Abstract
2-Amino-3-cyanopyridine is a simple precursor for the synthesis of analogues of Egyptian natural products visnagin and khellin. Fused pyrido[2,3-d]pyrimidines were prepared under mild reaction conditions. The detailed syntheses and spectroscopic data of the synthesised compounds are reported. Some isolated compounds show antibacterial and antifungal activity.
Introduction
Bicyclic nitrogen-containing heterocyclic compounds such as purines [1–3], quinazolines [4–6], pteridines and pyrido-pyrimidines [7, 8] are well-known pharmacophores in drug discovery. Gefitinib and erlotinib are examples of market drugs with a bicyclic core structure, which are quinazoline derivatives acting as tyrosine kinase inhibitors and both are used for treatment of non-small cell lung cancer.
Pyrido[2,3-d]pyrimidines, as analogues of quinazoline, have been intensively investigated. This scaffold is associated with a wide range of biological activities including dihydrofolate reductase (DHFR) inhibition, antitumor activity [9–11], adenosine kinase inhibition [12] and tyrosine kinase inhibition [13, 14], among other properties [15–18]. Part of our ongoing interest is to explore new scaffolds based on analogues of Egyptian natural products such as khellinone and its analogues.
Results and discussion
Chemistry
The interesting biological activity of khellinone derivatives [19] prompted us to continue our investigation of pyrido[2,3-d]pyrimidine incorporating 4,7-dimethoxy-1-benzofuran-5-ol moiety or trimethoxyphenyl moiety. A facile synthesis of 2-amino-3-cyanopyridine derivatives in a one-pot reaction was achieved using aromatic aldehyde, methyl ketone, malononitrile and ammonium acetate [20] or by preparing α,β-unsaturated ketone followed by reaction with malononitrile in the presence of ammonium acetate [21, 22]. 2-Amino-3-cyanopyridine is considered a simple and convenient precursor for the synthesis of pyrido[2,3-d]pyrimidine incorporating some new khellinone derivatives and its analogues.
Thus, refluxing substrate 1a [21, 22] or 1b with anhydrous ammonium acetate and malononitrile in ethanol for 8 h led to the formation of the product 2a or 2b, respectively, in good yield (Scheme 1). Treatment of 2a with formic acid yielded pyrido[2,3-d]pyrimidine-4(3H)-one 3 in a moderate yield (Scheme 2). Treatment of 3 with phosphorus oxychloride in dioxane led to the formation of a pyrido[2,3-d]pyrimidine derivative 4 in poor yield. We believe that the formation of a hydrochloride salt of the pyrido[2,3-d]pyrimidine substrate may be responsible for the low yield. The dichloro-pyrido[2,3-d]pyrimidine 4 was allowed to react with hydrazine hydrate to give derivative 5 in low yield. Compound 5 was transformed into triazolo[4,3-c]pyrimidines 6a–c (Scheme 2), which may possess pharmacological properties similar to theophylline [23–26].
The poor yield was a problem in the synthesis of a variety of fused pyridopyrimidine derivatives. Herein, we explored a method that can offer a better yield of pyridopyrimidine products. As can be seen from Scheme 3, compounds 2a,b were allowed to react with carbon disulphide in the presence of hydrogen sodium carbonate yielding the respective dithiones 7a and 7b in good yield. Compound 7b was allowed to react with chloroacetic acid and benzaldehyde in the presence of sodium acetate under reflux in a mixture of acetic acid and acetic anhydride to afford the product 8 in a moderate yield.
The alkylation of compound 7b with the appropriate functionalised halo compounds, followed by intramolecular cyclisation, led to the formation of the corresponding pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidine derivatives 8–11.
The introduction of a good leaving group was pursued in another approach. Thus, compounds 7a,b were treated with iodomethane leading to formation of the respective methylthio derivatives 12a,b in good yield. The nucleophilic substitution of the methylthio group took place by treatment of compounds 12a,b with hydrazine hydrate leading to the formation of hydrazino derivatives 13a,b (Scheme 4). Compound 13a was allowed to react with two ortho esters and carbon disulphide to furnish the respective thiones 14a, 14b and 15. Yet, another approach to the construction of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine derivatives utilises the reaction of compound 13b with appropriate carboxylic acid in the presence of phosphorus oxychloride. Compounds 16a,b were synthesised in this way. A different methodology for the preparation of unfused biheterocyclic products 17 and 18 involves conjugate addition of the hydrazine derivative 13b with appropriate α,β-unsaturated nitriles in the presence of piperidine as a catalyst. Compound 13b was also allowed to react with benzoin in the presence of phosphorus oxychloride (Scheme 4). This reaction led to the formation of the fused tricyclic thione 19.
Biological activity
Some of the synthesised compounds were evaluated for their antimicrobial activity. The results were compared with the activity of well-known antimicrobial and antifungal standards. The results of the preliminary screening tests are given in Table 1. As can be seen, some khellinone derivatives show higher antimicrobial activity than the standard.
