against S. aureus strain. This is an outstanding result when compared with the activity of penicillin (30 mm, 3.12 μg/mL) and streptomycin (28 mm, 6.25 μg/mL). Compound 5d shows also good activity to inhibit the growth of S. aureus and S. typhi bacteria. Derivatives 4i and 5f having electron withdrawing 4-acetyl and N-benzhydryl substituents exhibit half-fold (3.12 μg/mL) and equipotent (6.25 μg/mL) inhibition of B. cereus bacteria in comparison to activity of streptomycin (6.25 μg/mL). Against the E. coli strain, compounds 4g, 5g, and streptomycin show similar MIC. Compounds 4e and 5i demonstrate equipotent efficacy against S. typhi bacteria with penicillin (MIC, 12.5 μg/mL) and streptomycin (MIC, 3.12 μg/mL), respectively.
In vitro antimicrobial activity of selected compounds 4 and 5.
| Entry | Zone of inhibition (mm) (MIC, μg/mL) | |||||
|---|---|---|---|---|---|---|
| Gram positive | Gram negative | Fungal strains | ||||
| S. aureus | B. cereus | E. coli | S. typhi | A. niger | A. clavatus | |
| 4e | 12 (200) | 08 (25) | 20 (100) | 10 (3.12) | 15 (100) | 23 (100) |
| 4g | 23 (6.25) | 22 (200) | 15 (3.12) | 11 (6.25) | 20 (200) | 20 (200) |
| 4i | 27 (25) | 27 (3.12) | 24 (100) | 16 (12.5) | 19 (400) | 19 (400) |
| 5b | 32 (1.56)b | 12 (100) | 16 (400) | 24 (6.25) | 23 (100) | 19 (400) |
| 5d | 28 (3.12) | 16 (50) | 17 (12.5) | 20 (3.12) | 12 (400) | 20 (100) |
| 5f | 11 (400) | 13 (3.12) | 24 (400) | 18 (50) | 23 (100) | 15 (400) |
| 5g | 18 (25) | 18 (50) | 21 (3.12) | 11 (12.5) | 20 (200) | 23 (100) |
| 5i | 20 (6.25) | 26 (50) | 17 (50) | 07 (3.12) | 18 (200) | 15 (400) |
| Penicillina | 30 (3.12) | 28 (1.56) | 26 (6.25) | 23 (12.5) | – | – |
| Streptomycina | 28 (6.25) | 24 (6.25) | 23 (3.12) | 26 (3.12) | – | – |
| Griseofulvina | – | – | – | – | 24 (100) | 23 (100) |
†Standard. bSuperior inhibition profile.
In vitro antifungal activity
Antifungal activity data (Table 1) show that two compounds are highly active. These are compound 5b and 4e with electron-donating N-methylpiperazino and 4-methyl moieties that show the zone of inhibition of 23 mm against A. niger and A. clavatus fungi.
In vitro antitubercular activity
Table 2 indicates that the synthesized compounds are active against tubercular strain M. tuberculosis H37Rv strain.
In vitro antitubercular activity of selected compounds 4 and 5.
| Entry | BACTEC MGIT methoda | |
|---|---|---|
| MICb | % Inhibition | |
| 4a | 6.25 | 92 |
| 4i | 6.25 | 99 |
| 4j | 6.25 | 94 |
| 5b | 6.25c | 99c |
| 5g | 6.25 | 96 |
| 5j | >6.25 | 91 |
| Isoniazid | 0.20 | 99 |
| Refampicin | 0.25 | 99 |
| Ethambutol | 3.12 | 99 |
| Pyrazinamide | 6.25 | 99 |
aEach value is the mean of three independent experiment. bIn μg/mL. cSuperior inhibition profile.
Conclusion
Two series of amino-substituted s-triazines 4a–j and piperazino derivatives 5a–j were synthesized by simple and efficient methods. Compounds were screened against a wide range of pathogenic bacteria, fungi, and H37Rv mycobacterial strains. Compound 5b is the best bioactive derivative.
Experimental
2,4,6-Trichloro-1,3,5-triazine, cyclopropylamine, and 4-aminobenzonitrile were purchased from Sigma-Aldrich. Acetone and tetrahydrofuran were purchased from Merck and used without further purification. Melting points of the products were determined in open capillaries using Veego electronic apparatus and are uncorrected. The IR spectra (4000–400 cm-1) were recorded using KBr pellets. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on Varian 400 spectrometer using DMSO-d6 as a solvent.
Synthesis of 4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]benzonitrile (1)
Potassium carbonate (14.9 g, 108 mmol) was slowly added at 0–5°C to a solution of cyanuric chloride (10 g, 54 mmol) and 4-aminobenzonitrile (6.41 g, 54 mmol) in dry THF (150 mL). The solution was stirred for 4–5 h at 0–5°C. After completion of the reaction based on TLC monitoring (toluene/acetone 7:3), the mixture was treated with crushed ice, followed by neutralization with dilute hydrochloric acid. The crude product 1 was then filtered, dried, and crystallized from acetone; yield 11.0 g (79%); mp 247–250°C; IR: 3277 (N-H), 2228 (C≡N), 833, 802 cm-1; 1H NMR: δ 8.61 (s, 1H, NH), 7.86–7.78 (m, 4H, Ar-H); 13C NMR: δ 171.7 (triazine), 166.6 (triazine), 165.4 (triazine), 140.8 (Ar-C-NH), 132.2 (Ar-CH), 125.4 (Ar-CH), 122.6 (Ar-CH), 120.7 (Ar-CH), 119.3 (Ar-CN), 100.8 (Ar-C-CN); MS (ESI): m/z 265.94 [M+]. Anal. Calcd for C10H5Cl2N5 (264.99): C, 45.14; H, 1.89; N, 26.32. Found: C, 45.11; H, 1.92; N, 26.34.
