Synthesis of Some New Pyridine-2,6-carboxamide-derived Schiff Bases as Potential Antimicrobial Agents
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
*
Author to whom correspondence should be addressed.
Molecules 2010, 15(7), 4711-4721; https://doi.org/10.3390/molecules15074711
Submission received: 13 June 2010
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Revised: 30 June 2010
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Accepted: 1 July 2010
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Published: 6 July 2010
Abstract
:A series of pyridine-bridged 2,6-bis-carboxamide Schiff's bases has been prepared starting from 2,6-pyridinedicarbonyl dichloride (1) and L-alanine or 2-methyl-alanine methyl ester. The coupling of acid chloride 1 with L-alanine methyl ester hydrochloride -or 2-methylalanine methyl ester hydrochloride gave the corresponding 2,6-bis-carboxamide pyridine methyl esters 2a,b. Hydrazonolysis of 2 with hydrazine hydrate afforded the corresponding bis-hydrazides 3a,b. Treatment of 3a,b with appropriate aromatic or heterocyclic aldehydes afforded the corresponding pyridine- bridged 2,6-bis-carboxamide Schiff's bases 4a-f and 5a-f, respectively. The newly synthesized compounds 2-5 were screened for their bactericidal and fungicidal activities. Many of the obtained compounds exhibited significant antimicrobial activity, comparable to streptomycin and fusidic acid, which were used as reference antibiotic drugs.
1. Introduction
In our previous work, we have reported that certain of substituted pyridine and Schiff base derivatives as antimicrobial, anti-inflammatory and anticancer agents [1,2,3,4,5,6]. Also, Schiff base and other heterocyclic derivatives were reported to possess diverse biological activities, such as antibacterial [7,8,9,10] and anti-inflammatory [11,12,13] properties. In addition, several substituted pyridines and their derivatives were reported to exhibit significant antimicrobial [14], anti-inflammatory [15] and anticancer activities [16]. In continuation of our interest in the chemical and pharmacological properties of disubstituted pyridine derivatives [17,18,19,20], we report herein the synthesis and antimicrobial activities of a new series of hydrazides and their corresponding N2,N6-bis(1-oxo-1-(2-(substituted-benzylidene)-hydrazinyl)propan-2-yl)pyridine-2,6-di-carboxamide derivatives (Schiff's bases).
2. Results and Discussion
2.1. Chemistry
L-Alanine and/or 2-methylalanine methyl esters were initially coupled with 2,6-pyridinedicarbonyl dichloride (1) (acid chloride method) [21] to give the corresponding 2,6-bis-carboxamide pyridine methyl esters 2a,b. Treatment of 2,6-bis-esters 2a,b with hydrazine hydrate in absolute ethanol afforded the corresponding 2,6-bis-hydrazides 3a,b (Scheme 1). Some physical properties of these compounds are listed in Table 1.
Scheme 1.
Synthetic Pathway for Compounds 2a,b and 3a,b.
Table 1.
Melting points, crystallization solvents, yields, molecular formulae and molecular weights of compounds 2a,b and 3a,b.
| Comp. No. | R | Mp (ºC) | Cryst. Solv. | Yield (%) | [α]30D | Molecular Formula (Mol. Wt.) |
|---|---|---|---|---|---|---|
| 2a | H | 182-184 | EtOH | 75 | +15 (DMF) | C15H19N3O6 (337.33) |
| 2b | CH3 | 196-198 | EtOH | 68 | - | C17H23N3O6 (365.38) |
| 3a | H | 252-254 | AcOH/H2O | 82 | +56 (DMF) | C13H19N7O4 (337.33) |
| 3b | CH3 | 246-248 | AcOH/H2O | 85 | - | C15H23N7O4 (365.39) |
Compounds 4a-f and 5a-f are new, and were synthesized via simple condensation of the hydrazides 3a,b with appropriate aromatic or heterocyclic aldehydes, namely, benzaldehyde, p-methoxy-benzaldehyde, 3,4,5-trimethoxybenzaldehyde, p-chlorobenzaldehyde, 2-chloro-6-flourobenzaldehyde, and/or 2-thiophenealdehyde in refluxing absolute ethanol giving the corresponding N2,N6-bis(1-(2-(substituted benzylidene)hydrazinyl)-1-oxopropan-2-yl)pyridine-2,6-dicarboxamides 4a-f and N2,N6-bis(1-(2-(substituted benzylidene)hydrazinyl)-2-methyl-1-oxopropan-2-yl)pyridine-2,6-dicarboxamides 5a-f (Scheme 2).