Antimicrobial activity of selected compounds.
| Tested compounds and standards (μg/mL) | Inhibition zone diameter (mm/mg sample) | ||||
|---|---|---|---|---|---|
| Escherichia coli (G-) | Staphylococcus aureus (G+) | Bacillus subtilis (G+) | Candida albicans (yeast) | Aspergillus niger (fungi) | |
| 1 | ++ | ++ | +++ | – | – |
| 2a | ++ | ++ | ++ | – | – |
| 3 | +++ | ++ | +++ | ++ | – |
| 4 | +++ | ++ | ++ | ++ | +++ |
| 5 | +++ | +++ | ++ | ++ | ++ |
| 6a | + | + | + | ++ | – |
| 6b | ++ | ++ | ++ | ++ | ++ |
| 6c | ++ | ++ | ++ | ++ | +++ |
| 7a | ++ | ++ | ++ | ++ | ++ |
| 12a | ++ | ++ | ++ | +++ | ++ |
| 13a | ++ | ++ | ++ | ++ | ++ |
| 14a | +++ | ++ | ++ | ++ | ++ |
| 14b | ++ | + | + | + | ++ |
| 14c | ++ | +++ | ++ | + | +++ |
| Levofloxacina | +++ | +++ | +++ | - | – |
| Nystatinb | – | – | – | +++ | +++ |
+++, Highly active (21–25 mm); ++, fairly active (16–20 mm); +, slightly active (15–10 mm); –, not active.
aLevofloxacin is an anti-Gram positive and anti-Gram negative antibiotic.
bNystatin is an antifungal antibiotic.
Experimental
General
Melting points are uncorrected. Microanalyses were carried out at the Microanalytical Unit, National Research Centre and Faculty of Science, Cairo University. The IR spectra were recorded in KBr pellets on an FT-IR NEXCES spectrophotometer (Shimadzu, Japan). 1H NMR (500 MHz) and 13C NMR (125 MHz) spectra were measured with a Jeol ECA 500 (Japan) in DMSO-d6 or CDCl3. Mass spectra (EI) were run at 70 eV with a Finnigan SSQ 7000 spectrometer (Thermo Instrument System Incorporation, USA). All reactions were followed up by TLC analysis.
Biological evaluation
The antimicrobial activity was determined by the cup plate technique method with some modifications. Levofloxacin and nystatin were used as reference antibiotics. The medium was nutrient agar for bacteria, potato dextrose for fungi, and the tested microorganisms were Gram-positive bacteria Staphylococcus aureus, Bacillus subtilis, Gram-negative bacteria Escherichia coli, yeast (single cell fungus) Candida albicans and multicellular fungus Aspergillus niger. Data were obtained according to the following procedure. A volume of 40 mL of the medium (at 55–60°C) was inoculated with 200 μL of the prepared test microorganism suspensions and poured into 15 cm diameter plates, mixed well and allowed to solidify. After solidification, holes (0.9 cm diameter) were made in the agar plates with the aid of a sterile cork-borer. In the holes, 50 μL of the dissolved sample was placed using an automatic micropipette. The Petri dishes were left at 5°C for 1 h to allow diffusion of the antibiotic through the agar medium prior to the growth of the test organism, and then they were incubated at 30°C for 24 h. The antimicrobial data are compiled in Table 1.
2-Amino-6-(5-hydroxy-4,7-dimethoxy-1-benzofuran-6-yl)-4-(4-methoxyphenyl)nicotinonitrile (2a)
Compound 1 (1 mmol), malononitrile (1.1 mmol) and anhydrous ammonium acetate (2 mmol) were heated under reflux in absolute ethanol (15 mL) for 8 h. The reaction mixture was cooled to room temperature and the precipitate was collected upon filtration, washed several times with water, dried and crystallised from ethanol to give compound 2a as yellow crystals in 53% yield; mp 201–203°C; IR (cm-1, ν): 3440 (br, OH), 3256, 3253 (NH2), 2224 (CN); 1H NMR (CDCl3): δ 3.85 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.1 (s, 3H, OCH3), 7.11 (d, J = 7.25 Hz, 1H, CH), 7.45 (d, J = 8.4 Hz, 2H, ArH), 7.69 (d, J = 8.4 Hz, 2H, ArH), 7.73 (s, 1H, ArH), 7.78 (d, J = 7.3 Hz 1H, CH) and 8.2 (br, s, 2H, NH2, D2O exchangeable); 13C NMR (CDCl3): δ 46.6, 46.8, 52.7, 99.1, 111.3, 128.1, 134, 138, 143, 145, 146.2, 147.1, 147.4, 147.7, 147.8, 148.6, 148.9, 149.2, 149.6, 149.8,151.3; MS: m/z 414 (M+, 100%). Anal. Calcd for C23H19N3O5: C, 66.18; H, 4.59; N, 10.07. Found: C, 66.35; H, 4.78; N, 10.19.
2-Amino-4-(2,4,6-trimethoxyphenyl)-6-(3,4,5-trimethoxyphenyl)nicotinonitrile (2b)
A mixture of 1 (1 mmol), malononitrile (1.2 mmol) and anhydrous ammonium acetate (80 mmol) in absolute ethanol was heated on a water bath for 8 h. After cooling, the obtained product was filtered and washed several times with water, dried and then crystallised from ethanol affording 2b in 78% yield; mp 256°C; IR (cm-1, ν): 3266, 3242 (NH2), 2231 (CN); 1H NMR (DMSO-d6): δ 3.62 (s, 6H, 2 OCH3), 3.71 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.86 (s, 6H, 2 OCH3), 6.81 (s, 2H, ArH), 7.01 (s, 2H, ArH), 7.75 (s, 1H, CH), 8.07–8.10 (br, 2H, NH2, exchangeable with D2O); 13C NMR (DMSO-d6): δ 55.1, 55.9, 57.1, 59.7, 92.4, 97.6, 103.6, 114.2, 118.1, 119.9, 124.1, 147.4, 151.9, 152.4, 158.4, 158.9, 159.3, 164.7. Anal. Calcd for C24H25N3O6: C, 63.85; H, 5.58; N, 9.31. Found: C, 63.69; H, 5.78.; N, 9.19.
