- Research article
- Open Access
Bis-pyrimidine acetamides: design, synthesis and biological evaluation
- Received: 22 June 2017
- Accepted: 1 August 2017
- Published: 8 August 2017
Abstract
Background
In the past few years, increased resistance of microorganisms towards antimicrobial agents become a serious health problem, so there is a need for the discovery of new antimicrobial agents. On the other hand, bis-pyrimidines possess various types of biological activity. In view of this, in the present study we have designed and synthesized a new series of bis-pyrimidine acetamides by Claisen–Schmidt condensation and screened for its in vitro antimicrobial and anticancer activities.
Results
The synthesized bis-pyrimidine acetamide derivatives were confirmed by IR, 1H/13C-NMR, Mass spectral studies as well C, H, N analyses. The synthesized compounds were evaluated for their in vitro antimicrobial potential against Gram positive (Staphylococcus aureus and Bacillus subtilis); Gram negative (Escherichia coli, Pseudomonas aeruginosa and Salmonella enterica) bacterial and fungal (Candida albicans and Aspergillus niger) strains by tube dilution technique and the minimum inhibitory concentration (MIC) recorded in µmol/mL was comparable to reference drugs, cefadroxil (antibacterial) and fluconazole (antifungal). The in vitro anticancer activity (IC50 value) determined against human colorectal carcinoma (HCT116) cancer cell line by Sulforhodamine B (SRB) technique and 5-fluorouracil used as reference drug.
Conclusions
SAR of bis-pyrimidine acetamides
Keywords
- Bis-pyrimidines
- Claisen–Schmidt condensation
- Antimicrobial
- Anticancer
- SAR
Background
Some marketed drugs contains pyrimidine moiety
Biological profile of pyrimidine acetamide derivatives found in the resent literature
Results and discussion
Chemistry
Synthesis of N, N′-(6,6′-(1,4-phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl)) bis(2-chloroacetamide) analogues
Antimicrobial activity
Antimicrobial and anticancer screening results of synthesized compounds
Compounds No. | Minimum inhibitory concentration (MIC = µmol/mL) | IC50 (µmol/mL) Cancer cell line | ||||||
---|---|---|---|---|---|---|---|---|
Bacterial species | Fungal species | |||||||
Gram positive | Gram negative | |||||||
S. aureus MTCC-3160 | B. subtilis MTCC-441 | P. aeruginosa MTCC-3542 | S. enterica MTCC-1165 | E. coli MTCC-443 | C. albicans MTCC-227 | A. niger MTCC-281 | HCT-116 | |
1. | 0.72 | 0.36 | 1.45 | 0.72 | 1.45 | 1.45 | 1.45 | 3.86 |
2. | 0.72 | 0.72 | 0.72 | 0.72 | 1.45 | 0.72 | 1.45 | 3.86 |
3. | 1.31 | 0.33 | 0.66 | 0.66 | 1.31 | 0.66 | 1.31 | 3.50 |
4. | 0.75 | 0.19 | 0.75 | 0.75 | 1.50 | 0.75 | 1.50 | 4.00 |
5. | 0.78 | 0.78 | 0.78 | 1.56 | 1.56 | 0.78 | 1.56 | 4.16 |
6. | 0.74 | 0.37 | 0.74 | 1.48 | 1.48 | 1.48 | 1.48 | 3.96 |
7. | 0.67 | 0.67 | 1.34 | 0.67 | 1.34 | 1.34 | 1.34 | 3.58 |
8. | 0.72 | 1.45 | 1.45 | 0.72 | 1.45 | 0.72 | 1.45 | 3.86 |
9. | 0.74 | 0.74 | 0.74 | 1.48 | 1.48 | 0.74 | 1.48 | 1.98 |
10. | 0.74 | 0.19 | 0.74 | 1.48 | 1.48 | 0.74 | 1.48 | 3.96 |
11. | 0.39 | 0.39 | 0.77 | 0.77 | 0.77 | 0.77 | 1.55 | 1.52 |
12. | 0.39 | 0.39 | 0.77 | 0.77 | 1.55 | 0.77 | 1.55 | 0.74 |
13. | 0.17 | 0.34 | 0.67 | 0.67 | 1.34 | 0.67 | 1.34 | 3.58 |
14. | 1.51 | 0.75 | 0.38 | 1.51 | 1.51 | 0.75 | 1.51 | 4.02 |
15. | 0.38 | 0.38 | 0.75 | 0.75 | 0.75 | 0.75 | 1.51 | 2.17 |
16. | 0.17 | 0.17 | 0.34 | 0.67 | 0.67 | 0.67 | 1.34 | 0.98 |
17. | 0.17 | 0.34 | 0.34 | 0.69 | 1.37 | 0.69 | 1.37 | 1.22 |
18. | 0.34 | 0.69 | 0.69 | 0.69 | 1.37 | 0.34 | 1.37 | 0.73 |
19. | 0.75 | 0.38 | 0.75 | 0.75 | 1.50 | 0.75 | 1.50 | 4.00 |
20. | 0.19 | 0.38 | 0.75 | 0.75 | 1.50 | 0.75 | 1.50 | 2.16 |
DMSO | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | – |
Cefadroxil | 1.72 | 0.86 | 1.72 | 1.72 | 1.72 | – | – | – |
Fluconazole | – | – | – | – | – | 1.02 | 2.04 | – |
5-Fluorouracil | – | – | – | – | – | – | – | 7.67 |
Antibacterial screening results against Gram positive species
Antibacterial screening results against Gram negative species
Antifungal screening results against fungal species
Anticancer activity
Anticancer screening results of the synthesized compounds
Structure activity relationship of bis-pyrimidine acetamides
Experimental part
Preparatory materials for the research work were obtained from commercial sources and were used without further purification. All reactions were monitored by thin-layer chromatography on 0.25 mm silica gel (Merck) plates, using benzene as mobile phase and spots were observed by exposure to iodine vapours or visualized with UV light. Melting points of synthesized compounds was determined in open capillary tube. An infrared spectrum was recorded (KBr-pellets) in Bruker 12060280, Software: OPUS 7.2.139.1294 spectrometer. 1H-NMR and 13C-NMR were recorded at 600 and 150 MHz, respectively on Bruker Avance III 600 NMR spectrometer by appropriate deuterated solvents. The results are conveyed in parts per million (δ, ppm) downfield from tetramethyl silane (internal standard). 1H-NMR spectral details of the synthesized derivatives are represented with multiplicity like singlet (s); doublet (d); triplet (t); multiplet (m) and the number hydrogen ion. Elemental analysis of the new synthesized compounds was obtained by Perkin–Elmer 2400 C, H and N analyzer. All the compounds gave C, H and N analysis within ±0.4% of the theoretical results. Mass spectra were taken on Waters Micromass Q-ToF Micro instrument. The synthesized compounds were characterized by the determination of their physicochemical and spectral characteristics.