Scheme 2.
Synthetic Pathway for Compounds 4a-f and 5a-f.
Table 2.
Melting points, crystallization solvents, yields, specific rotation, molecular formulae and molecular weights of compounds 4a-h and 5a-h.
| Comp. No. | Ar | Mp (ºC) | Cryst. Solv. | Yield (%) | [α]30D (DMF) | Molecular Formula (Mol. Wt.) |
|---|---|---|---|---|---|---|
| 4a |  | 122-124 | EtOH/ n-hexane | 68 | + 18 | C27H27N7O4(513.55) |
| 4b |  | 210-212 | AcOH/H2O | 75 | + 32 | C29H31N7O6(573.60) |
| 4c |  | 148-150 | AcOH | 80 | + 24 | C33H39N7O10 (693.70) |
| 4d |  | 205-207 | EtOH/ n-hexane | 65 | + 54 | C27H25Cl2N7O4 (582.44) |
| 4e |  | 168-170 | AcOH/H2O | 72 | + 12 | C27H23Cl2F2N7O4 (618.42) |
| 4f |  | 185-187 | EtOH/ n-hexane | 60 | + 16 | C23H23N7O4S2 (525.60) |
| 5a |  | 240-242 | EtOH | 70 | - | C29H31N7O4 (541.60) |
| 5b |  | 120-122 | Dioxane | 75 | - | C31H35N7O6 (601.65) |
| 5c |  | 135-137 | AcOH/H2O | 66 | - | C35H43N7O10 (721.76) |
| 5d |  | 155-157 | AcOH/H2O | 78 | - | C29H29Cl2N7O4 (610.49) |
| 5e |  | 213-215 | AcOH/H2O | 86 | - | C29H27Cl2F2N7O4 (646.47) |
| 5f |  | 220-222 | EtOH | 60 | - | C25H27N7O4S2 (553.66) |
The structures of all the newly synthesized compounds 2a,b, 3a,b, 4a-f and 5a-f were confirmed by their IR, 1H-NMR, 13C-NMR and mass spectra.
2.2. Antimicrobial testing
Preliminary biological activity screening of the synthesized compounds has been performed at 50 μg/mL against microorganisms representing Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus), Gram-negative bacteria (Escherichia coli) and fungi (Candida albicans and Aspergillus niger), using the bioassay technique for antibiotics [22] specified in the US Pharmacopeia. From Table 3 it appears that the Schiff's bases 4b-f and 5b-f have significant antimicrobial activities. Among these Schiff's bases, the 4-methoxy- 4b,5b, 3,4,5-trimethoxy- 4c,5c, 4-chloro-4d,5d, 2-chloro-6-flouro-4e,5e and 2-thienyl- derivatives 4f,5f have antimicrobial activities higher those of 4a,5a with an unsubstituted phenyl group. The hydrazides 3a,b were found to have lower antimicrobial activities, while the esters 2a,b didn’t show any antifungal activity. Streptomycin and fusidic acid were used as antibacterial and antifungal reference drugs, respectively.