Synthesis of 4-{[4-chloro-6-(cyclopropylamino)-1,3,5-triazin-2-yl]amino}benzonitrile (2)
A mixture of compound 1 (5 g, 18 mmol) and cyclopropylamine (1.07 g, 18 mmol) was stirred in dry DMF at room temperature. To this solution, K2CO3 (5.18 g, 37 mmol) was slowly added, and stirring was continued for 4–5 h, with the progress of the reaction monitored by TLC using hexanes/ethyl acetate (6:4) as an eluent. After completion of the reaction, the mixture was treated with crushed ice and neutralized with diluted hydrochloric acid. The precipitate was filtered, dried, and crystallized from methanol to afford desired compound 2; yield 3.6 g (67%); mp 189–191°C; IR: 3357 (N-H), 2251 (C≡N), 846 (s-triazine), 789 cm-1; 1H NMR: δ 7.33 (d, J = 7 Hz, 2H, Ar-H), 7.06 (d, J = 7 Hz, 2H, Ar-H), 6.43 (s, 1H, NH), 3.46 (s, 1H, NH), 2.29 (m, 1H, CH), 1.10–0.63 (m, 4H, CH); 13C NMR: δ 170.3 (triazine), 165.4 (triazine), 160.3 (triazine), 145.7 (Ar-C-NH), 133.2 (Ar-CH), 129.4 (Ar-CH), 123.2 (Ar-CH), 121.9 (Ar-CH), 117.0 (Ar-CN), 101.7 (Ar-C-CN), 22.4 (CH), 7.8 (CH2), 7.5 (CH2); MS (ESI): m/z 287.10 [M+]. Anal. Calcd for C13H11ClN6 (286.07): C, 54.46; H, 3.87; N, 29.31. Found: C, 54.43; H, 3.89; N, 29.35.
Synthesis of 4-{[4-(4-chloroanilino)-6-(cyclopropylamino)-1,3,5-triazin-2-yl]amino}benzonitrile (3)
A mixture of compound 2 (5 g, 17 mmol) and 4-chloroaniline (2.21 g, 17 mmol) was heated under reflux in dry DMF for 3–4 h. Progress of the reaction was monitored by TLC using toluene/acetone (9:1) as an eluent. The mixture was treated with K2CO3 (4.69 g, 34 mmol) and poured onto crushed ice. The product 3 was filtered, dried, and crystallized from methanol; yield 4.6 g (71%); mp 164–166°C; IR: 3334 (N-H), 2851 (C-H aliphatic) 2291 (C≡N), 861 cm-1; 1H NMR: δ 7.48 (d, J = 7 Hz, 2H, Ar-H), 7.26–7.02 (m, 4H, Ar-H), 6.76 (d, J = 7 Hz, 2H, Ar-H), 6.49 (s, 1H, NH), 6.13 (s, 1H, NH), 3.61 (s, 1H, NH), 2.28 (m, 1H, CH), 1.30–0.59 (m, 4H, CH2); 13C NMR: δ 168.2 (triazine), 165.1 (triazine), 158.6 (triazine), 148.8 (Ar-C-NH), 140.4 (Ar-C-NH), 133.6 (Ar-CH), 132.5 (Ar-CH), 131.6 (Ar-CH), 130.2 (Ar-CH), 129.1 (Ar-C-Cl), 123.7 (Ar-CH), 121.1 (Ar-CH), 121.0 (Ar-CH), 120.9 (Ar-CH), 117.6 (Ar-CN), 99.7 (Ar-C-CN), 22.6 (CH), 8.1 (CH2), 7.9 (CH2); MS (ESI): m/z 378.09 [M+]. Anal. Calcd for C19H16ClN7 (377.11): C, 60.40; H, 4.27; N, 25.95. Found: C, 60.38; H, 4.25; N, 25.94.
General method for the preparation of compounds 4a–j and 5a–j
A mixture of compound 3 (5 mmol), 30% aqueous solution of a substituted amine or piperazine (5.4 mL, 27 mmol), and copper powder (10 mol%) was magnetically stirred at 100°C in a sealed tube. Progress of the reaction was monitored by TLC using hexanes/ethyl acetate (6:4) as an eluent. The mixture was cooled to room temperature and ethyl acetate (20 mL) was added to extract the product. The organic layer was separated, and the aqueous layer was additionally extracted with ethyl acetate (3×10 mL). The combined extracts were dried with anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a crude product 4a–j or 5a–j that was purified by silica gel column chromatography.
