Nonsymmetrically substituted
In addition, silver complexes have been reported to have anticancer activity
Within this paper we present a new series of nonsymmetrically
All reactions were carried out under aerobic conditions. All silver(I) acetate reactions were carried out under exclusion of light. 1H-Imidazole, 1H-benzimidazole, benzyl bromide, 4-methylbenzyl bromide, methyl 4-(bromomethyl)benzoate, 4-cyanobenzyl bromide, silver(I) acetate, and K2CO3 were procured commercially from Sigma-Aldrich Chemical Company and were used without further purification. IR spectra were recorded on a Perkin-Elmer Paragon 1000 FT-IR spectrometer employing a KBr disc. NMR spectra were measured either on a Varian 300 MHz or 400 MHz spectrometer. All chemical shifts are reported in ppm and referenced to TMS. ESI MS was performed on a quadrupole tandem mass spectrometer (Quattro Micro, Micromass/Water’s Corp., USA), using solutions in 100% MeOH. MS spectra were obtained in the ES+ (electron spray positive ionisation) mode for all compounds. CHN Analysis was carried out in an Exeter Analytical CE-440 elemental analyzer. Crystal Data was collected using an Agilent Technologies (former Oxford Diffraction) SuperNova diffractometer fitted with an Atlas detector.
Crystal data and structure refinement for
Empirical formula | C25 H22 N3 O2 Ag |
Formula weight [g/mol] | 504.33 |
Crystal system | Monoclinic |
Space group | P21/n (#14) |
Unit cell dimensions [Å] a | 7.6287(2) |
b | 12.4073(3) |
c | 23.0001(6) |
| 94.496(3)° |
Volume [Å3] | 2170.30(10) |
Z | 4 |
Density [mg/m3] (calc.) | 1.543 |
Absorption coefficient [mm−1] | 0.956 |
F(000) | 1024 |
Crystal size [mm3] | 0.2663 × 0.1227 × 0.1080 |
Theta range for data collection | 3.32 to 26.42°. |
Index ranges | –9 ≤ h≤ 9 |
–15 ≤ k ≤ 15 | |
–28 ≤ l ≤ 28 | |
Reflections collected | 35074 |
Independent reflections | 4454 [R(int) = 0.0421] |
Completeness to | 99.6% |
Max. and min. transmission | 0.913 and 0.808 |
Data/restraints/parameters | 4454/0/287 |
Goodness of fit in F2 | 1.086 |
Final R indices (I > 2 | R1 = 0.0238 |
wR2 = 0.0512 | |
R indices (all data) | R1 = 0.0301 |
wR2 = 0.0543 | |
Largest diff. peak and hole | 0.871 and 0.323 e·Å−3 |
CCDC 853680 (for
1H-Imidazole (1.478 g, 22.03 mmol), 4-(bromomethyl)benzonitrile (4.319 g, 22.03 mmol), and K2CO3 (4.560 g, 33.00 mmol) were stirred in CH3CN at room temperature for 2 d. After the solvent was removed under reduced pressure, water (30 mL) was added. The aqueous phase was extracted with CH2Cl2(3x, 20 mL), and the combined organic phases were dried with magnesium sulfate. After removing the solvent under reduced pressure, the product (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3427 (m), 3132 (s), 3063 (m), 2981 (s), 2852 (s), 2226 (s), 1608 (m), 1567 (s), 1411 (s), 1355 (m), 1209 (s), 1161 (s), 769 (m), 634 (m), 550 (m).
MS (
Microanalysis calculated for C11H9N3 (183.21): calcd.: C, 72.11%; H, 4.95%; N, 22.94%; found: C, 72.03%; H, 5.05%; N, 22.92%.
4-(1H-Imidazole-1-ylmethyl)benzonitrile (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3461 (m), 3130 (s), 3058 (s), 2980 (s), 2920 (s), 2226 (s), 1608 (m), 1567 (s), 1411 (m), 1355 (m), 1209 (s), 1160 (s), 770 (s), 634 (m), 549 (m).