7-(5-Hydroxy-4,7-dimethoxybenzofuran-6-yl)-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-4(3H)-one (3)
A mixture of compound 2 (1 mmol) and formic acid (5 mL) was heated and stirred for 8 h. The precipitate, isolated after neutralisation with sodium hydroxide solution, was crystallised from ethanol to furnish compound 3 as shiny yellow crystals in 55% yield; mp 188°C; IR (cm-1, ν): 3443 (br, OH), 3358, (NH), 1668 (C=O); 1H NMR (CDCl3): δ 3.83 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.1(s, 3H, OCH3), 7.15 (d, J = 7.3 Hz, 1H, CH), 7.45 (d, J = 8.4 Hz, 2H, ArH), 7.69 (d, J = 8.4 Hz, 2H, ArH), 7.74 (s, 1H, ArH), 7.78 (d, J = 7.3 Hz, 1H, CH), 8.31 (s, 1H, ArH), 8.49 (br, s, 1H, NH, D2O exchangeable); MS: m/z 417 (M+, 100%). Anal. Calcd for C24H19N3O6: C, 64.72; H, 4.30; N, 9.43. Found: C, 64.59; H, 4.08; N, 9.23.
4-Chloro-7-(6-chloro-4,7-dimethoxy-1-benzofuran-6-yl)-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine (4)
A mixture of compound 3 (5 mmol) and phosphorus oxychloride (10 mL) in dry dioxane (15 mL) was heated under reflux for 1 h, then the mixture was cooled to room temperature and poured into crushed ice. The resultant precipitate was filtered, washed with ice water and dried to afford compound 4 in 56% yield; mp 175°C; IR (cm-1, ν): 3349 (NH); 1H NMR (CDCl3): δ 3.85 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.0 (s, 3H, OCH3), 7.22 (d, J = 6.7 Hz, 1H, CH), 7.45 (d, J = 8.7 Hz, 2H, ArH), 7.73 (d, J = 8.7 Hz, 2H, ArH), 7.77 (d, J = 6.7 Hz, 1H, CH), 7.69 (s, 1H, CH), 8.28 (s, 1H, CH); 13C NMR (CDCl3): δ 43.6, 46.8, 52.8 (3 OCH3), 99.1, 111.3, 128.1, 134.0, 138.0, 143.0, 145.0, 146.2, 147.4, 147.7, 147.8, 148.3, 148.6, 148.7, 148.9, 149.2, 149.6, 149.8, 151.3. Anal. Calcd for C24H17Cl2N3O4: C, 59.77; H, 3.55; N, 8.71. Found: C, 56.59; H, 3.87; N, 8.58.
7-(5-Chloro-4,7-dimethoxy-1-benzofuran-6-yl)-4-hydrazino-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine (5)
A solution of compound 4 (5 mmol) and hydrazine hydrate (0.15 mL) in ethanol (15 mL) was stirred under reflux for 10 h (under TLC control) whereby a greenish yellow precipitate was formed. The precipitate was filtered, washed with water, dried and crystallised from ethanol to furnish 5 in a yield of 48%; mp 204–206°C; IR (cm-1, ν): 3344 (NH), 3277, 3270 (NH2); 1H NMR (DMSO-d6): δ 3.74 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.1 (s, 3H, OCH3), 6.65 (br, s, 2 H, NH2, D2O exchangeable), 7.40 (d, J = 6.7 Hz, 1H, CH), 7.55 (d, J = 8.6 Hz, 2H, ArH), 7.77 (d, J = 8.6 Hz, 2H, ArH), 7.81 (s, 1H, CH), 7.88 (d, J = 6.7 Hz 1H, CH), 8.56 (s, 1H, Ar-H), 9.12 (br, s, H, NH, D2O exchangeable); 13C NMR (DMSO-d6): δ 43.6, 46.8, 52.8 (3 OCH3), 99.1, 111.3, 128.1, 134.0, 138.0, 143.0, 145.0, 146.2, 147.1, 147.4, 147.7, 147.8, 148.3, 148.6, 148.7, 148.9, 149.2, 149.6, 149.8 and 151.3. Anal. Calcd for C24H20ClN5O4: C, 60.30; H, 4.22; N, 14.65. Found: C, 59.98; H, 4.57; N, 14.43.
General procedure for pyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 6a–c
A mixture of compound 5 (1 mmol), formic acid (1 mL) and concentrated hydrochloric acid (1 mL) in the case of 6a or acetic anhydride (5 mL) in the case of 6b or carbon disulphide (1 mL) in the case of 6c, was heated gently on a water bath for 6–8 h (under TLC control). The reaction mixture was cooled to room temperature, poured into cold water (100 mL), and the resultant precipitate was collected by filtration, washed several times with water, dried and crystallised from ethanol.