4-{[4-(Cyclopropylamino)-6-(4-(4-nitroanilino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (4a)
Yield 1.8 g (78%); mp 154–157oC; IR: 3365 (N-H), 3052 (C-H, aromatic), 2917 (C-H, aliphatic), 2652 (-CH2, cyclopropylamine), 2268 (C≡N), 1533 (NO2), 1362 (C-N), 851 cm-1; 1H NMR: δ 8.11 (d, J = 6 Hz, 2H, Ar-H), 7.81–7.12 (m, 4H, Ar-H), 7.02–6.86 (m, 6H, Ar-H), 6.58 (s, 1H, NH), 6.34 (s, 1H, NH), 6.15 (s, 1H, Ar-NH), 3.72 (s, 1H, NH), 2.87 (m, 1H, CH), 1.31–0.42 (m, 4H, CH2); 13C NMR: δ 168.1, 162.6, 160.6 (s-triazine), 152.5, 149.2, 147.2, 145.1, 137.5, 134.5, 130.3, 127.2, 126.1, 118.1, 113.3, 103.8 (Ar-C), 119.2 (Ar-CN), 24.48 (CH), 6.92 (2C, CH2); MS (ESI): m/z 480.42 [M+]. Anal. Calcd for C25H21N9O2 (479.49): C, 62.62; H, 4.41; N, 26.29. Found: C, 62.56; H, 4.42; N, 26.23.
4-{[4-(Cyclopropylamino)-6-(4-(3-nitroanilino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (4b)
Yield 1.5 g (64%); mp 137–142°C; IR: 3435 (N-H), 3095 (C-H, aromatic), 2920 (C-H, aliphatic), 2667 (CH2, cyclopropylamine), 2222 (C≡N), 1518 (NO2), 1346 (C-N), 869 cm-1; 1H NMR: δ 7.96 (d, J = 7 Hz, 1H, Ar-H), 7.89–7.38 (m, 4H, Ar-H), 7.28–6.98 (m, 7H, Ar-H), 6.34 (s, 1H, NH), 6.14 (s, 1H, NH), 5.87 (s, 1H, Ar-NH), 3.51 (s, 1H, NH), 3.14 (m, 1H, CH), 1.14–0.33 (m, 4H, CH2); 13C NMR: δ 169.9, 166.1, 162.3 (s-triazine), 155.2, 150.0, 148.7, 146.2, 138.3, 135.5, 132.7, 129.8, 128.1, 123.1, 119.3, 115.7, 111.7, 107.0 (Ar-C), 119.9 (Ar-CN), 23.5 (CH), 6.29 (2C, CH2); MS (ESI): m/z 480.61 [M+]. Anal. Calcd for C25H21N9O2 (479.49): C, 62.62; H, 4.41; N, 26.29. Found: C, 62.48; H, 4.40; N, 26.35.
4-{[4-(Cyclopropylamino)-6-(4-(2-nitroanilino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (4c)
Yield 1.4 g (61%); mp 122–125°C; IR: 3458 (N-H, secondary), 3064 (C-H, aromatic), 2932 (C-H, aliphatic), 2699 (CH2), 2232 (C≡N), 1552 (NO2), 1301 (C-N), 858 cm-1; 1H NMR: δ 8.14 (d, J = 7 Hz, 1H, Ar-H), 7.97–7.52 (m, 4H, Ar-H), 7.417.15 (m, 7H, Ar-H), 6.34 (s, 1H, NH), 6.31 (s, 1H, NH), 6.04 (s, 1H, Ar-NH), 3.45 (s, 1H, NH), 3.03 (m, 1H, CH), 1.32–0.21 (m, 4H, CH2); 13C NMR: δ 165.8, 164.4, 158.5 (s-triazine), 152.4, 151.2, 147.1, 145.4, 139.6, 132.1, 130.3, 128.8, 125.9, 122.0, 119.5, 114.4, 110.4, 104.5 (Ar-C), 120.7 (Ar-CN), 25.6 (CH), 7.6 (CH2); MS (ESI): m/z 480.49 [M+]. Anal. Calcd for C25H21N9O2 (479.49): C, 62.62; H, 4.41; N, 26.29. Found: C, 62.79; H, 4.42; N, 26.22.
4-{[4-(Cyclopropylamino)-6-(4-(o-tolylamino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (4d)
Yield 1.7 g (79%); mp 200–203°C; IR: 3391 (N-H, secondary), 3047 (C-H, aromatic), 2966 (C-H, aliphatic), 2640 (-CH2, cyclopropylamine), 2201 (C≡N), 1316 (C-N stretch), 868 cm-1; 1H NMR: δ 8.20 (d, J = 7 Hz, 1H, Ar-H), 7.82–7.60 (m, 4H, Ar-H), 7.53–7.24 (m, 7H, Ar-H), 6.64 (s, 1H, NH), 6.40 (s, 1H, NH), 6.17 (s, 1H, Ar-NH), 3.18 (s, 1H, NH), 2.97 (m, 1H, CH), 2.31 (s, 3H, CH3), 1.43–0.13 (m, 4H, CH2); 13C NMR: δ 166.4, 162.5, 160.2 (s-triazine), 153.6, 150.4, 147.3, 144.7, 138.1, 135.8, 132.5, 129.2, 126.7, 120.2, 118.5, 115.4, 111.4, 106.2 (Ar-C), 119.4 (Ar-CN), 24.2 (CH), 16.5 (Ar-CH3), 8.1 (CH2); MS (ESI): m/z 449.50 [M+]. Anal. Calcd for C26H24N8 (448.52): C, 69.62; H, 5.39; N, 24.98. Found: C, 69.49; H, 5.38; N, 24.95.