MS (
Microanalysis calculated for C18H16BrN3 (354.24): calcd.: C, 61.03%; H, 4.55%; N, 11.86%; Found: C, 60.96%; H, 4.52%, N, 11.68%.
4-(1H-Imidazole-1-ylmethyl)benzonitrile (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3455 (m), 3130 (s), 3052 (s), 2981 (s), 2852 (s), 2227 (s), 1609 (m), 1566 (s), 1411 (m), 1209 (m), 1160 (s), 769 (s), 635 (m), 551 (s).
MS (
Microanalysis calculated for C19H18BrN3 (368.27): calcd.: C, 61.97%; H, 4.93%; N, 11.41%. Found: C, 62.34%; H, 5.01%; N, 11.21%.
4-(1H-Imidazole-1-ylmethyl)benzonitrile (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3414 (m), 3059 (s), 2986 (s), 2964 (s), 2223 (s), 1610 (m), 1553 (s), 1516 (s), 1257 (m), 1146 (s), 1032 (m), 846 (m), 629 (s), 562 (m).
MS (
Microanalysis calculated for C19H18BrN3O (384.27): calcd.: C, 59.39%; H, 4.72%; N, 10.94%. Found: C, 59.01%; H, 4.80%; N, 10.47%.
4-(1H-Imidazole-1-ylmethyl)benzonitrile (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3403 (m), 3132 (s), 3062 (s), 2983 (s), 2851 (s), 2226 (s), 1718 (m), 1609 (m), 1566 (s), 1412 (s), 1286 (s), 1161 (s), 769 (s), 635 (m), 556 (s).
MS (
Microanalysis calculated for C20H18BrN3O2 (412.28): calcd.: C, 58.26%; H, 4.40%; N, 10.19%; found: C, 59.01%; H, 4.68%; N, 10.89%.
1-Benzyl-3-(4-cyanobenzyl)-2,3-dihydro-1H-imidazole-2-ylium bromide (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3410 (s), 3154 (s), 2230 (s), 1564 (s), 1411 (s), 1237 (m), 777 (m), 672 (w), 557 (m).
MS (
Microanalysis calculated for C20H18AgN3O2 (440.24): calcd.: C, 54.56%; H, 4.12%; N, 9.54%; found: C, 55.01%; H, 4.24%; N, 9.07%.
1-(4-Cyanobenzyl)-3-(4-methylbenzyl)-2,3-dihydro-1H-imidazole-2-ylium bromide (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3391 (s), 3053 (m), 2227 (s), 1567 (s), 1410 (s), 1238 (m), 1158 (m), 771 (s), 690 (s), 624 (m).
MS (
Microanalysis calculated for C21H20AgN3O2 (454.27): calcd.: C, 55.52%; H, 4.44%; N, 9.25%; found: C, 55.48%; H, 4.62%; N, 9.09%.
1-(4-Cyanobenzyl)-3-[4-(methoxycarbonyl)benzyl]-2,3-dihydro-1H-imidazole-2-ylium bromide (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3417 (s), 3080 (s), 2229 (s), 1720 (m), 1566 (s), 1412 (s), 1281 (w), 656 (s).
MS (
Microanalysis calculated for C22H20AgN3O4 (498.28): calcd.: C, 53.03%; H, 4.05%; N, 8.43%; found: C, 52.66%; H, 4.12%, N, 8.01%.
1H-Benzimidazole (1.488 g, 12.70 mmol), 4-(bromomethyl)benzonitrile (2.489 g, 12.70 mmol), and K2CO3 (2.633 g, 19.05 mmol) were stirred in CH3CN at room temperature for 2 d. After the solvent was removed under reduced pressure, water (30 mL) was added. The aqueous phase was extracted with CH2Cl2(3x, 20 mL), and the combined organic phases were dried with magnesium sulfate. After removing the solvent under reduced pressure, the product (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3427 (m), 3060 (m), 2222 (s), 1615 (m), 1490 (s), 1457 (s), 1364 (m), 1284 (s), 1259 (s), 1167 (s), 761 (m), 745 (m), 556 (s).