General procedure of the synthesized bis-pyrimidine acetamide derivatives (1–20)
Step i: Synthesis of 3,3′-(1,4-phenylene)bis(1-(4-nitrophenyl)prop-2-en-1-one) (I)
A mixture of 1-(4-nitrophenyl)ethanone (0.02 mol) and terephthalaldehyde (0.01 mol) in methanol (5–10 mL) was stirred with drop wise addition of 40% sodium hydroxide solution (10 mL) at room temperature till a dark yellow mass was obtained (2–3 h). Then reaction mixture was allowed to stand overnight at room temperature and then was poured into icecold water and acidified with hydrochloric acid and the precipitated 3,3′-(1,4-phenylene)bis(1-(4-nitrophenyl) prop-2-en-1-one) was filtered, dried and recrystallized from methanol [23, 24].
Step ii: Synthesis of 6,6′-(1,4-phenylene)bis(4-(4-nitrophenyl)pyrimidin-2-amine) (II)
The solution of 3,3′-(1,4-phenylene)bis(1-(4-nitrophenyl)prop-2-en-1-one) (0.01 mol) (synthesized in previous step-i) in methanol (80 mL) was added with 0.01 mol of potassium hydroxide and 40 mL of 0.50 M solution of guanidine nitrate and refluxed for 5–6 h. The reaction mixture was then cooled and acidified with few drops of hydrochloric acid (20 mL of 0.5 M solution) and the resultant precipitate, 6,6′-(1,4-phenylene)bis(4-(4-nitrophenyl) pyrimidin-2-amine) was separated dried and recrystallized from methanol [23, 24].
Step iii: Synthesis of N,N′-(6,6′-(1,4-phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis (2-chloroacetamide) (III)
In ethanol (30 mL), chloroacetyl chloride (0.02 mol) and 2–3 drops of triethylamine were added and the mixture was stirred in water bath for 10 min after that the solution of 6,6′-(1,4-phenylene)bis(4-(4-nitrophenyl)pyrimidin-2-amine) (synthesized in previous step-ii) (0.01 mol) in ethanol (80 mL) was added drop wise and refluxed for 2–3 h. The reaction mixture was then cooled and poured into icecold water and resultant precipitate was filtered and washed with water, dried and recrystallized from alcohol [25].
Step iv: Synthesis of final (1–20) bis-pyrimidine acetamide derivatives
The reaction mixture of N,N′-(6,6′-(1,4-phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-chloroacetamide) (0.01 mol) and substituted aniline (0.02 mol) in ethanol was refluxed for 4–5 h. The reaction progress was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was poured into icecold water and the precipitated title compound was filtered, dried and recrystallized from methanol.
Spectral data interpretation of the synthesized compounds (Fig. 8)
3,3′-(1,4-Phenylene)bis(1-(4-nitrophenyl)prop-2-en-1-one) (I)
Number of hydrogen and carbon atoms is present in the synthesized compounds
6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidin-2-amine) (II)
IR (KBr pellets, cm−1): 3107 (C–H str., phenyl nucleus), 1518 (C=C str., phenyl nucleus), 3370 (C–NH2 str.), 1600 (N=CH str., of pyrimidine), 1349 (C–N sym str., Ar–NO2); 1H-NMR (δ, DMSO-d 6): 7.43–8.40 {m, 12H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2}, 7.86 (s, 2H, (CH)2 of pyrimidine), 6.97 (s, 2H, (NH)2); 13C-NMR (δ, DMSO-d 6): 128.5 (C-2, C-3, C-5, C-6), 134.6 (C-1, C-4); 157.8 (C-1′, C-3′, C-5′), 102 (C-2′), 149.7 (C-5′) pyrimidine; 141.5 (C-1″), 126.4 (C-2″, C-6″), 124.4 (C-3″, C-5″), 148.3 (C-4″); Elem. Anal. Calcd. C26H18N8O4: C, 61.66; H, 3.58; N, 22.12; Found: C, 61.64; H, 3.51; N, 22.15; MS ES + (ToF): m/z 507 [M++1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-chloroacetamide) (III)
IR (KBr pellets, cm−1): 3105 (C–H str., phenyl nucleus), 1519 (C=C str., phenyl nucleus), 1688 (NH–C=O str.), 1599 (N=CH str., of pyrimidine), 2928 (C–H str., CH2), 761 (C–Cl str., Ar–Cl), 1349 (C–N sym. str., Ar–NO2); 1H-NMR (δ, DMSO-d 6): 7.54–8.93 {m, 12H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2}, 7.42 (s, 2H, (CH)2 of pyrimidine), 8.10 (s, 2H, (NH)2), 3.66 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 128.5 (C-2, C-3, C-5, C-6), 136.6 (C-1, C-4); 162.0 (C-1′, C-3′), 108.0 (C-2′), 149.7 (C-5′) pyrimidine; 141.0 (C-1″), 126.6 (C-2″, C-6″), 124.5 (C-3″, C-5″), 149.8 (C-4″), 188.0 (C = O), 44.3(CH2); Elem. Anal. Calcd. C30H20Cl2N8O6: C, 54.64; H, 3.06; N, 16.99; Found: C, 54.60; H, 3.00; N, 16.92; MS ES + (ToF): m/z 660 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((3-nitrophenyl) amino)acetamide) (1)