4-{[4-(Cyclopropylamino)-6-(4-(p-tolylamino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (4e)
Yield 1.3 g (58%); mp 148–151°C; IR: 3452 (N-H, secondary), 3031 (C-H, aromatic), 2932 (C-H, aliphatic), 2618 (-CH2, cyclopropylamine), 2249 (C≡N), 1349 (C-N), 818 cm-1; 1H NMR: δ 8.14 (d, J = 7 Hz, 1H, Ar-H), 7.96–7.68 (m, 4H, Ar-H), 7.57–7.31 (m, 7H, Ar-H), 6.72 (s, 1H, NH), 6.38 (s, 1H, NH), 6.18 (s, 1H, Ar-NH), 3.36 (s, 1H, NH), 3.04 (m, 1H, CH), 2.66 (s, 3H,CH3), 1.42–0.27 (m, 4H, CH2); 13C NMR: δ 164.4, 161.5, 160.6 (s-triazine), 151.2, 150.6, 148.5, 143.8, 139.7, 133.3, 130.1, 129.7, 124.5, 117.8, 112.1, 104.2 (Ar-C), 119.2 (Ar-CN), 25.2 (CH), 14.1 (Ar-CH3), 7.5 (CH2); MS (ESI): m/z 449.52 [M+]. Anal. Calcd for C26H24N8 (448.52): C, 69.62; H, 5.39; N, 24.98. Found: C, 69.44; H, 5.37; N, 24.93.
4-{[4-(Cyclopropylamino)-6-(4-(anilino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (4f)
Yield 1.7 g (80%); mp 122–125°C; IR: 3432 (N-H, secondary), 3064 (C-H, aromatic), 2984 (C-H, aliphatic), 2632 (-CH2, cyclopropylamine), 2294 (C≡N), 1354 (C-N), 842 cm-1; 1H NMR: δ 7.84–7.63 (m, 4H, Ar-H), 7.48–7.25 (m, 5H, Ar-H), 7.15–6.84 (m, 4H, Ar-H), 6.57 (s, 1H, NH), 6.28 (s, 1H, NH), 6.02 (s, 1H, Ar-NH), 3.45 (s, 1H, NH), 3.24 (m, 1H, CH), 1.24–0.27 (m, 4H, CH2); 13C NMR: δ 165.73, 162.48, 159.17 (s-triazine), 153.2 152.6 149.3, 142.3, 138.4, 135.5, 131.1, 128.6, 123.2, 118.4, 115.8, 105.8 (Ar-C), 119.9 (Ar-CN), 26.5 (CH), 6.3 (CH2); MS (ESI): m/z 435.41 [M+]. Anal. Calcd for C25H22N8 (434.50): C, 69.11; H, 5.10; N, 25.79. Found: C, 69.08; H, 5.09; N, 25.72.
4-{[4-(4-(Cyclohexylamino)anilino)-6-(cyclopropylamino)-1,3,5-triazin-2-yl]amino}benzonitrile (4g)
Yield 1.3 g (63%); mp 197–199°C; IR: 3412 (N-H, secondary), 3054 (C-H, aromatic), 2956 (C-H, aliphatic), 2632 (CH2, cyclopropylamine), 2154 (C≡N), 1354 (C-N), 832 cm-1; 1H NMR: δ 7.26–6.98 (m, 4H, Ar-H), 6.90–6.85 (m, 4H, Ar-H), 6.64 (s, 1H, NH), 6.38 (s, 1H, NH), 6.21 (s, 1H, Ar-NH), 4.12 (s, 1H, NH), 3.84 (m, 1H, CH), 3.21 (m, 1H, -CH), 1.83 (m, 4H, CH2), 1.66 (m, 6H, CH2), 1.36–0.16 (m, 4H, CH2); 13C NMR: δ 164.3, 161.1, 158.4 (s-triazine), 148.6, 145.1, 135.6, 131.6, 125.9, 122.4, 116.6, 104.1 (12 C, Ar-C), 120.3 (Ar-CN), 56.8 (CH), 38.5 (CH2), 28.3 (CH2), 25.82 (CH2), 24.90 (CH), 7.26 (CH2); MS (ESI): m/z 441.54 [M+]. Anal. Calcd for C25H28N8 (440.54): C, 68.16; H, 6.41; N, 25.44. Found: C, 68.25; H, 6.39; N, 25.47.