8-(5-Chloro-4,7-dimethoxy-1-benzofuran-6-yl)-10-(4-methoxyphenyl)pyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (6a)
This compound was isolated in 61% yield; mp 161–162°C; 1H NMR (CDCl3): δ 3.78 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.10 (s, 3H, OCH3), 7.20 (d, J = 6.7 Hz, 1H, CH), 7.55 (d, J = 8.7 Hz, 2H, ArH), 7.66 (s, 1H, CH), 7.77 (d, J = 8.7 Hz, 2H, ArH), 7.88 (d, J = 6.7 Hz, 1H, CH), 8.56 (s, 1H, CH, ArH), 8.68 (s, 1H, CH, ArH). Anal. Calcd for C25H18ClN5O4: C, 61.54; H, 3.72; N, 14.35. Found: C, 61.38; H, 3.57; N, 14.21.
8-(5-Chloro-4,7-dimethoxy-1-benzofuran-6-yl)-10-(4-methoxyphenyl)-3-methylpyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (6b)
This compound was isolated in 58% yield; mp 183–184°C; yellow crystals; 1H NMR (CDCl3): δ 2.21 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.08 (s, 3H, OCH3), 7.20 (d, J = 6.7 Hz, 1H, CH), 7.55 (d, J = 8.7 Hz, 2H, ArH), 7.78 (d, J = 8.7 Hz, 2H, ArH), 7.84 (s, 1H, CH, ArH), 7.88 (d, J = 6.7 Hz, 1H, CH), 8.66 (s, 1H, CH, ArH). Anal. Calcd for C26H20ClN5O4: C, 62.22; H, 4.02; N, 13.95. Found: C, 61.95; H, 3.77; N, 14.21.
8-(5-Chloro-4,7-dimethoxy-1-benzofuran-6-yl)-10-(4-methoxyphenyl)pyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-3-thiol (6c)
This compound was isolated in 67% yield; mp 211–212°C; IR (cm-1, ν): 3440 (br, NH); 1H NMR (DMSO-d6): δ 1.77 (s, 1H, SH), 3.78 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.07 (s, 3H, OCH3), 7.20 (d, J = 6.7 Hz, 1H, CH), 7.57 (d, J = 8.7 Hz, 2 H, ArH), 7.77 (d, J = 8.7 Hz, 2 H, ArH), 7.81 (s, 1H, CH, ArH), 7.88 (d, J = 6.7 Hz, 1H, CH), 8.56 (s, 1H, CH, ArH). Anal. Calcd for C26H18ClN5O4S: C, 57.75; H, 3.49; N, 13.47. Found: C, 57.57; H, 3.77; N, 13.19.
7-(5-Hydroxy-4,7-dimethoxybenzofuran-6-yl)-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dithione (7a)
A mixture of compound 2a (10 mmol) and sodium bicarbonate solution [0.084 g of sodium bicarbonate dissolved in 15 mL water/ethanol mixture (2:3)] was heated under reflux for 2 h and then cooled to room temperature. Carbon disulphide (0.08 mL) was then added and the heating was continued on a water bath for an additional 2 h. The formed precipitate was isolated after neutralisation with diluted hydrochloric acid, washed with water, dried and crystallised from an ethanol/dioxane mixture (3:1) affording 7a in 71% yield; mp 304–305°C; IR (cm-1, ν): 3430 (OH), 3345 (NH), 1555 (SH); 1H NMR (CDCl3): δ 1.60 (s, 1H, SH), 3.74 (s, H, OCH3), 3.86 (s, H, OCH3), 4.04 (s, 3H, OCH3), 7.25 (d, J = 7.2 Hz, 1H, CH), 7.65 (d, J = 8.4 Hz, 2 H, ArH), 7.74 (d, J = 8.4 Hz, 2 H, ArH), 7.77 (s, 1H, CH, ArH), 7.79 (d, J = 7.2 Hz, 1H, CH), 8.60 (br, s, 1H, NH, D2O exchangeable) and 10.60 (br, s, 1H, NH, D2O exchangeable); 13C NMR (CDCl3): δ 46.6, 48.8, 52.8 (3 OCH3), 100.3, 113.4, 128.6, 133.8, 138.6, 145.7, 145.8, 146.8, 147.6, 147.9, 148.3, 148.6, 148.8, 149, 150, 150.6, 151, 151.6, 153.1, 166.8, 168.9; MS: m/z 493 (M+, 100%). Anal. Calcd for C24H19N3O5S2: C, 58.40; H, 3.88; N, 8.51. Found: C, 58.57; H, 4.12; N, 8.72.
5-(2,4,6-Trimethoxyphenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dithione (7b)
Compound 2b (1 mmol) was subjected to the procedure described above. Product 7b was obtained as yellowish brown powder; yield 78%; mp 295–296°C; IR (cm-1, ν): 3349 (NH) and 1561 (SH); 1H NMR (DMSO-d6): δ 3.64 (s, 6H, 2 OCH3), 3.73 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.92 (s, 6H, 2 OCH3), 6.92 (s, 2H, ArH), 7.04 (s, 2H, ArH), 7.76 (s, 1H, CH), 8.84–8.79 ppm (br, 1H, NH, D2O exchangeable), 9.60 (br, s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6): δ 169.2, 164.7, 154.2, 152.3, 151.1, 147.7, 138.7, 128.1, 127.6, 126.2, 112.1, 103.5, 92.1, 59.3, 55.9, 55.8, 54.8. Anal. Calcd for C25H25N3O6S2: C, 56.91; H, 4.78; N, 7.96. Found: C, 56.79; H, 4.87; N, 7.68.