Brown crystals; Yield: 70.12%; M.p.: 252–254 °C; Rf value: 90.12; IR (KBr, cm−1): 3085 (C–H str., phenyl nucleus), 1528 (C=C str., phenyl nucleus), 1679 (NH–C=O str.), 1572 (N=CH str., of pyrimidine), 2863 (C–H str., CH2), 1217 (C–NH–str.), 1347 (C–N sym. str., Ar–NO2); 1H-NMR (δ, DMSO-d 6): 7.63–8.25 {m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-2‴, H-4‴,H-5‴, H-6‴) × 2}, 7.63 (s, 2H, (CH)2 of pyrimidine), 8.08 (s, 2H, (NH)2), 4.0 (s, 2H, (NH)2), 3.40 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 128.3, 128.4 (C-2, C-3, C-5, C-6), 136.5 (C-1, C-4); 165.0 (C-1′, C-3′), 109 (C-2′), 149.7 (C-5′) pyrimidine; 141.0 (C-1″), 126.5 (C-2″, C-6″), 124.5 (C-3″, C-5″), 149.6 (C-4″); 149.5 (C-1‴, C-3‴), 106.9 (C-2‴), 129.9 (C-5‴), 122.1 (C-6‴); 170.2 (C = O), 48.0 (CH2); Elem. Anal. Calcd. C42H30N12O10: C, 58.47; H, 3.50; N, 19.48; Found: C, 58.42; H, 3.49; N, 19.46; MS ES + (ToF): m/z 864 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((4-nitrophenyl) amino)acetamide) (2)
Dark brown crystals; M.p.: 262–264 °C; Rf value: 0.32; Yield: 92.45%; IR (KBr, cm−1): 3086 (C–H str., phenyl nucleus), 1530 (C=C str., phenyl nucleus), 1679 (NH–C = O str.), 1573 (N=CH str., of pyrimidine), 2929 (C–H str., CH2), 1219 (C–NH– str.), 1348 (C–N sym. str., Ar–NO2); 1H-NMR (δ, DMSO-d 6): 6.74–9.09 (m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-2‴, H-3‴, H-5‴, H-6‴) × 2}, 7.04 (s, 2H, CH of pyrimidine), 8.01 (s, 2H, (NH)2), 3.37 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 127.3 (C-2, C-3, C-5, C-6), 138.9 (C-1, C-4); 164.0 (C-1′, C-3′), 112 (C-2′), 148.3 (C-5′) pyrimidine; 126.3 (C-2″, C-6″), 121.5 (C-3″, C-5″), 147.6 (C-4″); 152.5 (C-1‴), 115.3 (C-2‴, C-6‴), 127.5 (C-3‴, C-5‴), 135.6 (C-4‴), 168.2 (C=O), 45.0 (CH2); Elem. Anal. Calcd. C42H30N12O10: C, 58.47; H, 3.50; N, 19.48; Found: C, 58.41; H, 3.48; N, 19.46; MS ES + (ToF): m/z 864 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((2,4-dinitrophenyl) amino)acetamide) (3)
Brown crystals; M.p.: 257–259 °C; Rf value: 0.41; Yield: 92.67%; IR (KBr pellets, cm−1): 3211 (C–H str., phenyl nucleus), 1529 (C=C str., phenyl nucleus), 1620 (NH–C=O str.), 1675 (N=CH str., of pyrimidine), 3086 (C–H str., CH2), 1274 (C–NH– str.), 1345 (C–N sym. str., Ar–NO2); 1H-NMR (δ, DMSO-d 6): 6.95–8.90 {m, 18H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-3‴, H-5‴, H-6‴) × 2}, 7.87 (s, 2H, (CH)2 of pyrimidine), 8.01 (s, 2H, (NH)2), 3.40 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 128.6 (C-2, C-3, C-5, C-6), 135.05 (C-1, C-4); 164.0 (C-1′, C-3′), 102 (C-2′), 149.7 (C-5′) pyrimidine; 141.0 (C-1″), 127.3 (C-2″, C-6″), 124.9 (C-3″, C-5″), 148.6 (C-4″); 152.5 (C-1‴), 135.6 (C-2‴), 119.7 (C-3‴), 138.9 (C-4‴), 130.2 (C-5‴); 168.2 (C=O), 51.0 (CH2); Elem. Anal. Calcd. C42H28N14O14: C, 52.95; H, 2.96; N, 20.58; Found: C, 52.85; H, 2.46; N, 20.48; MS ES + (ToF): m/z 954 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((4-methoxyphenyl) amino)acetamide) (4)
Brown crystals; M.p.: 215–217 °C; Rf value: 0.53; Yield: 89.44%; IR (KBr pellets, cm−1): 3084 (C–H str., phenyl nucleus), 1529 (C=C str., phenyl nucleus), 1680 (NH–C=O str.), 1572 (N=CH str., of pyrimidine), 1221 (C–NH– str.), 1347 (C–N sym. str., Ar–NO2), 1088 (C–O–C str., –OCH3); 1H-NMR (δ, DMSO-d 6): 7.04–9.09 {m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-2‴, H-3‴, H-5‴, H-6‴) × 2}, 7.75 (s, 2H, (CH)2 of pyrimidine), 8.0 (s, 2H, (NH)2), 3.38 (s, 6H, (OCH3)2); 13C-NMR (δ, DMSO-d 6): 127.3 (C-2, C-3, C-5, C-6), 138.5 (C-1, C-4); 164.0 (C-1′, C-3′), 108 (C-2′), 148.7 (C-5′) pyrimidine; 142.0 (C-1″), 127.5 (C-2″, C-6″), 124.9 (C-3″, C-5″), 149.6 (C-4″); 138.5 (C-1‴), 115.3 (C-2‴, C-6‴), 115.0 (C-3‴, C-5‴), 171.2 (C=O), 51.0 (CH2), 53.0 (p-OCH3); Elem. Anal. Calcd. C44H36N10O8: C, 63.46; H, 4.36; N, 16.82; Found: C, 63.44; H, 4.37; N, 16.85; MS ES + (ToF): m/z 834 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-(p-tolylamino) acetamide) (5)