| Comp. No. | Inhibition zones (cm) | ||||
|---|---|---|---|---|---|
| Gram-positive | Gram-negative | Fungi | |||
| Bacillus subtilis | Staphylococcus aureus | Escherichia coli | Candida albicans | Aspergillus niger | |
| 2a | 15 | 18 | 16 | - | - |
| 2b | 14 | 13 | 15 | - | - |
| 3a | 1 | 12 | 13 | 14 | 10 |
| 3b | 12 | 14 | 15 | 12 | 11 |
| 4a | 14 | 15 | 16 | 14 | 12 |
| 4b | 20 | 19 | 19 | 16 | 15 |
| 4c | 21 | 18 | 20 | 17 | 16 |
| 4d | 20 | 19 | 21 | 17 | 14 |
| 4e | 22 | 20 | 20 | 18 | 16 |
| 4f | 21 | 18 | 18 | 17 | 16 |
| 5a | 16 | 15 | 17 | 12 | 10 |
| 5b | 21 | 18 | 20 | 14 | 15 |
| 5c | 19 | 20 | 19 | 16 | 16 |
| 5d | 20 | 17 | 18 | 16 | 14 |
| 5e | 22 | 20 | 20 | 17 | 14 |
| 5f | 20 | 19 | 21 | 16 | 15 |
| Streptomycin | 22 | 21 | 22 | - | - |
| Fusidic acid | - | - | - | 18 | 17 |
3. Experimental
3.1. General
Melting points (ºC) were measured in open glass capillaries using a Barnstead 9001 Electrothermal melting point apparatus and are uncorrected. NMR spectra were obtained on a Bruker AC 500 Ultra Shield NMR spectrometer (Bruker, Fällanden, Switzerland) operating at 500.13 MHz for 1H and 125.76 MHz for 13C; the chemical shifts are expressed in δ (ppm) downfield from tetramethylsilane (TMS) used as internal standard. Electrospray ionization mass spectra (ESI-MS) were recorded on a Waters QuatroMicro triple quadrupole tandem mass spectrometer at 4.0 and 3.5 kV for positive and negative ions, respectively. Elemental analyses (C, H, N, Cl, S) were in full agreement with the proposed structures within ± 0.4% of the theoretical values. Monitoring of reactions and checking of purity of the final products were carried out by thin layer chromatography (TLC) using silica gel precoated aluminum sheets (60 F254, Merck) and visualization with ultraviolet light (UV) at 365 and 254 nm.
3.2. Chemistry
3.2.1. N2,N6-Bis(1-methoxy-oxopropan-2-yl)pyridine-2,6-dicarboxamides 2a,b
To a solution of L-alanine and/or 2-methylalanine methyl esters (2 mmol), 2,6-pyridinedicarboyl dichloride 1 (0.204 g, 1 mmol) in dichloromethane (15 mL) was added at -10 ºC with stirring. Triethylamine was added dropwise to the reaction mixture in order to keep the reaction mixture slightly basic (pH ~ 8). Stirring was continued for 3 h more at -15 ºC and then 12 h at r.t. The reaction mixture was then washed with water, 1N hydrochloric acid, 1N sodium bicarbonate and finally with water and dried over anhydrous calcium chloride. The solvent was evaporated under reduced pressure to dryness and the obtained solid was crystallized from the appropriate solvent indicated in Table 1 to give the corresponding bis-esters 2a,b.
N2,N6-Bis(1-methoxy-1-oxopropan-2-yl)pyridine-2,6-dicarboxamide (2a). IR (KBr, cm-1): ν 3352-3268 (NH), 1745 (C=O, ester), 1678 (C=O, amide); 1H-NMR (DMSO-d6): δ 1.32 (d, 6H, 2 CH3), 3.62 (s, 6H, 2OCH3), 4.25 (m, 2H, 2CH), 8.18-8.26 (m, 3H, pyridine-H), 8.62 (s, 2H, 2NH exchangeable with D2O); 13C-NMR: 17.32 (2C, 2CH3), 47.88 (2C, 2CH), 56.15 (2C, 2OCH3), 123.12, 138.54, 149.65 (5C, pyridine-C), 159.96, 171.86 (4C, 4C=O); MS, m/z (%): 337 (M+, 5), 306 (15), 275 (100), 219 (12), 163 (26), 133 (75), 105 (14), 77 (65).