4-{[4-(Cyclopropylamino)-6-(4-(m-tolylamino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (4h)
Yield 1.5 g (70%); mp 161–164°C; IR: 3462 (N-H, secondary), 3031 (C-H, aromatic), 2902 (C-H, aliphatic), 2621 (CH2, cyclopropylamine), 2264 (C≡N), 1354 (C-N), 835 cm-1; 1H NMR: δ 7.96 (d, J = 7 Hz, 1H, Ar-H), 7.58–7.36 (m, 4H, Ar-H), 7.24–7.08 (m, 7H, Ar-H), 6.86 (s, 1H, NH), 6.52 (s, 1H, NH), 6.27 (s, 1H, Ar-NH), 3.89 (s, 1H, NH), 3.16 (m, 1H, CH), 2.45 (s, 3H, CH3), 1.43–0.13 (m, 4H, CH2); 13C NMR: δ 168.1, 163.4, 159.6 (s-triazine), 152.5, 150.2, 145.6, 142.3, 139.9, 134.3, 131.4, 128.4, 125.5, 121.6, 117.3, 112.2, 110.2, 103.9 (Ar-C), 118.7 (Ar-CN), 25.6 (CH,), 15.42 (Ar-CH3), 7.76 (CH2); MS (ESI): m/z 449.52 [M+]. Anal. Calcd for C26H24N8 (448.52): C, 69.62; H, 5.39; N, 24.98. Found: C, 69.47; H, 5.40; N, 24.92.
4-{[4-(4-(4-Acetylanilino)anilino)-6-(cyclopropylamino)-1,3,5-triazin-2-yl]amino}benzonitrile (4i)
Yield 1.3 g (58%); mp 119–122°C; IR: 3344 (N-H), 3042 (C-H, aromatic), 2911 (C-H, aliphatic), 2632 (CH2, cyclopropylamine), 2261 (C≡N), 1695 (C=O), 1322 (C-N), 820 cm-1; 1H NMR: δ 8.24 (d, J = 7 Hz, 2H, Ar-H), 7.97–7.75 (m, 4H, Ar-H), 7.61–7.43 (m, 6H, Ar-H), 6.87 (s, 1H, NH), 6.56 (s, 1H, NH), 6.29 (s, 1H, Ar-NH), 4.09 (s, 1H, NH), 3.35 (m, 1H, CH), 2.87 (s, 3H, CH3), 1.43–0.18 (m, 4H, CH2); 13C NMR: δ 193.6 (CO-CH3), 166.2, 164.9, 159.3 (s-triazine), 154.5, 148.7, 145.3, 140.7, 137.2, 134.3, 130.3, 128.9, 122.4, 118.8, 111.7, 103.1 (Ar-C), 119.3 (Ar-CN), 28.6 (CO-CH3), 24.9 (CH,), 7.48 (CH2); MS (ESI): m/z 477.53 [M+]. Anal. Calcd for C27H24N8O (476.53): C, 68.05; H, 5.08; N, 23.51. Found: C, 68.25; H, 5.07; N, 23.55.
4-{[4-(4-(4-Cyanoanilino)-6-(cyclopropylamino)-1,3,5-triazin-2-yl]amino}benzoic acid (4j)
Yield 1.5 g (66%); mp 161–164°C; IR: 3497 (-COOH), 3470 (N-H, secondary), 3032 (C-H, aromatic), 2931 (C-H, aliphatic), 2645 (CH2, cyclopropylamine), 2201 (C≡N), 1708 (C=O), 1317 (C-N), 802 cm-1; 1H NMR: δ 11.24 (s, 1H, COOH), 8.05 (d, J = 7 Hz, 2H, Ar-H), 7.84–7.62 (m, 4H, Ar-H), 7.55–7.39 (m, 6H, Ar-H), 6.76 (s, 1H, NH), 6.47 (s, 1H, NH), 6.22 (s, 1H, Ar-NH), 3.86 (s, 1H, NH), 3.28 (m, 1H, CH), 1.21–0.35 (m, 4H, -CH2); 13C NMR: δ 169.5 (COOH), 163.4, 160.8, 158.2 (s-triazine), 150.7, 148.1, 145.9, 144.1, 137.5, 134.7, 131.9, 127.1, 125.7, 118.4, 115.5, 101.1 (Ar-C), 120.2 (Ar-CN), 24.9 (CH), 6.9 (CH2); MS (ESI): m/z 479.53 [M+]. Anal. Calcd for C26H22N8O2 (478.51): C, 65.26; H, 4.63; N, 23.42. Found: C, 65.16; H, 4.62; N, 23.46.
4-{[4-(Cyclopropylamino)-6-(4-(4-ethylpiperazino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (5a)
Yield 1.6 g (70%); mp 124–126°C; IR: 3392 (N-H, secondary), 3149 (C-H, aromatic), 2933 (C-H, aliphatic), 2810 (-CH2, cyclopropylamine), 2220 (C≡N), 1359 (C-N), 835 cm-1; 1H NMR: δ 8.11 (d, J = 7 Hz, 2H, Ar-H), 7.83–7.67 (m, 4H, Ar-H), 7.53–7.31 (m, 2H, Ar-H), 6.98 (s, 1H, NH), 6.52 (s, 1H, Ar-NH), 3.68 (s, 1H, NH), 3.08 (m, 4H, CH2), 2.79 (m, 4H, CH2), 2.45–2.38 (m, 3H, CH), 1.21 (t, J = 7 Hz, 3H, CH3), 1.01–0.71 (m, 4H, CH2); 13C NMR: δ 165.1, 164.0, 163.6 (s-triazine), 145.2, 144.7, 139.1, 132.7, 128.4, 125.3, 121.3, 102.2 (Ar-C), 119.5 (Ar-CN), 52.3 (piperazine), 51.6 (piperazine), 51.0 (CH2), 23.5 (CH), 11.9 (CH3), 6.3 (CH2); MS (ESI): m/z 456.31 [M+]. Anal. Calcd for C25H29N9 (455.56): C, 65.91; H, 6.42; N, 27.67. Found: C, 66.06; H, 6.40; N, 27.60.