Brown crystals; M.p.: 250–252 °C; Rf value: 0.30; Yield: 85.43%; IR (KBr pellets, cm−1): 3084 (C–H str., phenyl nucleus), 1529 (C=C str., phenyl nucleus), 1681 (NH–C=O str.), 1569 (N=CH str., of pyrimidine), 2866 (C–H str., CH2), 1217 (C–NH– str.), 1348 (C–N sym. str., Ar–NO2); 1H-NMR (δ, DMSO-d 6): 6.99–8.56 {m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-2‴, H-3‴, H-5‴, H-6‴) × 2}, 7.48 (s, 2H, (CH)2 of pyrimidine), 8.03 (s, 2H, (NH)2), 2.51 (s, 6H, (CH3)2); 13C-NMR (δ, DMSO-d 6): 128.8, 128.4 (C-2, C-3, C-5, C-6), 136.8, (C-1, C-4); 168.0 (C-1′, C-3′), 108 (C-2′), 149.7 (C-5′) pyrimidine; 141.0 (C-1″), 126.4 (C-2″, C-6″), 123.8 (C-3″, C-5″), 149.7 (C-4″); 144.5 (C-1‴), 117.0 (C-2‴, C-6‴), 129.6 (C-3‴, C-5‴), 188.0 (C=O), 48.0 (CH2), 20.5 (p-CH3); Elem. Anal. Calcd. C44H36N10O6: C, 65.99; H, 4.53; N, 17.49; Found: C, 65.92; H, 4.49; N, 17.40; MS ES + (ToF): m/z 802 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((4-chlorophenyl) amino)acetamide) (6)
Brown crystals; M.p.: 168–170 °C; Rf value: 0.42; Yield: 87.58%; IR (KBr pellets, cm−1): 3084 (C–H str., phenyl nucleus), 1530 (C=C str., phenyl nucleus), 1687 (NH–C=O str.), 1603 (N=CH str., of pyrimidine), 2866 (C–H str., CH2), 1215 (C–NH– str.), 1348 (C–N sym. str., Ar–NO2), 739 (C–Cl str., Ar–Cl); 1H-NMR (δ, DMSO-d 6): 6.35–9.08 {m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-2‴, H-3‴, H-5‴, H-6‴) × 2}, 7.49 (s, 2H, (CH)2 of pyrimidine), 8.00 (s, 2H, (NH)2), 3.36 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 128.4 (C-2, C-3, C-5, C-6), 134.5 (C-1, C-4); 164.0 (C-1′, C-3′), 106 (C-2′), 148.3 (C-5′) pyrimidine; 127.4 (C-2″, C-6″), 124.9 (C-3″, C-5″), 147.6 (C-4″); 145.5 (C-1‴), 115.1 (C-2‴, C-6‴), 129.9 (C-3‴, C-5‴), 126.1 (C-4‴); 165.2 (C=O), 53.0 (CH2); Elem. Anal. Calcd. C42H30Cl2N10O6: C, 59.94; H, 3.59; N, 16.64; Found: C, 59.90; H, 3.51; N, 16.60; MS ES + (ToF): m/z 843 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((2-chloro-4-nitro phenyl)amino)acetamide) (7)
Brown yellow crystals; M.p.: 170–172 °C; Rf value: 0.60; Yield: 87.12%; IR (KBr pellets, cm−1): 3085 (C–H str., phenyl nucleus), 1530 (C=C str., phenyl nucleus), 1688 (NH–C=O str.), 1603 (N=CH str., of pyrimidine), 2869 (C–H str., CH2), 1215 (C–NH– str.), 1348 (C–N sym. str., Ar–NO2), 740 (C–Cl str., Ar–Cl); 1H-NMR (δ, DMSO-d 6): 6.48–9.08 {m, 18H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-3‴, H-5‴, H-6‴) × 2}, 7.87 (s, 2H, (CH)2 of pyrimidine), 8.01 (s, 2H, (NH)2), 3.37 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 129.3 (C-2, C-3, C-5, C-6), 135.8 (C-1, C-4); 163.0 (C-1′, C-3′), 113 (C-2′), 148.7 (C-5′) pyrimidine; 126.3 (C-2″, C-6″), 124.9 (C-3″, C-5″), 149.3 (C-4″); 151.3 (C-1‴), 124.3 (C-2‴), 138.9 (C-4‴), 125.1 (C-3‴), 122.1 (C-5‴); 166.2 (C=O), 51.0 (CH2); Elem. Anal. Calcd. C42H28Cl2N12O10: C, 54.15; H, 3.03; N, 18.04; Found: C, 54.11; H, 3.00; N, 18.12; MS ES + (ToF): m/z 933 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((2-nitrophenyl) amino)acetamide) (8)