2-Benzylidene-5-thioxo-6-(2,4,6-trimethoxyphenyl)-8-(3,4,5-trimethoxyphenyl)-5H-pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidin-3(2H)-one (8)
A mixture of compound 7b (1 mmol), chloroacetic acid (1.2 mmol), benzaldehyde (1.2 mmol) and anhydrous sodium acetate (4 mmol) in a mixture of acetic acid and acetic anhydride (1:1) was heated under reflux for 8 h. The formed solid was collected and washed with acetic acid and ethanol several times yielding 8 in 76% yield; mp 310–311°C; 1H NMR (DMSO-d6): δ 3.61 (s, 6H, 2 OCH3), 3.75 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.95 (s, 6H, 2 OCH3), 6.96 (s, 2H, ArH), 7.03 (s, 2H, ArH), 7.28–7.36 (m, 5H, ArH), 8.32 (s, CH), 8.71 (s, CH); 13C NMR (DMSO-d6): δ 54.7, 55.2, 55.8, 59.3, 94.1, 96.3, 107.3, 113.7, 121.1, 124.2, 127.9, 128.3, 129.8, 131.7, 138.4, 139.9, 143.4, 145.6, 148.2, 152.4, 154.8, 159.7, 162.6, 163.9, 172.4. Anal. Calcd for C33H26N3O7S2: C, 61.86; H, 4.09; N, 6.56. Found: C, 61.48; H, 4.37; N, 6.78.
3-Amino-6-(2,4,6-trimethoxyphenyl)-8-(3,4,5-trimethoxyphenyl)-5H-pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-5-thione (9)
A mixture of compound 7b (1 mmol) and sodium methoxide (1.5 mmol) in methanol was stirred at room temperature for 1 h. Chloroacetonitrile (1.2 mmol) was added to the reaction mixture, followed by gentle heating for 3 h. The formed solid was filtered and washed several times with water, affording 9 in 67% yield; mp 283–284°C; 1H NMR (DMSO-d6): δ 3.63 (s, 6H, 2 OCH3), 3.72 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.97 (s, 6H, 2 OCH3), 5.8 (s, 1H), 6.43–6.76 (br, 2H, NH2, exchangeable with D2O), 6.96 (s, 2H, ArH), 7.02 (s, 2H, ArH), 8.25 (s, 1H, CH); 13C NMR (DMSO-d6): δ 54.8, 55.1, 55.9, 59.4, 93.4, 95.6, 108.2, 115.1, 117.2, 122.6, 124.1, 138.1, 147.1, 149.4, 151.3, 153.9, 157.6, 159.1, 159.9, 162.2, 170.3. Anal. Calcd for C27H26N4O6S2: C, 57.23; H, 4.62; N, 9.89. Found: C, 57.06; H, 4.79; N, 9.57.
Ethyl 3-amino-5-thioxo-6-(2,4,6-trimethoxyphenyl)-8-(3,4,5-trimethoxyphenyl)-5H-pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-2-carboxylate (10)
A mixture of compound 7b (1 mmol) and sodium methoxide (1.5 mmol) in methanol was stirred at room temperature for 1 h, then treated with ethyl chloro(cyano)acetate (1.2 mmol), and the mixture was heated for 5 h. The resultant solid was filtered and washed several times with water, affording 10 in 63% yield; mp 292–293°C; 1H NMR (DMSO-d6): δ 1.34 (t, 3H, J = 7.1 Hz, CH2-CH3), 3.61 (s, 6H, 2 OCH3), 3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.96 (s, 6H, 2 OCH3), 4.21 (q, 2H, J = 7.1 Hz, CH2-CH3), 6.43–6.76 (br, 2H, NH2, exchangeable with D2O), 6.98 (s, 2H, ArH), 7.06 (s, 2H, ArH), 8.29 (s, CH). Anal. Calcd for C30H30N4O8S2: C, 56.41; H, 4.73; N, 8.72. Found: C, 56.24; H, 4.93; N, 8.59.
3-Amino-5-thioxo-6-(2,4,6-trimethoxyphenyl)-8-(3,4,5-trimethoxyphenyl)-5H-pyrido [2,3-d][1,3]thiazolo[3,2-a]pyrimidine-2-carbonitrile (11)
A mixture of compound 7b (1 mmol) and sodium methoxide (1.5 mmol) in methanol was stirred at room temperature for 1 h, then treated with bromomalononitrile (1.2 mmol), and the mixture was heated for 5 h. The resultant solid was filtered and washed several times with water, affording 11 in 69% yield; mp 284–285°C; 1H NMR (DMSO-d6): δ 3.61 (s, 6H, 2 OCH3), 3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.96 (s, 6H, 2 OCH3), 5.98–6.11 (br, 2H, NH2, exchangeable with D2O), 6.93 (s, 2H, ArH), 7.08 (s, 2H, ArH), 8.36 (s, CH). Anal. Calcd for C28H25N5O6S2: C, 56.84; H, 4.26; N, 11.84. Found: C, 56.69; H, 4.53; N, 11.72.
