Synthesis of Some New Pyridine-2,6-carboxamide-derived Schiff Bases as Potential Antimicrobial Agents

Al-Omar, Mohamed A.; Amr, Abd El-Galil E.

doi:10.3390/molecules15074711

Open AccessArticle

Synthesis of Some New Pyridine-2,6-carboxamide-derived Schiff Bases as Potential Antimicrobial Agents

by

Mohamed A. Al-Omar

and

Abd El-Galil E. Amr

^*

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 / Revised: 30 June 2010 / Accepted: 1 July 2010 / Published: 6 July 2010

Download

Browse Figures

Versions Notes

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.

Keywords:

2,6-pyridinedicarbonyl dichloride; pyridine-2,6-carboxamides; Schiff's base; antimicrobial activity

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.

**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]³⁰_D	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.

**Table 2.** Melting points, crystallization solvents, yields, specific rotation, molecular formulae and molecular weights of compounds **4a-h** and **5a-h**.
Comp. No.	Mp (ºC)	Cryst. Solv.	Yield (%)	[α]³⁰_D (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.

Table 3. Antimicrobial activities of the new synthesized compounds 2a,b, 3a,b, 4a-f and 5a-f.

**Table 3.** Antimicrobial activities of the new synthesized compounds **2a,b, 3a,b, 4a-f** and **5a-f**.
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