4-{[4-(Cyclopropylamino)-6-(4-(4-methylpiperazino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (5b)
Yield 1.4 g (64%); mp 183–185°C; IR: 3340 (N-H, secondary), 3159 (C-H, aromatic), 2914 (C-H, aliphatic), 2864 (CH2, cyclopropylamine), 2222 (C≡N), 1367 (C-N), 869 cm-1; 1H NMR: δ 7.91 (d, J = 7 Hz, 2H, Ar-H), 7.76–7.52 (m, 4H, Ar-H), 7.47–7.21 (m, 2H, Ar-H), 6.47 (s, 1H, NH), 6.26 (s, 1H, Ar-NH), 3.88 (s, 1H, NH), 3.34 (m, 4H, CH2), 2.94 (m, 4H, CH2), 2.38 (m, 1H, CH), 1.87 (s, 3H, CH3), 1.31–0.46 (m, 4H, CH2); 13C NMR: δ 166.4, 163.6, 160.4 (s-triazine), 148.7, 145.6, 138.1, 135.9, 129.4, 127.2, 120.8, 101.2 (Ar-C), 119.1 (Ar-CN), 50.4 (piperazine), 49.9 (, piperazine), 47.1 (CH3), 24.9 (CH), 7.24 (2C, CH2,); MS (ESI): m/z 442.54 [M+]. Anal. Calcd for C24H27N9 (441.53): C, 65.29; H, 6.16; N, 28.55. Found: C, 65.11; H, 6.14; N, 28.47.
4-{[4-(Cyclopropylamino)-6-(4-(4-phenylpiperazino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (5c)
Yield 1.9 g (76%); mp 167–169°C; IR: 3318 (N-H, secondary), 3172 (C-H, aromatic), 2946 (C-H, aliphatic), 2833 (CH2, cyclopropylamine), 2216 (C≡N), 1334 (C-N), 866 cm-1; 1H NMR: δ 7.78 (d, J = 7 Hz, 2H, Ar-H), 7.57–7.36 (m, 5H, Ar-H), 7.14–6.83 (m, 6H, Ar-H), 6.38 (s, 1H, NH), 6.14 (s, 1H, Ar-NH), 3.46 (s, 1H, NH), 3.25 (m, 4H, CH2), 2.84 (m, 4H, CH2), 2.55 (m, 1H, CH), 1.24–0.27 (m, 4H, CH2); 13C NMR: δ 164.4, 162.1, 161.6 (s-triazine), 151.8, 146.6, 142.9, 139.5, 133.4, 130.4, 129.1, 126.6, 122.3, 121.7, 120.1, 117.9, 101.5 (Ar-C), 119.6 (Ar-CN), 51.2(piperazine), 48.6 (piperazine), 22.9 (CH), 8.1 (CH2); MS (ESI): m/z 504.58 [M+]. Anal. Calcd for C29H29N9 (503.60): C, 69.16; H, 5.80; N, 25.03. Found: C, 69.06; H, 5.82; N, 25.00.
4-{[4-(Cyclopropylamino)-6-(4-(4-methyl-2-phenylpiperazino)anilino)-1,3,5-triazin-2-yl)]amino}benzonitrile (5d)
Yield 2.0 g (79%); mp 142–144°C; IR: 3310 (N-H, secondary), 3124 (C-H, aromatic), 2957 (C-H, aliphatic), 2864 (-CH2, cyclopropylamine), 2245 (C≡N), 1368 (C-N), 847 cm-1; 1H NMR: δ 8.12 (d, J = 7 Hz, 2H, Ar-H), 7.96–7.72 (m, 6H, Ar-H), 7.12–6.95 (m, 5H, Ar-H), 6.47 (s, 1H, NH), 6.10 (s, 1H, Ar-NH), 4.87 (t, 1H, J = 4 Hz, CH2), 3.84 (dt, 2H, J = 4 Hz, -CH2), 3.43 (s, 1H, NH), 2.84–2.67 (m, 4H, CH2), 2.51 (s, 3H, CH3), 2.14 (m, 1H, CH), 1.46–0.23 (m, 4H, CH2); 13C NMR: δ 162.58, 161.47, 160.18 (s-triazine), 148.8, 145.3, 143.5, 135.9, 130.4, 129.2, 128.6, 127.5, 125.1, 122.7, 121.2, 103.1 (Ar-C), 119.8 (Ar-CN), 62.5 (CH), 58.9 (CH2), 50.8 (CH2), 48.2 (CH2,), 45.6 (CH3), 24.18 (CH), 6.47 (2C, CH2); MS (ESI): m/z 518.60 [M+]. Anal. Calcd for C30H31N9 (517.63): C, 69.61; H, 6.04; N, 24.35. Found: C, 69.46; H, 6.03; N, 24.37.