7-(5-Hydroxy-4,7-dimethoxybenzofuran-6-yl)-5-(4-methoxyphenyl)-2-(methylthio)-2,3-dihydropyrido[2,3-d]pyrimidine-4(1H)-thione (12a)
A mixture of ethanolic sodium hydrogen carbonate solution [0.084 g of sodium bicarbonate dissolved in 15 mL water/ethanol mixture (2:3)] and compound 4 (1 mmol) was stirred for 4 h at room temperature, then heated under reflux for 3 min, and cooled to room temperature. Iodomethane (1.4 mmol) was added to sodium salt 4 and heating was continued for an additional 2 h. The reaction mixture was cooled to room temperature and poured onto cold water (25 mL). The resultant precipitate was filtered, washed well with water, dried and crystallised from an ethanol/dioxane mixture (3:2) to furnish 12a as pale yellow powder in 55% yield; mp 251–252°C; IR (cm-1, ν): 3430 (br, OH), 3345 (NH); 1H NMR (CDCl3): δ 2.63 (s, 3H, SCH3), 3.78 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.1 (s, 3H, OCH3), 7.25 (d, J = 7.2 Hz, 1H, CH), 7.65 (d, J = 8.7 Hz, 2H, ArH), 7.74 (d, J = 8.7 Hz, 2H, ArH), 7.77 (s, 1H, CH, ArH), 7.79 (d, J = 7.2 Hz, 1H, CH), 9.70 (br, s, 1H, NH, D2O exchangeable); MS: m/z 521 (M+, 100%). Anal. Calcd for C25H21N3O5S2: C. 59.16; H, 4.17; N, 8.28. Found: C, 59.39; H, 4.41; N, 8.35.
2-(Methylthio)-5-(2,4,6-trimethoxyphenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine-4(3H)-thione (12b)
A mixture of compound 7b (1 mmol) and sodium methoxide (1.5 mmol) in methanol was stirred at room temperature for 1 h. Iodomethane (1.2 mmol) was added to the reaction mixture, followed by gentle heating on a water bath for 2 h. The reaction mixture was cooled and poured onto cold water. The resultant precipitate was filtered and washed several times with water yielding 12b in 83% yield, mp 212–213°C; 1H NMR (DMSO-d6): δ 2.72 (s, 3H, CH3), 3.61 (s, 6H, 2 OCH3), 3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.96 (s, 6H, 2 OCH3), 6.96 (s, 2H, ArH), 7.01 (s, 2H, ArH), 8.26 (s, CH), 9.57 (s, 1H, NH, exchangeable with D2O). Anal. Calcd for C26H27N3O6S2: C, 57.65; H, 5.02; N, 7.76. Found: C, 57.45; H, 5.23; N, 7.54.
2-Hydrazinyl-7-(5-hydroxy-4,7-dimethoxybenzofuran-6-yl)-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-4(3H)-thione (13a)
A mixture of compound 6 (1 mmol) and hydrazine hydrate (99%, 1.5 mL) in ethanol (10 mL) was heated on a water bath for 8 h (monitored by TLC) whereby a yellow precipitate was formed. The precipitate was filtered, washed well with water, dried and crystallised from an ethanol/dioxane mixture (3:1) to afford 13a in 80% yield; mp 291–292°C; IR (cm-1, ν): 3445 (br, OH), 3325 (NH), 3240, 3244(NH2); 1H NMR (DMSO-d6): δ 3.79 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.05 (s, 3H, OCH3), 7.25 (d, J = 7.2 Hz, 1H, CH), 7.65 (d, J = 8.4 Hz, 2H, ArH), 7.74 (d, J = 8.4 Hz, 2H, ArH), 7.77 (s, 1H, CH, ArH), 7.79 (d, J = 7.2 Hz, 1H, CH), 8.15 (br, s, 2H, NH2, D2O exchangeable), 9.42 (s, 1H, NH, exchangeable with D2O), 10.70 (br, s, 1H, NH, D2O exchangeable); MS: m/z 491 (M+, 100%). Anal. Calcd for C24H21N5O5S: C, 58.65; H, 4.31; N, 14.25. Found: C. 58.45; H, 4.13; N, 14.41.
2-Hydrazino-5-(2,4,6-trimethoxyphenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine-4(3H)-thione (13b)
A mixture of compound 12b (1 mmol) and hydrazine hydrate (99%, 1.5 mmol) in ethanol (10 mL) was stirred on a water bath for 8 h. A yellow precipitate was formed after all the starting material was consumed (monitoring by TLC). The precipitate was filtered, washed well with water, dried and crystallised from an ethanol/dioxane mixture affording 13b in 86% yield; mp 303–305°C; IR (cm-1, ν): 3325 (NH), 3240, 3244 (NH2); 1H NMR (DMSO-d6) δ ppm: 3.63 (s, 6H, 2 OCH3), 3.79 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.02 (s, 6H, 2 OCH3), 6.98 (s, 2H, ArH), 7.04 (s, 2H, ArH), 8.26 (s, CH, ArH), 8.39 (br, 2H, NH2, D2O exchangeable), 9.47 (s, 1H, NH, exchangeable with D2O), 10.32 (br, 1H, NH, D2O exchangeable). Anal. Calcd for C25H27N5O6S: C, 57.13; H, 5.18; N, 13.33. Found: C, 57.03; H, 5.42.; N, 13.08.
General procedure for pyrido[2,3-d][1,2,4]-triazolo[4,3-a]pyrimidine-5(1H)-thiones 14a,b
A mixture of compound 12a (1 mmol) and trimethyl orthoformate (5 mL for 14a) or triethyl orthoacetate (5 mL for 14b) was heated gently on a water bath for 6–8 h (under TLC control). The formed precipitate was collected upon filtration, dried and crystallised from ethanol.