N2,N6-Bis(1-methoxy-2-methyl-1-oxopropan-2-yl)pyridine-2,6-dicarboxamide (2b). IR (KBr, cm-1): ν 3332-3278 (NH), 1747 (C=O, ester), 1676 (C=O, amide); 1H-NMR (DMSO-d6): δ 1.46 (s, 12H, 4 CH3), 3.56 (s, 6H, 2OCH3), 8.15-8.28 (m, 3H, pyridine-H), 8.42 (s, 2H, 2NH exchangeable with D2O); 13C-NMR: 23.78 (4C, 4CH3), 55.18 (2C, NH-C(CH3)2CO), 123.18, 139.05, 149.72 (5C, pyr-C), 160.12, 172.65 (4C, 4C=O); MS, m/z (%): 365 (M+, 8), 334 (25), 303 (80), 218 (100), 148 (6), 133 (42), 105 (34), 77 (78).
3.2.2. N2,N6-Bis(1-hydrazinyl)pyridine-2,6-dicarboxamides 3a,b
A mixture of bis-esters 2a or 2b (1 mmol) and hydrazine hydrate (0.8 mL, 16 mmol) in absolute ethanol (50 mL) was refluxed for 6 h. Excess solvent was evaporated under reduced pressure to dryness, the obtained residue was triturated with ethanol and the resulting solid was crystallized from the appropriate solvent to give bis-hydrazide derivatives 3a,b, respectively (Table 1).
N2,N6-Bis(1-hydrazinyl-1-oxopropan-2-yl)pyridine-2,6-dicarboxamide (3a). IR (KBr, cm-1): ν 3465-3228 (NH, NH2), 1680, 1675 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.36 (d, 6H, 2 CH3), 4.12 (s, 4H, 2NH2 exchangeable with D2O), 4.62 (m, 2H, 2CH), 8.12-8.24 (m, 3H, pyridine-H), 8.68, 9.05 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 18.05 (2C, 2CH3), 50.12 (2C, 2CH), 123.34, 139.05, 149.78 (5C, pyridine-C), 160.08, 171.24 (4C, 4C=O); MS, m/z (%): 337 (M+, 15), 321 (8), 305 (5), 275 (10), 219 (12), 176 (16), 133 (100), 105 (24), 77 (45).
N2,N6-Bis(1-hydrazinyl-2-methyl-1-oxopropan-2-yl)pyridine-2,6-dicarboxamide (3b). IR (KBr, cm-1): ν 3470-3218 (NH, NH2), 1678, 1672 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.35 (s, 12H, 4 CH3), 4.15 (s, 4H, 2NH2 exchangeable with D2O), 8.18-8.26 (m, 3H, pyridine-H), 8.18, 8.98 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 25.86 (4C, 4CH3), 59.64 (2C, NH-C(CH3)2CO), 123.42, 139.00, 149.88 (5C, pyridine-C), 160.08, 178.65 (4C, 4C=O); MS, m/z (%): 365 (M+, 4), 333 (5), 233 (100), 148 (65), 133 (48), 105 (56), 77 (76).
3.2.3. General procedure for the synthesis of N2,N6-bis(1-(substituted)pyridine-2,6-dicarboxamides 4a-f and 5a-f
A mixture of the hydrazide derivative 3a or 3b (1 mmol) and the appropriate aldehyde, namely benzaldehyde, p-methoxybenzaldehyde, 3,4,5-trimethoxybenzaldehyde, p-chlorobenzaldehyde, 2 chloro-6-flourobenzaldehyde, and/or 2-thiophenealdehyde (2 mmol) in absolute ethanol (25 mL) was heated under reflux for 4-6 h. The excess solvent was evaporated under reduced pressure, the residue was washed with n-hexane and triturated with diethyl ether. The obtained solid was filtered off, washed with ether, and crystallized from the appropriate solvent (see Table 2) to give the corresponding dicarboxamide derivatives 4a-f and 5a-f, respectively.