Ethyl 4-{4-[4-(4-cyanoanilino)-6-(cyclopropylamino)-1,3,5-triazin-2-yl)amino]phenyl}piperazine-1-carboxylate (5e)
Yield 2.0 g (81%); mp 198–201°C; IR: 3392 (N-H, secondary), 3172 (C-H, aromatic), 2964 (C-H, aliphatic), 2834 (-CH2), 2279 (C≡N), 1740 (COO-), 1334 (C-N), 818 cm-1; 1H NMR: δ 7.96 (d, J = 7 Hz, 2H, Ar-H), 7.74–7.53 (m, 4H, Ar-H), 7.37–7.22 (m, 2H, Ar-H), 6.96 (s, 1H, NH), 6.45 (s, 1H, Ar-NH), 4.25 (m, 2H, CH2), 3.73 (s, 1H, NH), 3.47 (m, 4H, CH2), 2.66 (m, 4H, CH2), 2.28 (m, 1H, CH), 1.73–0.41 (m, 7H, CH); 13C NMR: δ 166.18, 165.61, 162.33 (s-triazine), 156.42 (CO), 148.2, 145.6, 138.2, 131.1, 129.7, 126.9, 122.1, 101.6 (Ar-C), 118.9 (Ar-CN), 63.9 (CH2), 49.3 (piperazine), 44.3 (piperazine), 24.4 (CH), 15.9 (CH3), 8.13 (CH2); MS (ESI): m/z 500.52 [M+]. Anal. Calcd for C26H29N9O2 (499.57): C, 62.51; H, 5.85; N, 25.23. Found: C, 62.33; H, 5.83; N, 25.17.
4-{[(4-(4-Diphenylmethyl)piperazino)anilino)-6-(cyclopropylamino)-1,3,5-triazin-2-yl]amino}benzonitrile (5f)
Yield 1.6 g (55%); mp 133–135°C; IR: 3311 (N-H), 3146 (C-H, aromatic), 2912 (C-H, aliphatic), 2832 (CH2), 2248 (C≡N), 1392 (C-N), 818 cm-1; 1H NMR: δ 8.13–7.83 (m, 6H, Ar-H), 7.61–7.42 (m, 7H, Ar-H), 7.12–6.62 (m, 5H, Ar-H), 6.25 (s, 1H, NH), 6.13 (s, 1H, Ar-NH), 5.31 (s, 1H, CH), 3.93 (s, 1H, NH), 3.25 (m, 4H, CH2), 2.66 (m, 4H, CH2), 2.12 (m, 1H, CH), 1.24–0.15 (m, 4H, CH2); 13C NMR: δ 162.3, 161.7, 160.3 (s-triazine), 149.2, 148.7, 142.8, 135.4, 131.2, 129.8, 127.8, 125.4, 125.0, 123.6, 121.5, 103.7 (Ar-C), 119.2 (Ar-CN), 79.5 (CH), 52.7 (piperazine), 50.4 (piperazine), 22.7 (CH), 6.9 (CH2); MS (ESI): m/z 592.75 [M+]. Anal. Calcd for C36H35N9 (593.72): C, 72.83; H, 5.94; N, 21.23. Found: C, 72.95; H, 5.96; N, 21.17.
4-{[4-(Cyclopropylamino)-6-(4-(4-(2-(2-hydroxyethoxy)ethyl)piperazino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (5g)
Yield 1.5 g (59%); mp 218–219°C; IR: 3498 (OH), 3364 (N-H, secondary), 3124 (C-H, aromatic), 2979 (C-H, aliphatic), 2857 (CH2), 2216 (C≡N), 1346 (C-N), 834 cm-1; 1H NMR: δ 7.68 (d, J = 7 Hz, 2H, Ar-H), 7.42–7.27 (m, 4H, Ar-H), 6.94–6.54 (m, 2H, Ar-H), 6.31 (s, 1H, NH), 6.18 (s, 1H, Ar-NH), 4.25 (s, 1H, NH), 4.05 (s, 1H, OH), 3.78–3.50 (m, 6H, CH2), 3.26 (m, 4H, CH2), 2.83 (m, 4H, CH2), 2.57 (t, J = 5 Hz, 2H, CH2), 2.15 (m, 1H, CH), 1.62–0.38 (m, 4H, CH2); 13C NMR: δ 164.6, 162.4, 161.2 (s-triazine), 149.2, 142.1, 134.4, 131.6, 126.1, 124.8, 121.4, 103.1 (Ar-C), 120.9 (Ar-CN), 71.9 (O-CH2), 68.6 (CH2O), 63.0 (CH2OH), 57.3 (NCH2), 51.4 (piperazine), 48.7 (piperazine), 23.2 (CH), 8.8 (CH2); MS (ESI): m/z 516.55 [M+]. Anal. Calcd for C27H33N9O2 (515.61): C, 62.89; H, 6.45; N, 24.45. Found: C, 62.74; H, 6.44; N, 24.49.