8-(5-Hydroxy-4,7-dimethoxybenzofuran-6-yl)-6-(4-methoxyphenyl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-5(1H)-thione (14a)
This compound was isolated as pale yellow crystals; yield 53%; mp 188–190°C; IR (cm-1, ν): 3400 (br, OH), 3333 (NH); 1H NMR (DMSO-d6): δ 3.79 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 7.40 (d, J = 6.7 Hz, 1H, CH), 7.55 (d, J = 8.7 Hz, 2H, ArH), 7.77 (d, J = 8.7 Hz, 2H, ArH), 7.81 (s, 1H, CH, ArH), 7.88 (d, J = 6.7 Hz, 1H, CH), 8.23 (s, 1H), 9.12 (br, s, H, NH, D2O exchangeable); 13C NMR (DMSO-d6): δ 43.6, 46.8, 52.7 (3 CH3), 99.1, 111.3, 128.1, 134, 138, 143, 145, 146.2, 147.1, 147.4, 147.7, 147.8, 148.3, 148.6, 148.7, 148.9, 149.2, 149.6, 149.8, 151.3; MS: m/z 501 (100%).
8-(5-Hydroxy-4,7-dimethoxybenzofuran-6-yl)-6-(4-methoxyphenyl)-3-methylpyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-5(1H)-thione (14b)
This compound was isolated as shiny yellow crystals in 61% yield; mp 206–208°C; IR (cm-1, ν): 3408 (br, OH), 3335 (NH); 1H NMR (DMSO-d6): δ 2.34 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 7.40 (d, J = 6.7 Hz, 1H, CH), 7.57 (d, J = 8.7 Hz, 2H, ArH), 7.77 (d, J = 8.7 Hz, 2H, ArH), 7.80 (d, J = 6.7 Hz, 1H, CH), 7.86 (s, 1H, CH, ArH) and 10.11 (br, s, 1H, NH, D2O exchangeable); MS: m/z 515 (100%), 516 (31%).
8-(5-Hydroxy-4,7-dimethoxybenzofuran-6-yl)-3-mercapto-6-(4-methoxyphenyl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-5(1H)-thione (15)
To a warm ethanolic sodium hydroxide solution [prepared by dissolving sodium hydroxide (1 mmol) in ethanol (10 mL)], compound 12a (1 mmol) and carbon disulphide (3 mL) were added. The mixture was heated on a water bath at 80°C under reflux for 8 h, and then cooled, poured into cold water (25 mL) and neutralised with dilute acetic acid. The formed precipitate was filtered, dried and crystallised from ethanol/dioxane (15 mL, 2:1) to yield 15 as yellow powder in 52% yield; mp 223–225°C; IR (cm-1, ν): 3408 (br, -OH), 3335 (NH); 1H NMR (DMSO-d6): δ 1.82 (s, 1H, SH), 3.78 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 7.40 (d, J = 6.7 Hz, 1H, CH), 7.55 (d, J = 8.4 Hz, 2H, ArH), 7.77 (d, J = 8.4 Hz, 2H, ArH), 7.80 (d, J = 6.7 Hz, 1H, CH), 7.86 (s, 1H, CH, ArH), 10.11 (br, s, 1H, NH, D2O exchangeable); MS: m/z 533.08 (100%), 534.09 (27%).
3-Phenyl-6-(2,4,6-trimethoxyphenyl)-8-(3,4,5-trimethoxyphenyl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-5(1H)-thione (16a)
A mixture of compound 13b (1 mmol) and benzoic acid (1.2 mmol) in phosphorus oxychloride (5 mL) was stirred under reflux for 2 h. The reaction mixture was cooled and poured onto ice with stirring. The produced precipitate was filtered, washed well with water, dried and crystallised from dioxane, affording 16a in 81% yield; mp 316–317°C; IR (cm-1, ν): 3325 (NH); 1H NMR (DMSO-d6): δ 3.62 (s, 6H, 2 OCH3), 3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.96 (s, 6H, 2 OCH3), 6.96 (s, 2H, ArH), 7.01 (s, 2H, ArH), 7.34–7.53 (m, 5H, ArH), 8.26 (s, CH), 11.12 (s, 1H, NH, exchangeable with D2O); 13C NMR (DMSO-d6) δ ppm: 173.1, 162.6, 157.2, 156.8, 153.7, 151.1, 149.6, 148.9, 145.7, 141.2, 135.1, 130.3, 129.6, 128.9, 122.3, 119.6, 118.2, 112.9, 94.6, 89.9, 59.6, 55.3, 54.8, 53.9. Anal. Calcd for C32H29N5O6S: C, 62.84; H, 4.78; N, 11.45. Found: C, 62.66; H, 4.55.; N, 11.28.