N2,N6-Bis(1-(2-benzylidenehydrazinyl)-1-oxopropan-2-yl)pyridine-2,6-dicarboxamide (4a). IR (KBr, cm‑1): ν 3356-3198 (NH), 1675, 1674 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.32 (d, 6H, 2 CH3), 4.56 (m, 2H, 2CH), 7.15-7.76 (m, 10H, 2Ph-H), 8.16-8.35 (m, 5H, pyridine-H + 2CH=N), 8.72, 10.54 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 17.76 (2C, 2CH3), 50.85 (2C, 2CH), 127.16, 128.60, 130.48, 132.98 (12C, 2Ph), 123.36, 138.70, 149.56 (5C, pyridine-C), 143.75 (2C, 2 CH=N), 160.28, 176.86 (4C, 4C=O); MS, m/z (%): 514 (M++1, 12), 436 (4), 359 (16), 317 (24), 275 (100), 245 (65), 216 (32), 176 (46), 133 (90), 105 (64), 77 (52).
N2,N6-Bis(1-(2-(4-methoxybenzylidene)hydrazinyl)-1-oxopropan-2-yl)pyridine-2,6-dicarboxamide (4b). IR (KBr, cm-1): ν 3348-3210 (NH), 1680, 1676 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.34 (d, 6H, 2 CH3), 3.72 (s, 6H, 2OCH3), 4.52 (m, 2H, 2CH), 7.18 (d, 4H, Ar-H), 7.78 (d, 4H, Ar-H), 8.18 (s, 2H, 2CH=N), 8.23-8.32 (m, 3H, pyridine-H), 8.68, 10.62 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 17.72 (2C, 2CH3), 51.05 (2C, 2CH), 54.66 (2C, 2OCH3), 114.05, 125.60, 129.78, 162.56 (12C, 2Ar-C), 123.30, 138.75, 149.50 (5C, pyridine-C), 144.00 (2C, 2 CH=N), 161.02, 176.82 (4C, 4C=O); MS, m/z (%): 574 (M++1, 6), 542 (12), 511 (6), 353 (24), 322 (18), 220 (100), 204 (65), 189 (13), 133 (76), 118 (46), 105 (46), 77 (44).
N2,N6-Bis(1-oxo-1-(2-(3,4,5-trimethoxybenzylidene)hydrazinyl)propan-2-yl)pyridine-2,6-dicarbox-amide (4c). IR (KBr, cm-1): ν 3354-3218 (NH), 1677, 1674 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.28 (d, 6H, 2 CH3), 3.76 (s, 18H, 6OCH3), 4.48 (m, 2H, 2CH), 7.12 (s, 4H, Ar-H), 8.14 (s, 2H, 2CH=N), 8.24-8.36 (m, 3H, pyridine-H), 8.72, 10.76 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 18.05 (2C, 2CH3), 51.55 (2C, 2CH), 55.10 (4C, 4OCH3), 58.72 (2C, 2OCH3), 104.52, 127.65, 140.68, 152.82 (12C, 2Ar-C), 123.45, 139.06, 149.65 (5C, pyridine-C), 145.18 (2C, 2 CH=N), 161.25, 176.88 (4C, 4C=O); MS, m/z (%): 694 (M++1, 4), 662 (8), 631 (12), 526 (18), 412 (28), 280 (100), 204 (45), 189 (8), 167 (34), 133 (82), 105 (66), 77 (56).