Light Brown crystals; M.p.: 163–165 °C; Rf value: 0.34; Yield: 84.23%; IR (KBr pellets, cm−1): 3085 (C–H str., phenyl nucleus), 1530 (C=C str., phenyl nucleus), 1688 (NH–C=O str.), 1603 (N=CH str., of pyrimidine), 2868 (C–H str., CH2), 1215 (C–NH– str.), 1348 (C–N sym. str., Ar–NO2); 1H-NMR (δ, DMSO-d 6): 7.03-8.25 {m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-3‴, H-4‴, H-5‴, H-6‴) × 2}, 7.79 (s, 2H, (CH)2 of pyrimidine), 8.04 (s, 2H, (NH)2), 3.38 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 127.4 (C-2, C-3, C-5, C-6), 135.6 (C-1, C-4); 162.0 (C-1′, C-3′), 105 (C-2′), 148.7 (C-5′) pyrimidine; 141.0 (C-1″), 126.5 (C-2″, C-6″), 124.3 (C-3″, C-5″), 149.6 (C-4″); 147.5 (C-1‴), 130.1 (C-2‴), 125.9 (C-3‴), 119.1 (C-4‴), 136.2 (C-5‴); 164.2 (C=O), 50.0 (CH2); Elem. Anal. Calcd. C42H30N12O10: C, 58.47; H, 3.50; N, 19.48; Found: C, 58.42; H, 3.45; N, 19.41; MS ES + (ToF): m/z 864 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-(2-chlorophenyl) acetamide) (9)
Canary yellow crystals; M.p.: 150–152 °C; Rf value: 0.58; Yield: 75.25%; IR (KBr pellets, cm−1): 3075 (C–H str., phenyl nucleus), 1521 (C=C str., phenyl nucleus), 1690 (NH–C=O str.), 1598 (N=CH str., of pyrimidine), 2851 (C–H str., CH2), 1210 (C–NH– str.), 1344 (C–N sym. str., Ar–NO2), 757 (C–Cl str., Ar–Cl); 1H-NMR (δ, DMSO-d 6): 7.80–8.25 {m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-3‴, H-4‴, H-5‴, H-6‴) × 2}, 7.80 (s, 2H, (CH)2 of pyrimidine), 8.00 (s, 2H, (NH)2), 3.37 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 128.6 (C-2, C-3, C-5, C-6), 135.5 (C-1, C-4); 163.0 (C-1′, C-3′), 107 (C-2′), 149.7 (C-5′) pyrimidine; 141.0 (C-1″), 127.5 (C-2″, C-6″), 123.5 (C-3″, C-5″), 149.8 (C-4″); 134.5 (C-1‴), 129.1 (C-2‴, C-3‴, C-4‴), 127.9 (C-5‴), 133.1 (C-6‴); 156.2 (C=O), 39 (CH2); Elem. Anal. Calcd. C42H30Cl2N10O6: C, 59.94; H, 3.59; N, 16.64; Found: C, 59.90; H, 3.53; N, 16.61; MS ES + (ToF): m/z 843 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-(2-chlorophenyl) acetamide) (10)
Light yellow crystals; M.p.: 138–140 °C; Rf value: 0.31; Yield: 80.22%; IR (KBr pellets, cm−1): 3074 (C–H str., phenyl nucleus), 1521 (C=C str., phenyl nucleus), 1690 (NH–C=O str.), 1597 (N=CH str., of pyrimidine), 2854 (C–H str., CH2), 1210 (C–NH– str.), 1344 (C–N sym. str., Ar–NO2), 757 (C–Cl str., Ar–Cl); 1H-NMR (δ, DMSO-d 6): 7.82 {m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-2‴, H-4‴, H-5‴, H-6‴) × 2}, 7.80 (s, 2H, (CH)2 of pyrimidine), 8.00 (s, 2H, (NH)2), 3.38 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 128.3 (C-2, C-3, C-5, C-6), 135.5 (C-1, C-4); 165.0 (C-1′, C-3′), 108 (C-2′), 149.8 (C-5′) pyrimidine; 142.0 (C-1″), 127.5 (C-2″, C-6″), 123.5 (C-3″, C-5″), 149.6 (C-4″); 149.5 (C-1‴), 110 (C-2‴), 134.9 (C-3‴), 120.4 (C-5‴); 163.2 (C=O), 56.0 (CH2); Elem. Anal. Calcd. C42H30Cl2N10O6: C, 59.94; H, 3.59; N, 16.64; Found: C, 59.90; H, 3.52; N, 16.67; MS ES + (ToF): m/z 843 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((4-fluorophenyl) amino)acetamide) (11)
Yellow crystals; M.p.: 123–125 °C; Rf value: 0.33; Yield: 85.63%; IR (KBr pellets, cm−1): 3073 (C–H str., phenyl nucleus), 1518 (C=C str., phenyl nucleus), 1665 (NH–C=O str.), 1596 (N=CH str., of pyrimidine), 2852 (C–H str., CH2), 1210 (C–NH– str.), 1338 (C–N sym. str., Ar–NO2), 1105 (C–F str., Ar–F); 1H-NMR (δ, DMSO-d 6): 7.25–8.69 {m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-2‴, H-3‴, H-5‴, H-6‴) × 2}, 7.39 (s, 2H, (CH)2 of pyrimidine), 8.01 (s, 2H, (NH)2), 3.34 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 129.3 (C-2, C-3, C-5, C-6), 136.7 (C-1, C-4); 161.0 (C-1′, C-3′), 105 (C-2′), 149.8 (C-5′) pyrimidine; 142.0 (C-1″), 126.4 (C-2″, C-6″), 124.5 (C-3″, C-5″), 147.4 (C-4″); 144.5 (C-1‴), 115.9 (C-3‴, C-5‴), 119.0 (C-2‴, C-6‴), 159.8 (C-5‴); 169.2 (C=O), 68.0 (CH2); Elem. Anal. Calcd. C42H30F2N10O6: C, 62.37; H, 3.74; N, 17.32; Found: C, 62.33; H, 3.72; N, 17.35; MS ES + (ToF): m/z 810 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((2-fluorophenyl) amino)acetamide) (12)