MS (
Micro analysis calculated for C15H11N3 (223.27): calcd.: C, 77.23%, H, 4.75%; N, 18.01%; found: C, 76.47%; H, 4.73%; N, 17.77%.
4-(1H-Benzimidazole-1-ylmethyl)benzonitrile (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3451 (s), 3384 (s), 3121 (s), 3035 (s), 2877 (s), 2228 (s), 1607 (m), 1554 (s), 1454 (s), 1184 (s), 1020 (m), 770 (s), 622 (m).
MS (
Microanalysis calculated for C22H18BrN3 (404.30): calcd.: C, 65.36%; H, 4.49%; N, 10.39%; found: C, 65.40%; H, 4.40%, N, 10.21%.
4-(1H-Benzimidazole-1-ylmethyl)benzonitrile (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3465 (s), 3397 (s), 3127 (s), 3032 (s), 2968 (s), 2885 (s), 2230 (s), 1608 (m), 1561 (s), 1416 (m), 1372 (s), 1191 (s), 1019 (m), 761 (s), 613 (m), 554 (m).
MS (
Microanalysis calculated for C23H20BrN3 (418.33): calcd.: C, 66.04%; H, 4.82%; N, 10.04%; found: C, 65.99%; H, 4.79%, N, 10.04%.
4-(1H-Benzimidazole-1-ylmethyl)benzonitrile (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3420 (s), 3122 (s), 3035 (s), 2968 (s), 2840 (s), 2229 (s), 1792 (w), 1609 (s), 1555 (s), 1514 (s), 1459 (s), 1370 (s), 1254 (s), 1178 (s), 1112 (s), 1013 (s), 763 (s), 613 (s).
MS (
Microanalysis calculated for C23H20BrN3O (434.33): calcd.: C, 63.60%; H: 4.64%; N, 9.67%; found: C, 63.41%; H, 4.70%; N, 9.69%.
4-(1H-Benzimidazole-1-ylmethyl)benzonitrile (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3433 (s), 2963 (s), 2228 (s), 1717 (s), 1560 (m), 1435 (m), 1416 (m), 1283 (s), 1189 (m), 1107 (m), 748 (m), 601 (m).
MS (
Microanalysis calculated for C24H20BrN3O2 (462.34): calcd.: C, 62.35%; H, 4.36%; N, 9.09%; found: C, 61.90%; H, 4.14%; N, 9.10%.
1-Benzyl-3-(4-cyanobenzyl)-2,3-dihydro-1H-benzimidazole-2-ylium bromide (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3476–3364 (m), 3037-2922 (s), 2229 (m), 1607 (s), 1562 (s), 1390 (s), 1335 (m), 740 (s), 657 (s), 614 (s), 552 (m), 454 (m).
MS (
Microanalysis calculated for C24H20AgN3O2 (490.30): calcd.: C, 58.79%; H, 4.11%; N, 8.57%; found: C, 58.71%; H, 4.03%; N, 8.69%.
1-(4-Cyanobenzyl)-3-(4-methylbenzyl)-2,3-dihydro-1H-benzimidazole-2-ylium bromide (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3417 (m), 3030 (s), 2229 (m), 1571 (s), 1391 (s), 796 (m), 743 (m), 668 (m), 612 (m)
MS (
Microanalysis calculated for C25H22AgN3O2 (504.33): calcd.: C, 59.54%; H, 4.40%; N, 8.33%; found: C, 60.04%; H, 4.38%, N, 8.37%.
1-(4-Cyanobenzyl)-3-(4-methoxybenzyl)-2,3-dihydro-1H-benzimidazole-2-ylium bromide (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3390 (m), 2929 (s) [C–H], 2228 (s), 1608 (s), 1571 (s), 1513 (s), 1393 (s), 1249 (s), 1176 (s), 1116 (w), 1024 (s), 799 (s), 745 (s), 538 (s).
MS (
Microanalysis calculated for C25H22AgN3O3 (520.33): calcd.: C, 57.71%; H, 4.26%; N, 8.08%; found: C, 57.72%; H, 4.18%; N, 8.27%.