N2,N6-Bis(1-(2-(4-chlorobenzylidene)hydrazinyl)-1-oxopropan-2-yl)pyridine-2,6-dicarboxamide (4d). IR (KBr, cm-1): ν 3352-3198 (NH), 1677, 1675 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.28 (d, 6H, 2 CH3), 4.48 (m, 2H, 2CH), 7.42 (d, 4H, Ar-H), 7.65 (d, 4H, Ar-H), 8.16-8.35 (m, 5H, pyridine-H + 2CH=N), 8.72, 10.82 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 18.04 (2C, 2CH3), 50.95 (2C, 2CH), 127.82, 128.62, 130.88, 135.76 (12C, 2Ar-C), 123.45, 139.08, 149.45 (5C, pyridine-C), 143.86 (2C, 2 CH=N), 160.94, 176.55 (4C, 4C=O); MS, m/z (%): 582 (M+, 6), 584 (M++2, 2), 548 (12), 546 (4), 511 (15), 435 (18), 359 (16), 204 (100), 133 (65), 105 (32), 77 (78).
N2,N6-Bis(1-(2-(2-chloro-6-fluorobenzylidene)hydrazinyl)-1-oxopropan-2-yl)pyridine-2,6-dicarbox-amide (4e). IR (KBr, cm-1): ν 3410-3235 (NH), 1682, 1674 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.34 (d, 6H, 2 CH3), 4.55 (m, 2H, 2CH), 7.24-7.72 (m, 6H, Ar-H), 8.15-8.38 (m, 5H, pyridine-H + 2CH=N), 8.80, 10.74 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 17.88 (2C, 2CH3), 51.10 (2C, 2CH), 112.68, 117.78, 124.86, 133.56, 134.48, 160.65 (12C, 2Ar-C), 124.00, 139.24, 149.56 (5C, pyridine-C), 142.94 (2C, 2 CH=N), 160.76, 176.55 (4C, 4C=O); MS, m/z (%): 618 (M+, 15), 620 (M++2, 6), 488 (13), 490 (4), 359 (100), 318 (66), 275 (88), 204 (96), 133 (45), 105 (86), 77 (84).
N2,N6-Bis(1-oxo-1-(2-(thiophen-2-ylmethylene)hydrazinyl)propan-2-yl)pyridine-2,6-dicarboxamide (4f). IR (KBr, cm-1): ν 3390-3212 (NH), 1680, 1675 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.42 (d, 6H, 2 CH3), 4.46 (m, 2H, 2CH), 7.10-7.65 (m, 6H, thiophene-H), 8.22-8.35 (m, 5H, pyridine-H + 2CH=N), 8.76, 10.65 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 17.92 (2C, 2CH3), 51.08 (2C, 2CH), 126.76, 127.65, 139.32, 143.84 (8C, 2 thiophene-C), 124.05, 139.32, 149.48 (5C, pyridine-C), 132.88 (2C, 2 CH=N), 160.65, 176.62 (4C, 4C=O); MS, m/z (%): 525 (M+, 6), 442 (14), 400 (32), 329 (10), 317 (4), 196 (75), 204 (86), 133 (100), 105 (68), 77 (72).
N2,N6-Bis(1-(2-benzylidenehydrazinyl)-2-methyl-1-oxopropan-2-yl)pyridine-2,6-dicarboxamide (5a). IR (KBr, cm-1): ν 3360-3210 (NH), 1678, 1674 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.42 (s, 12H, 4 CH3), 7.25-7.82 (m, 10H, 2Ph-H), 8.12-8.25 (m, 3H, pyridine-H), 8.28 (s, 2H, 2CH=N), 8.45, 10.65 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 25.48 (4C, 4CH3), 59.78 (2C, 2 NHC(CH3)2CO), 128.10, 128.90, 130.48, 133.05 (12C, 2Ph-C), 124.12, 139.01, 149.48 (5C, pyridine-C), 143.65 (2C, 2 CH=N), 160.12, 178.86 (4C, 4C=O); MS, m/z (%): 541 (M+, 6), 464 (4), 387 (12), 345 (24), 303 (100), 218 (45), 133 (65), 105 (74), 77 (48).