Gold Yellow crystals; M.p.: 170–172 °C; Rf value: 0.25; Yield: 77.12%; IR (KBr pellets, cm−1): 3108 (C–H str., phenyl nucleus), 1519 (C=C str., phenyl nucleus), 1665 (NH–C=O str.), 1600 (N=CH str., of pyrimidine), 2934 (C–H str., CH2), 1211 (C–NH– str.), 1340 (C–N sym. str., Ar–NO2), 1106 (C–F str., Ar–F); 1H-NMR (δ, DMSO-d 6): 7.91–839 {m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-3‴, H-4‴, H-5‴, H-6‴) × 2}, 7.90 (s, 2H, (CH)2 of pyrimidine), 3.38 (s, 4H, (CH2), 8.00 (s, 2H, (NH)2); 13C-NMR (δ, DMSO-d 6): 129.3 (C-2, C-3, C-5, C-6), 135.5 (C-1, C-4); 162.0 (C-1′, C-3′), 105 (C-2′), 149.7 (C-5′) pyrimidine; 127.5 (C-2″, C-6″), 124.7 (C-3″, C-5″), 147.6 (C-4″); 130.5 (C-1‴), 153.2 (C-3‴), 116.9 (C-3‴), 121.9 (C-4‴); 188.2 (C=O), 49.0 (CH2); Elem. Anal. Calcd. C42H30F2N10O6: C, 62.37; H, 3.74; N, 17.32; Found; C, 62.34; H, 3.67; N, 17.28; MS ES + (ToF): m/z 810 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((4-chloro-2-nitro phenyl)amino)acetamide) (13)
Light yellow crystals; M.p.: 175–177 °C; Rf value: 0.16; Yield: 85.25%; IR (KBr pellets, cm−1): 3107 (C–H str., phenyl nucleus), 1519 (C=C str., phenyl nucleus), 1665 (NH–C=O str.), 1600 (N=CH str., of pyrimidine), 2936 (C–H str., CH2), 1247 (C–NH– str.), 1341 (C–N sym. str., Ar–NO2), 761 (C–Cl str., Ar–Cl); 1H-NMR (δ, DMSO-d 6): 7.05–8.39 {m, 18H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-3‴, H-5‴, H-6‴) × 2}, 7.48 (s, 2H, (CH)2 of pyrimidine), 8.00 (s, 2H, (NH)2), 3.66 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 128.9 (C-2, C-3, C-5, C-6), 135.5 (C-1,C-4); 165.0 (C-1′, C-3′), 110 (C-2′), 149.8 (C-5′) pyrimidine; 141.0 (C-1″), 126.4 (C-2″, C-6″), 124.0 (C-3″, C-5″), 149.9 (C-4″); 143.5 (C-1‴), 132.2 (C-2‴), 126.5 (C-3‴), 122.9 (C-4‴), 134.1 (C-5‴), 118.1 (C-6‴); 188.2 (C=O), 52.5 (CH2); Elem. Anal. Calcd. C42H28Cl2N12O10: C, 54.15; H, 3.03; N, 18.04; Found: C, 54.13; H, 3.00; N, 18.01; MS ES + (ToF): m/z 933 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((2,6-dimethyl phenyl)amino)acetamide) (14)
Gold yellow crystals; M.p.: 158–160 °C; Rf value: 0.38; Yield: 82.33%; IR (KBr pellets, cm−1): 3074 (C–H str., phenyl nucleus), 1520 (C=C str., phenyl nucleus), 1692 (NH–C=O str.), 1601 (N=CH str., of pyrimidine), 2853 (C–H str., CH2), 1211 (C–NH– str.), 1343 (C–N sym. str., Ar–NO2);1H-NMR (δ, DMSO-d 6): 7.94–8.39 {m, 18H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-3‴, H-4‴, H-5‴) × 2}, 7.91 (s, 2H, (CH)2 of pyrimidine), 8.01 (s, 2H, (NH)2), 3.39 (s, 4H, (CH2)2), 2.09 (s, 6H, (CH3)2); 13C-NMR (δ, DMSO-d 6): 128.6 (C-2, C-3, C-5, C-6), 135.5 (C-1, C-4); 162.0 (C-1′, C-3′), 108 (C-2′), 149.8 (C-5′) pyrimidine; 141.0 (C-1″), 126.5 (C-2″, C-6″), 123.5 (C-3″, C-5″), 149.0 (C-4″); 145.5 (C-1‴), 119.0 (C-4‴), 127.2 (C-2‴, C-6‴), 127.9 (C-3‴, C-5‴); 170.2 (C=O), 52.5 (CH2), 17.8 (2,6-CH3); Elem. Anal. Calcd. C46H40N10O6: C, 66.66; H, 4.86; N, 16.90; Found: C, 66.63; H, 4.81; N, 16.87; MS ES + (ToF): m/z 830 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((2,4-dimethyl phenyl)amino)acetamide) (15)
Gold yellow crystals; M.p.: 135–137 °C; Rf value: 0.45; Yield: 89.63%; IR (KBr pellets, cm−1): 3074 (C–H str., phenyl nucleus), 1519 (C=C str., phenyl nucleus), 1664 (NH–C=O str.), 1597 (N=CH str., of pyrimidine), 2917 (C–H str., CH2), 1208 (C–NH– str.), 1339 (C–N sym. str., Ar–NO2); 1H-NMR (δ, DMSO-d 6): 6.58-8.40 {m, 18H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-3‴, H-5‴, H-6‴) × 2}, 7.47 (s, 2H, (CH)2 of pyrimidine), 8.00 (s, 2H, (NH)2), 3.36 (s, 4H, (CH2)2), 2.51(s, 6H, (CH3)2); 13C-NMR (δ, DMSO-d 6): 128.9 (C-2, C-3, C-5, C-6), 136.5 (C-1, C-4); 163.0 (C-1′, C-3′), 104 (C-2′), 149.8 (C-5′) pyrimidine; 141.0 (C-1″), 126.4 (C-2″, C-6″), 124.5 (C-3″, C-5″), 149.8 (C-4″); 143.6 (C-1‴), 126.5, 126.2 (C-2‴, C-5‴), 133.9 (C-3‴), 136.9 (C-4‴), 116.1 (C-6‴); 188.2 (C=O), 52.0 (CH2), 18.2 (o-CH3), 21.2 (p-CH3); Elem. Anal. Calcd. C46H40N10O6: C, 66.66; H, 4.86; N, 16.90; Found: C, 66.63; H, 4.87; N, 16.95; MS ES + (ToF): m/z 830 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((4-bromophenyl) amino)acetamide) (16)