1-(4-Cyanobenzyl)-3-[4-(methoxycarbonyl)benzyl]-2,3-dihydro-1H-benzimidazole-2-ylium bromide (
1H NMR (
13C NMR (
IR absorptions (KBr, cm−1): 3422 (m), 2952 (s), 2229 (m), 1715 (s), 1573 (s), 1394 (s), 1283 (s), 1106 (m), 1018 (w), 739 (m).
MS (
Microanalysis calculated for C26H22AgN3O4 (548.34): calcd.: C, 56.95%; H, 4.04%; N, 7.66%; found: C, 56.77%; H, 4.03%; N, 7.48%.
The silver(I) acetate complexes were screened in preliminary
To assess the biological activity of compounds
For each strain, 70
Preliminary
In Schemes
General reaction scheme for the synthesis of imidazole containing asymmetric substituted NHC precursors
General reaction scheme for the synthesis of benzimidazole containing asymmetric substituted NHC precursors
In the absence of light, the silver(I) acetate complexes (1-benzyl-3-(4-cyanobenzyl)-2,3-dihydro-1H-imidazole-2-ylidene) silver(I) acetate (
The asymmetric substituted
Furthermore, the solid state structure of the silver(I) acetate complex
Due to the positive charge of the molecule, the 1H NMR spectra of all NHC precursors
The crystal of
Selected bond lengths [Å] and angles [°] for
Bond length [Å] | Bond angle [°] | ||||
---|---|---|---|---|---|
Ag(1)–C(9) | 2.060(2) | C(9)–Ag(1) –O(1) | 170.76(7) | ||
Ag(1)–O(1) | 2.1088(14) | C(9)–Ag(2)–O(1) | 135.9(4) | ||
Ag(2)–C(9) | 2.074(5) | C(9)–Ag(2)–O(2) | 164.9(3) | ||
Ag(2)–O(1) | 2.408(6) | O(1)–Ag(2)–O(2) | 53.05(11) | ||
Ag(2)–O(2) | 2.554(5) | N(3)–C(9)–N(2) | 105.98(17) | ||
N(2)–C(9) | 1.350(3) | N(3)–C(9)–Ag(1) | 127.63(14) | ||
N(2)–C(10) | 1.395(2) | N(2)–C(9)–Ag(1) | 125.82(14) | ||
C(9)–N(3) | 1.348(2) | N(3)–C(9)–Ag(2) | 118.7(2) | ||
C(10)–C(15) | 1.388(3) | N(2)–C(9)–Ag(2) | 133.79(19) | ||
C(15)–N(3) | 1.391(3) | C(15)–C(10)–N(2) | 105.82(17) | ||
O(1)–C(24) | 1.276(3) | C(10)–C(15)–N(3) | 106.11(17) | ||
O(2)–C(24) | 1.237(2) | C(9)–N(3)–C(15) | 111.09(16) | ||
C(24)–C(25) | 1.511(3) | C(9)–N(2)–C(10) | 110.96(16) | ||
C(24)–O(1)–Ag(1) | 109.21(12) | ||||
C(24)–O(1)–Ag(2) | 93.9(2) | ||||
C(24)–O(2)–Ag(2) | 88.1(2) | ||||
O(2)–C(24)–O(1) | 124.18(19) | ||||
O(2)–C(24)–C(25) | 119.62(19) | ||||
O(1)–C(24)–C(25) | 116.19(18) |
X-ray diffraction structure of
X-ray diffraction structure of
The major species (95%, Figure
In comparison to this, the minor species (5%, Figure
Using the Kirby-Bauer disk diffusion method, the
Area of clearance on
Area of clearance on
Compounds
Our interest focuses on the probable difference in activity due to the influence of different lipophilicity in the two compound classes. The
Cytotoxicity curves from typical MTT assays showing the effect of compounds
Cytotoxicity curves from typical MTT assays showing the effect of compounds
It has been shown that there is no difference between the cytotoxic activities of the two compound classes, since all compounds show a good level of activity. The solubility of all compounds in DMSO was good, and they are stable in saline solution with respect to silver chloride precipitation.
In summary, a series of seven nonsymmetrically
This project was funded by the UCD School of Chemistry and Chemical Biology.