N2,N6-Bis(1-(2-(4-methoxybenzylidene)hydrazinyl)-2-methyl-1-oxopropan-2-yl)pyridine-2,6-dicarbox-amide (5b). IR (KBr, cm-1): ν 3354-3212 (NH), 1680, 1678 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.30 (s, 12H, 4 CH3), 3.68 (s, 6H, 2OCH3), 7.08 (d, 4H, Ar-H), 7.72 (d, 4H, Ar-H), 8.16 (s, 2H, 2CH=N), 8.18-8.30 (m, 3H, pyridine-H), 8.42, 10.68 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 25.36 (4C, 4CH3), 59.64 (2C, 2 NHC(CH3)2CO), 54.55 (2C, 2OCH3), 113.98, 125.56, 129.88, 162.34 (12C, 2Ar-C), 123.48, 139.05, 149.35 (5C, pyridine-C), 143.89 (2C, 2 CH=N), 160.75, 178.85 (4C, 4C=O); MS, m/z (%): 602 (M++1, 16), 570 (22), 539 (18), 336 (100), 218 (10), 203 (67), 205 (54), 133 (18), 118 (45), 105 (42), 77 (32).
N2,N6-Bis(2-methyl-1-oxo-1-(2-(3,4,5-trimethoxybenzylidene)hydrazinyl)propan-2-yl)pyridine-2,6-dicarboxamide (5c). IR (KBr, cm-1): ν 3362-3210 (NH), 1679, 1675 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.34 (s, 12H, 4 CH3), 3.72 (s, 18H, 6OCH3), 7.10 (s, 4H, Ar-H), 8.22 (s, 2H, 2CH=N), 8.18-8.28 (m, 3H, pyridine-H), 8.62, 10.48 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 25.67 (4C, 4CH3), 55.82 (4C, 4OCH3), 59.72 (2C, 2 NHC(CH3)2CO), 59.88 (2C, 2OCH3), 104.05, 127.64, 141.08, 153.28 (12C, 2Ar-C), 123.75, 139.12, 149.70 (5C, pyridine-C), 145.22 (2C, CH=N), 160.98, 179.12 (4C, 4C=O); MS, m/z (%): 722 (M++1, 14), 690 (18), 660 (6), 524 (18), 388 (12), 345 (10), 303 (100), 218 (45), 133 (56), 77 (66).
N2,N6-Bis(1-(2-(4-chlorobenzylidene)hydrazinyl)-2-methyl-1-oxopropan-2-yl)pyridine-2,6-dicarbox-amide (5d). IR (KBr, cm-1): ν 3360-3205 (NH), 1678, 1674 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.32 (s, 12H, 4 CH3), 7.44 (d, 4H, Ar-H), 7.66 (d, 4H, Ar-H), 8.22-8.37 (m, 5H, pyridine-H + 2CH=N), 8.64, 10.75 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 26.01 (4C, 4CH3), 59.68 (2C, 2 NHC(CH3)2CO), 127.66, 128.88, 130.84, 135.92 (12C, 2Ar-C), 123.65, 139.10, 149.34 (5C, pyridine-C), 143.90 (2C, 2 CH=N), 160.86, 179.55 (4C, 4C=O); MS, m/z (%): 610 (M+, 10), 612 (M++2, 3), 498 (18), 500 (5), 463 (6), 387 (24), 345 (35), 303 (78), 218 (100), 133 (25), 105 (30), 77 (82).