3-(4-Methoxyphenyl)-6-(2,4,6-trimethoxyphenyl)-8-(3,4,5-trimethoxyphenyl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-5(1H)-thione (16b)
A mixture of compound 13b (1 mmol) and anisic acid (1.2 mol) in phosphorus oxychloride (5 mL) was stirred under reflux for 2 h. The reaction mixture was cooled and poured onto ice with stirring. The produced precipitate was filtered, washed well with water, dried and crystallised from dioxane, affording 16b in 86% yield; mp 327–328°C; IR (cm-1, ν): 3329 (NH); 1H NMR (DMSO-d6): δ 3.63 (s, 6H, 2 OCH3), 3.77 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.97 (s, 6H, 2 OCH3), 6.98 (s, 2H, ArH), 7.05 (s, 2H, ArH), 7.34–7.37 (d, 2H, J = 9.0 Hz, ArH), 7.61–7.64 (d, 2H, J = 9.0 Hz, ArH), 8.26 (s, CH), 11.22 (s, 1H, NH, exchangeable with D2O); 13C NMR (DMSO-d6): δ 172.8, 161.9, 159.7, 158.1, 156.4, 153.8, 151.6, 149.7, 148.8, 145.8, 138.9, 131.9, 127.6, 123.4, 119.7, 118.7, 118.1, 116.3, 113.4, 94.7, 90.3, 59.8, 55.8, 55.1, 54.9, 54.2. Anal. Calcd for C33H31N5O7S: C. 61.77; H, 4.87; N, 10.91. Found: C, 61.51; H, 4.65; N, 10.84.
5-Amino-3-phenyl-1-[4-thioxo-5-(2,4,6-trimethoxyphenyl)-7-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]-1H-pyrazole-4-carbonitrile (17)
A mixture of compound 13b (1 mmol) and benzylidenemalononitrile (1.1 mmol) in ethanol was heated under reflux for 10 h, then concentrated under reduced pressure and the resultant solid was filtered and washed with ethanol and ether, affording 17 in 77% yield; mp 276–277°C; IR (cm-1, ν): 3425–3100 (NH2), 2210 (CN); 1H NMR (DMSO-d6): δ 3.62 (s, 6H, 2 OCH3), 3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.96 (s, 6H, 2 OCH3), 6.2 (br, 2H, NH2), 6.96 (s, 2H, ArH), 7.04 (s, 2H, ArH), 7.32–7.49 (m, 5H, ArH), 8.26 (s, CH), 9.82 (s, 1H, NH, exchangeable with D2O); 13C NMR (DMSO-d6): δ 171.3, 159.9, 157.8, 157.1, 155.4, 151.9, 149.6, 148.9, 144.9, 138.6, 131.9, 129.7, 127.2, 126.9, 123.6, 119.7, 118.9, 117.7, 113.8, 92.8, 89.6, 73.2, 59.8, 55.7, 54.8, 53.9. Anal. Calcd for C35H31N7O6S: C, 62.03; H, 4.61; N, 14.47. Found: C, 61.89; H, 4.75; N, 14.19.
Ethyl 5-amino-3-phenyl-1-[4-thioxo-5-(2,4,6-trimethoxyphenyl)-7-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]-1H-pyrazole-4-carboxylate (18)
A mixture of compound 13b (1 mmol) and ethyl-2-cyano-3-phenylacrylate (1.1 mmol) in ethanol was heated under reflux for 10 h, then concentrated under reduced pressure, and the resultant solid was filtered and washed with ethanol and ether, affording 18 in 69% yield; mp 256–257°C; IR (cm-1, ν): 3425–3100 (NH2); 1H NMR (DMSO-d6): δ 1.31 (t, 3H, J = 7.2 Hz, CH2-CH3), 3.62 (s, 6H, 2 OCH3), 3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.96 (s, 6H, 2 OCH3), 4.21 (q, 2H, J = 7.2 Hz, CH2-CH3), 5.96 (br, 2H, NH2), 6.96 (s, 2H, ArH), 7.01 (s, 2H, ArH), 7.32–7.49 (m, 5H, ArH), 8.26 (s, CH), 9.82 (s, 1H, NH, exchangeable with D2O). Anal. Calcd for C37H36N6O6S: C, 61.31; H, 5.01; N, 11.61. Found: C, 61.11; H, 4.85.; N, 11.49.
3,4-Diphenyl-7-(2,4,6-trimethoxyphenyl)-9-(3,4,5-trimethoxyphenyl)-1,4-dihydro-6H-pyrido[2′,3′:4,5]pyrimido[2,1-c][1,2,4]triazine-6-thione (19)
A mixture of compound 13b (1 mmol), benzoin (1.1 mmol) and phosphorus oxychloride (5 mL) was heated under reflux for 1 h, cooled and then poured onto ice. The precipitated product was collected and washed several times with water and dried yielding 19 in 68% yield; mp 385–386°C; IR (cm-1, ν): 3227 (NH); 1H NMR (DMSO-d6): δ 3.62 (s, 6H, 2 OCH3), 3.75 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.96 (s, 6H, 2 OCH3), 5.98 (s, 1H), 6.96 (s, 2H, ArH), 7.01 (s, 2H, ArH), 7.32–7.59 (m, 10 H, ArH), 8.36 (s, CH), 12.18 (s, 1H, NH, exchangeable with D2O); 13C NMR (DMSO-d6): δ 54.8, 55.9, 56.6, 57.1, 58.9, 89.4, 92.6, 112.9, 114.9, 119.4, 123.3, 126.9, 127.1, 127.9, 128.8, 129.5, 130.1, 136.9, 138.2, 142.8, 144.9, 147.9, 149.7, 151.3, 154.2, 156.1, 157.4, 159.2, 168.1. Anal. Calcd for C39H35N5O6S: C, 66.75; H, 5.03; N, 9.98. Found: C, 66.53; H, 4.85; N, 9.79.
Acknowledgments
We thank the Department of Microbiology, National Research Centre, Cairo, Egypt for performing antibacterial and antifungal testing.
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