4-{[4-(Cyclopropylamino)-6-(4-(4-(pyridin-2-yl)piperazino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (5h)
Yield 1.9 g (77%); mp 171–174°C; IR: 3364 (N-H, secondary), 3124 (C-H, aromatic), 2967 (C-H, aliphatic), 2856 (CH2), 2224 (C≡N), 1370 (C-N), 810 cm-1; 1H NMR: δ 8.24 (d, J = 7 Hz, 1H, Ar-H), 7.83 (d, J = 7 Hz, 2H, Ar-H), 7.69–7.48 (m, 5H, Ar-H), 7.12–6.60 (m, 4H, Ar-H), 6.33 (s, 1H, NH), 6.05 (s, 1H, Ar-NH), 4.16 (s, 1H, NH), 3.41 (m, 4H, CH2), 2.57 (m, 4H, CH2), 2.22 (m, 1H, CH), 1.29–0.33 (m, 4H, CH2); 13C NMR: δ 164.6, 162.3, 161.1 (s-triazine), 159.2, 148.6, 141.9, 112.7, 108.3 (pyridine), 147.8, 142.1, 134.9, 131.7, 126.6, 122.2, 120.2, 103.0 (Ar-C), 118.3 (Ar-CN), 51.7 (piperazine), 48.2 (piperazine), 23.2 (CH), 8.1 (CH2); MS (ESI): m/z 505.45 [M+]. Anal. Calcd for C28H28N10 (504.59): C, 66.65; H, 5.59; N, 27.76. Found: C, 66.48; H, 5.57; N, 27.69.
4-{[4-(Cyclopropylamino)-6-(4-(4-(2,3,4-trimethoxybenzyl)piperazino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (5i)
Yield 2.0 g (69%); mp 209–211°C; IR: 3346 (N-H, secondary), 3112 (C-H, aromatic), 2997 (C-H, aliphatic), 2846 (-CH2, cyclopropylamine), 2245 (C≡N), 1324 (C-N stretch), 853 cm-1; 1H NMR: δ 7.82 (d, J = 7 Hz, 2H, Ar-H), 7.55–7.23 (m, 4H, Ar-H), 7.11–6.44 (m, 4H, Ar-H), 6.25 (s, 1H, NH), 6.15 (s, 1H, Ar-NH), 3.92 (s, 6H, OCH3), 3.77 (s, 3H, OCH3), 3.63 (s, 1H, NH), 3.51 (s, 2H, CH2), 3.28 (m, 4H, CH2), 2.85 (m, 4H, CH2), 2.49 (m, 1H, CH), 1.18–0.36 (m, 4H, CH2); 13C NMR: δ 164.3, 162.1, 161.6 (s-triazine), 156.4, 152.7, 149.2, 143.1, 142.9, 135.1, 131.9, 127.1, 126.7, 124.2, 122.6, 120.4, 110.8, 104.9 (Ar-C), 118.3 (Ar-CN), 64.3 (OCH3), 63.5 (OCH3), 60.6 (CH2), 57.7 (OCH3), 49.4 (piperazine), 47.8 (piperazine), 25.8 (CH), 8.2 (CH2); MS (ESI): m/z 608.64 [M+]. Anal. Calcd for C33H37N9O3 (607.71): C, 65.22; H, 6.14; N, 20.74. Found: C, 65.29; H, 6.15; N, 20.68.
4-{[4-(Cyclopropylamino)-6-(4-(4-(3-methylbenzyl)piperazino)anilino)-1,3,5-triazin-2-yl]amino}benzonitrile (5j)
Yield 1.5 g (58%); mp 181–183°C; IR: 3346 (N-H, secondary), 3117 (C-H, aromatic), 2946 (C-H, aliphatic), 2812 (-CH2, cyclopropylamine), 2215 (C≡N), 1360 (C-N), 844 cm-1); 1H NMR: δ 8.14 (d, J = 7 Hz, 2H, Ar-H), 7.85–7.69 (m, 5H, Ar-H), 7.32–7.05 (m, 5H, Ar-H), 6.23 (s, 1H, NH), 6.10 (s, 1H, Ar-NH), 3.63 (s, 1H, NH), 3.42 (s, 2H, CH2), 3.28 (m, 4H, CH2), 2.85 (m, 4H, CH2), 2.41 (m, 1H, CH), 2.10 (s, 3H, CH3), 1.26–0.50 (m, 4H, -H2); 13C NMR: δ 163.2, 161.3, 159.7 (s-triazine), 149.9, 144.5, 138.1, 136.4, 133.3, 131.7, 129.9, 127.7, 127.2, 126.7, 125.3, 123.7, 121.2, 104.1 (Ar-C), 120.6 (Ar-CN), 67.1 (CH2), 51.3 (piperazine), 48.7 (piperazine), 25.9 (CH), 22.7 (CH3), 6.3 (CH2); MS (ESI): m/z 532.42 [M+]. Anal. Calcd for C31H33N9 (531.65): C, 70.03; H, 6.26; N, 23.71. Found: C, 70.08; H, 6.24; N, 23.77.
Acknowledgments
The authors are very thankful to Prof. Nisha K. Shah, head of the Department of Chemistry, School of Sciences, Gujarat University, Ahmedabad, India, for her kind cooperation in providing support and research facility. The authors wish to offer their deep gratitude to TB-care Laboratory, Ahmedabad, India, for carrying out the biological screenings. We are also thankful to NFDD-Rajkot, Gujarat, India, for carrying out IR, 1H NMR, and 13C NMR analyses. D.R.S. would like to acknowledge UGC New Delhi for his Junior Research Fellowship.
References
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