N2,N6-Bis(1-(2-(2-chloro-6-fluorobenzylidene)hydrazinyl)-2-methyl-1-oxopropan-2-yl)pyridine-2,6-di-carboxamide (5e). IR (KBr, cm-1): ν 3410-3232 (NH), 1680, 1676 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.35 (s, 12H, 4 CH3), 7.28-7.78 (m, 6H, Ar-H), 8.16-8.36 (m, 5H, pyridine-H + 2CH=N), 8.72, 10.70 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 26.01 (4C, 4CH3), 59.56 (2C, 2 NHC(CH3)2CO), 112.62, 117.66, 124.72, 133.46, 134.52, 160.60 (12C, 2Ar-C), 123.96, 139.12, 149.50 (5C, pyridine-C), 142.67 (2C, 2 CH=N), 160.66, 179.55 (4C, 4C=O); MS, m/z (%): 646 (M+, 6), 648 (M++2, 2), 516 (18), 518 (6), 387 (45), 345 (100), 303 (16), 133 (75), 105 (66), 77 (80).
N2,N6-Bis(2-methyl-1-oxo-1-((E)-2-(thiophen-2-ylmethylene)hydrazinyl)propan-2-yl)pyridine-2,6-di-carboxamide (5f). IR (KBr, cm-1): ν 3392-3208 (NH), 1680, 1676 (2C=O, amide); 1H-NMR (DMSO-d6): δ 1.35 (s, 12H, 4 CH3), 7.14-7.62 (m, 6H, thiophene-H), 8.24-8.38 (m, 5H, pyridine-H + 2CH=N), 8.36, 10.15 (2s, 4H, 4NH exchangeable with D2O); 13C-NMR: 26.02 (4C, 4CH3), 59.52 (2C, 2 NHC(CH3)2CO), 126.64, 127.55, 139.28, 143.92 (8C, 2 thiophene-C), 123.98, 139.36, 149.42 (5C, pyridine-C), 128.10 (2C, 2 CH=N), 160.55, 179.86 (4C, 4C=O); MS, m/z (%): 553 (M+, 16), 470 (24), 387 (13), 345 (12), 303 (24), 218 (100), 133 (860), 105 (64), 77 (54).
4. Conclusions
A series of pyridine-bridged 2,6-bis-carboxamide Schiff's bases was prepared starting from 2,6-pyridinedicarbonyl dichloride (1) and L-alanine or 2-methylalanine methyl ester. The structural assignments of the new compounds were based on chemical and spectroscopic evidence. The newly synthesized compounds 2-5 have been screened for their bactericidal and fungicidal activities, and the Schiff's bases 4b-f and 5b-f have significant antimicrobial activities compared to streptomycin and fusidic acid which were used as antibacterial and antifungal reference drugs, respectively. The substituted 4-methoxy- 4b,5b, 3,4,5-trimethoxy-4c,5c, 4-chloro-4d,5d, 2-chloro-6-flouro-4e,5e and 2-thienyl- derivatives 4f,5f have antimicrobial activities higher than that of 4a,5a with an unsubstituted phenyl group.
Acknowledgements
The financial support of the Research Center of the College of Pharmacy, King Saud University is greatly appreciated. The kind help of El-Sayed E. Mostafa, Department of Microbial Chemistry, National Research Center, Cairo, Egypt, for carrying out the antimicrobial screening is highly appreciated.
- Sample Availability: Samples of the compounds are available from the authors.
References and Notes
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Al-Omar, M.A.; Amr, A.E.-G.E. Synthesis of Some New Pyridine-2,6-carboxamide-derived Schiff Bases as Potential Antimicrobial Agents. Molecules 2010, 15, 4711-4721. https://doi.org/10.3390/molecules15074711
AMA Style
Al-Omar MA, Amr AE-GE. Synthesis of Some New Pyridine-2,6-carboxamide-derived Schiff Bases as Potential Antimicrobial Agents. Molecules. 2010; 15(7):4711-4721. https://doi.org/10.3390/molecules15074711
Chicago/Turabian StyleAl-Omar, Mohamed A., and Abd El-Galil E. Amr. 2010. "Synthesis of Some New Pyridine-2,6-carboxamide-derived Schiff Bases as Potential Antimicrobial Agents" Molecules 15, no. 7: 4711-4721. https://doi.org/10.3390/molecules15074711