Gold yellow crystals; M.p.: 138–140 °C; Rf value: 0.23; Yield: 87.77%; IR (KBr pellets, cm−1): 3107 (C–H str., phenyl nucleus), 1519 (C=C str., phenyl nucleus), 1665 (NH–C=O str.), 1599 (N=CH str., of pyrimidine), 2933 (C–H str., CH2), 1209 (C–NH– str.), 1341 (C–N sym. str., Ar–NO2), 697 (C–Br str., Ar–Br); 1H-NMR (δ, DMSO-d 6): 6.51–8.69 {m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-2‴, H-3‴, H-5‴, H-6‴) × 2}, 7.55 (s, 2H, (CH)2 of pyrimidine), 8.00 (s, 2H, (NH)2), 3.37 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 128.2 (C-2, C-3, C-5, C-6), 136.7 (C-1, C-4); 160.0 (C-1′, C-3′), 104 (C-2′), 149.8 (C-5′) pyrimidine; 141.5 (C-1″), 126.4 (C-2″, C-6″), 123.5 (C-3″, C-5″), 149.7 (C-4″); 145.5 (C-1‴), 115 (C-2‴, C-6‴), 132.0 (C-3‴, C-5‴), 118.8 (C-5‴); 188.2 (C = O), 52.5 (CH2); Elem. Anal. Calcd. C42H30Br2N10O6: C, 54.21; H, 3.25; N, 15.05; Found: C, 54.18; H, 3.20; N, 15.00; MS ES + (ToF): m/z 933 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((2,3-dichlorophenyl) amino)acetamide) (17)
Gold yellow crystals; M.p.: 195–197 °C; Rf value: 0.16; Yield: 72.01%; IR (KBr pellets, cm−1): 3108 (C–H str., phenyl nucleus), 1520 (C=C str., phenyl nucleus), 1666 (NH–C=O str.), 1599 (N=CH str., of pyrimidine), 2934 (C–H str., CH2), 1211 (C–NH– str.), 1341 (C–N sym. str., Ar–NO2), 700 (C–Cl str., Ar–Cl); 1H-NMR (δ, DMSO-d 6): 7.93–8.39 {m, 18H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-4‴, H-5‴, H-6‴) × 2}, 7.91 (s, 2H, (CH)2 of pyrimidine), 8.00 (s, 2H, (NH)2), 3.38 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 128.9 (C-2, C-3, C-5, C-6), 135.1 (C-1, C-4); 162.0 (C-1′, C-3′), 104.1 (C-2′), 149.0 (C-5′) pyrimidine; 126.4 (C-2″, C-6″), 123.8 (C-3″, C-5″), 149.6 (C-4″); 145.3 (C-1‴), 123.6 (C-2‴), 133.9 (C-3‴), 122.9 (C-4‴), 129.1 (C-5‴), 113.1 (C-6‴); 188.2 (C=O), 52.6 (CH2); Elem. Anal. Calcd. C42H28Cl4N10O6: C, 55.40; H, 3.10; N, 15.38; Found: C, 55.38; H, 3.07; N, 15.33; MS ES + (ToF): m/z 912 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((2,6-dichlorophenyl) amino)acetamide) (18)
Gold yellow crystals; M.p.: 129–131 °C; Rf value: 0.33; Yield: 75.30%; IR (KBr pellets, cm−1): 3107 (C–H str., phenyl nucleus), 1520 (C=C str., phenyl nucleus), 1666 (NH–C = O str.), 1599 (N=CH str., of pyrimidine), 2936 (C–H str., CH2), 1211 (C–NH– str.,), 1342 (C–N sym. str., Ar–NO2), 700 (C–Cl str., Ar–Cl); 1H-NMR (δ, DMSO-d 6): 7.04–9.09 {m, 18H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-3‴, H-4‴, H-5‴) × 2}, 7.75 (s, 2H, (CH)2 of pyrimidine), 8.01 (s, 2H, (NH)2), 3.38 (s, 4H, (CH2)2); 13C-NMR (δ, DMSO-d 6): 127.3 (C-2, C-3, C-5, C-6), 134.5 (C-1, C-4); 164.0 (C-1′, C-3′), 102 (C-2′), 148.3 (C-5′) pyrimidine; 126.4 (C-2″, C-6″), 124.5 (C-3″, C-5″), 148.6 (C-4″); 144.5 (C-1‴), 123.5 (C-2‴, C-6‴), 128.5 (C-3‴, C-5‴), 121.1 (C-6‴); 165.2 (C=O), 53.0 (CH2); Elem. Anal. Calcd. C42H28Cl4N10O6: C, 55.40; H, 3.10; N, 15.38; Found: C, 76.13; H, 4.24; N, 11.12; MS ES + (ToF): m/z 912 [M+ + 1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-((3-methoxyphenyl) amino)acetamide) (19)
Gold yellow crystals; M.p.: 198–200 °C; Rf value: 0.21; Yield: 75.30%; IR (KBr pellets, cm−1): 3074 (C–H str., phenyl nucleus), 1519 (C=C str., phenyl nucleus), 1666 (NH–C=O str.), 1598 (N=CH str., of pyrimidine), 2836 (C–H str., CH2), 1210 (C–NH– str.), 1341 (C–N sym. str., Ar–NO2), 1105 (C–O–C str., Ar–OCH3); 1H-NMR (δ, DMSO-d 6): 5.22–8.69 {m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-2‴, H-4‴, H-5‴, H-6‴) × 2}, 7.41 (s, 2H, (CH)2 of pyrimidine), 8.01 (s, 2H, (NH)2), 3.73 (s, 4H, (CH2)2, 3.38 (s, 6H, (OCH3)2); 13C-NMR (δ, DMSO-d 6): 128.3 (C-2, C-3, C-5, C-6), 136.7 (C-1, C-4); 160.0 (C-1′, C-3′), 106 (C-2′), 149.8 (C-5′) pyrimidine; 141.5 (C-1″), 126.4 (C-2″, C-6″), 123.5 (C-3″, C-5″), 148.3 (C-4″); 149.7 (C-1‴), 106.4 (C-2‴, C-6‴), 113.3 (C-5‴); 188.2 (C=O), 54.4 (CH2), 55.1 (OCH3); Elem. Anal. Calcd. C44H36N10O8: C, 63.46; H, 4.36; N, 16.82; Found: C, 63.39; H, 4.30; N, 16.86; MS ES + (ToF): m/z 834 [M+ +1].