Attia, A.; Abdel-Salam, O.I.; Abo-Ghalia, M.H.; Amr, A.E. Chemical and biological reactivity of newly synthesized 2-chloro-6-ethoxy-4-acetylpyridine. Egypt. J. Chem. 1995, 38, 543–553. [Google Scholar]
Attia, A.; Abdel-Salam, O.I.; Amr, A.E. Utilization of 2,6-disubstituted isonicotinic acid hydrazides in the synthesis of some antibacterial agents. Egypt. J. Chem. 1997, 40, 317–325. [Google Scholar]
Attia, A.; Abdel-Salam, O.I.; Amr, A.E. Synthesis of some 2,6-di- and 1,2,6-trisubstituted-1,4-dihydropyridines as antimicrobial agents. Egypt. J. Chem. 2000, 43, 297–307. [Google Scholar]
Amr, A.E. Synthesis of some heterocyclic compounds as potential antimicrobial agents using 2,6-diacetylpyridine as synthon. Indian J. Heterocycl. Chem. 2000, 10, 49–58. [Google Scholar]
Abou-Ghalia, M.H.; Amr, A.E.; Abdulla, M.M. Synthesis of some new (N^α-dipicolinoyl)-bis-L-leucyl-DL-norvalyl linear tetra and cyclic octa bridged peptides as new anti-inflammatory Agents. Z. Naturforsch. 2003, 58b, 903–910. [Google Scholar]
Abou-Ghalia, M.H.; Amr, A.E. Synthesis and investigation of a new cyclo-(N^α-dipicolinoyl) pentapeptide of a breast and CNS cytotoxic activity and an ionophoric specifity. Amino Acids 2004, 26, 283–289. [Google Scholar]
Bayrak, H.; Demirbas, A.; Karaoglu, S.A.; Demirbas, N. Synthesis of some new 1,2,4-triazoles, their Mannich and Schiff bases and evaluation of their antimicrobial activities. Eur. J. Med. Chem. 2009, 44, 1057–1066. [Google Scholar] [CrossRef]
Ashok, M.; Holla, B.S.; Boojary, B. Convenient one pot synthesis and antimicrobial evaluation of some new Mannich bases carrying 4-methylthiobenzyl moiety. Eur. J. Med. Chem. 2007, 42, 1095–1101. [Google Scholar] [CrossRef]
Karthikeyan, M.S.; Prasad, D.J.; Boojary, B.; Bhat, K.S.; Holla, B.S.; Kumari, N.S. Synthesis and biological activity of Schiff and Mannich bases bearing 2,4-dichloro-5-fluorphenyl moiety. Bioorg. Med. Chem. 2006, 14, 7482–7489. [Google Scholar] [CrossRef]
Tozkoparan, B.; Küpeli, E.; Yeşilada, E.; Ertan, M. Preparation of 5-aryl-3-alkylthio-l,2,4-triazoles and corresponding sulfones with antiinflammatory–analgesic activity. Bioorg. Med. Chem. 2007, 15, 1808–1814. [Google Scholar] [CrossRef]
Labanauskas, L.; Udrenaite, E.; Gaidelis, P.; Brukštus, A. Synthesis of 5-(2,3,4-methoxy-phenyl)-4H-1,2,4-triazole-3-thiol derivatives exhibiting anti-inflammatory activity. II Farmaco 2004, 59, 255–259. [Google Scholar] [CrossRef]
Navidpour, L.; Shafaroodi, H.; Abdi, K.; Amini, M.; Ghahremani, M.H.; Dehpour, A.R.; Shafiee, A. Design, synthesis, and biological evaluation of substituted 3-alkylthio-4,5-diaryl-4H-1,2,4-triazoles as selective COX-2 inhibitors. Bioorg. Med. Chem. 2006, 14, 2507–2517. [Google Scholar] [CrossRef]
Maxwell, J.R.; Wasdahl, D.A.; Wolfson, A.C.; Stenberg, V.I. Synthesis of 5-aryl-2H-tetrazoles, 5-aryl-2H-tetrazole-2-acetic acids, and [(4-phenyl-5-aryl-4H-1,2,4-triazol-3-yl)thio]acetic acids as possible superoxide scavengers and anti-inflammatory agents. J. Med. Chem. 1984, 27, 1565–1570. [Google Scholar] [CrossRef]
Amr, A.E.; Abo-Ghalia, M.; Abdalah, M.M. Synthesis of novel macrocyclic peptido-calix[4]arenes and peptidopyridines as precursors for potential molecular metallacages, chemosensors and biologically active candidates. Z. Naturforsch. 2006, 61b, 1335–1345. [Google Scholar]
Amr, A.E.; Mohamed, A.M.; Ibrahim, A.A. Synthesis of some new chiral tricyclic and macrocyclic pyridine derivatives as antimicrobial agents. Z. Naturforsch. 2003, 58b, 861–868. [Google Scholar]
Amr, A.E.; Mohamed, A.M.; Mohamed, S.F.; Abdel-Hafez, N.A.; Hammam, A.G. Anticancer activities of some newly synthesized pyridine, pyrane, and pyrimidine derivatives. Bioorg. Med. Chem. 2006, 14, 5481–5488. [Google Scholar] [CrossRef]
Amr, A.E.; Sabrry, N.M.; Abdalla, M.M.; Abdel-Wahab, B.F. Synthesis, antiarrhythmic and anticoagulant activities of novel thiazolo derivatives from methyl 2-(thiazol-2-ylcarbamoyl)-acetate. Eur. J. Med. Chem. 2009, 44, 725–735. [Google Scholar] [CrossRef]
Fakhr, I.M.; Amr, A.E.; Sabry, N.M.; Abdalah, M.M. Anti-Inflammatory and analgesic activities of newly synthesized chiral peptide derivatives using (3-benzoyl-4,5-dioxo-2-phenyl-pyrrolidin-1-yl)acetic acid ethylester ass material. Arch. Pharm. Chem. Life Sci. 2008, 341, 174–180. [Google Scholar] [CrossRef]
Mohamed, S.F.; Flefel, E.M.; Amr, A.E.; Abd El-Shafy, D.N. Anti-HSV-1 activity and mechanism of action of some new synthesized substituted pyrimidine, thiopyrimidine and thiazolopyrimidine derivatives. Eur. J. Med. Chem. 2010, 45, 1494–1501. [Google Scholar] [CrossRef]
Amr, A.E.; Ali, K.A.; Abdalla, M.M. Cytotoxic, antioxidant activities and structure activity relationship of some newly synthesized terpenoidal oxaliplatin analogs. Eur. J. Med. Chem. 2009, 44, 901–907. [Google Scholar] [CrossRef]
Attia, A.; Abdel-Salam, O.I.; Amr, A.E.; Stibor, I.; Budesinsky, M. Synthesis and antimicrobial activity of some new chiral bridged macrocyclic pyridines. Egypt. J. Chem. 2000, 43, 187–201. [Google Scholar]
Abou-Zeid, A.A.; Shehata, Y.M. A simple technique for assaying antibiotics using methylene blue as an indicator. Indian J. Pharm. 1969, 31, 72–75. [Google Scholar]

© 2010 by the authors; licensee MDPI, Basel, Switzerland. This article is an Open Access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

Share and Cite

MDPI and ACS Style

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 Style

Al-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

APA Style

Al-Omar, M. A., & Amr, A. E. -G. E. (2010). Synthesis of Some New Pyridine-2,6-carboxamide-derived Schiff Bases as Potential Antimicrobial Agents. Molecules, 15(7), 4711-4721. https://doi.org/10.3390/molecules15074711

Article Menu

Synthesis of Some New Pyridine-2,6-carboxamide-derived Schiff Bases as Potential Antimicrobial Agents

Abstract

1. Introduction