N,N′-(6,6′-(1,4-Phenylene)bis(4-(4-nitrophenyl)pyrimidine-6,2-diyl))bis(2-(2-methoxyphenyl) acetamide (20)
Canary yellow crystals; M.p.: 179–180 °C; Rf value: 0.32; Yield: 89.23%; IR (KBr pellets, cm−1): 3076 (C–H str., phenyl group), 1519 (C=C str., phenyl group), 1666 (NH–C=O str.), 1599 (N=CH str., of pyrimidine), 2842 (C–H str., CH2), 1211 (C–NH– str.), 1340 (C–N sym. str., Ar–NO2), 1107 (C–O–C str., Ar–OCH3); 1H-NMR (δ, DMSO-d 6): 7.14-8.39 {m, 20H, Ar = H-2, H-3, H-5, H-6, (H-2″, H-3″, H-5″, H-6″) × 2, (H-3‴, H-4‴, H-5‴, H-6‴) × 2}, 7.47 (s, 2H, (CH)2 of pyrimidine), 8.00 (s, 2H, (NH)2), 3.82 (s, 4H, (CH2)2), 3.75 (s, 6H, (OCH3)2); 13C-NMR (δ, DMSO-d 6): 128.9 (C-2, C-3, C-5, C-6), 136.7 (C-1, C-4); 164.0 (C-1′, C-3′), 110.0 (C-2′), 149.8 (C-5′) pyrimidine; 141.5 (C-1″), 126.4 (C-2″, C-6″), 124.5 (C-3″, C-5″), 149.7 (C-4″); 126.5 (C-1‴), 158.0 (C-2‴), 55.5 (OCH3), 113.3 (C-3‴), 128.9 (C-4‴), 121.3 (C-5‴), 133.2 (C-6‴); 188.2 (C=O), 39.0 (CH2); Elem. Anal. Calcd. C44H36N10O8: C, 63.46; H, 4.36; N, 16.82; Found: C, 63.40; H, 4.31; N, 16.85; MS ES + (ToF): m/z 834 [M+ +1].
Biological study (antimicrobial and anticancer)
The antimicrobial activity i.e. The minimum inhibitory concentration (MIC) of the synthesized compounds (1–20) was determined by tube dilution method [26] using cefadroxil (antibacterial) and fluconazole (antifungal) as reference drugs against Gram-positive [S. aureus, MTCC-3160 (Microbial Type Culture Collection); B. subtilis, MTCC-441] and Gram-negative bacteria (E. coli, MTCC-443; P. aeruginosa, MTCC-3542; S. enterica, MTCC-1165). The antifungal activity was assayed against yeast (C. albicans, MTCC-227) and mould (A. niger, MTCC-281). Serial dilutions of the test compounds and reference drugs were prepared in double strength nutrient broth I.P. (bacteria) or sabouraud dextrose broth I.P. (fungi) [27]. The stock solution of the test compounds and reference drugs was prepared in dimethyl sulfoxide (DMSO). Further progressive dilutions were done to obtain final concentrations of 50, 25, 12.5, 6.25, 3.125 and 1.562 µg/mL. The samples were incubated at 37 ± 1 °C for 24 h (bacteria), at 25 ± 1 °C for 7 days (A. niger) and at 37 ± 1 °C for 48 h (C. albicans) respectively and the results were recorded in terms of MIC. The MIC was the lowest concentration of the tested compound that yields no visible growth of microorganisms in the tube. To ensure that the solvent had no effect on the bacterial growth, a control was performed with the test medium supplemented with DMSO at the same dilutions as used in the experiments and DMSO had no effect on the microorganisms in the concentrations studied. The anticancer screening (IC50 = µmol/mL) of synthesized compounds was determined against human colorectal carcinoma [HCT-116 (ATCC (American Type Culture Collection) CCL-247)] cancer cell line using sulforhodamine-B (SRB) assay. In this study, the culture material was fixed with trichloroacetic acid and then stained for 30 min with 0.4% (w/v) sulforhodamine B mixed with 1% acetic acid. Unbound dye was discarded by five washes of 1% acetic acid solution and protein-bound dye was extracted with 10 mM Tris base [tris(hydroxymethyl) aminomethane] for confirmation of optical density in a computer-interfaced, 96-well microtiter plate reader [28].
Conclusion
In summary, a series of new bis-pyrimidine acetamide molecules was synthesized in good yields and its chemical structures were confirmed by 1H/13C-NMR, Mass, FT-IR studies and elemental analyses. All the synthesized compounds were tested for their in vitro antimicrobial and anticancer potentials. Among the synthesized compounds, compounds, 3, 13, 16, 17 and 18 exhibited good antimicrobial potential against different microorganism (bacterial species: S. aureus, B. subtilis, E. coli, P. aeruginosa, S. enterica and fungal species: A. niger and C. albicans) than the standard drugs cefadroxil and fluconazole. Similarly, compounds, 12, 16 and 18 were found to be more effective against HCT 116 cancer cell line than the standard drug, 5-fluorouracil.
Declarations
Authors’ contributions
BN and SK have designed, synthesized and carried out the antimicrobial activity of the bis-pyrimidine acetamide derivatives. KR, SAAS, SML and VM have carried out the spectral analysis, interpretation and anticancer evaluation of synthesized compounds. All authors read and approved the final manuscript.
Acknowledgements
The authors are thankful to Head, Department of Pharmaceutical Sciences, M. D. University, Rohtak for providing necessary facilities to carry out this research work.
Competing interests
The authors declare that they have no competing interests.
Ethics approval and consent to participate
Not applicable.
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