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Synthesis and antimicrobial activity of some linear dipeptide pyridine and macrocyclic pentaazapyridine candidates

  • Mohamed E. Azab , Eman M. Flefel , Nermien M. Sabry and Abd El-Galil E. Amr EMAIL logo
Published/Copyright: May 12, 2016
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Zeitschrift für Naturforschung B
From the journal Zeitschrift für Naturforschung B Volume 71 Issue 7

Abstract

A series of tetracarboxamide and macrocyclic tripeptides have been prepared starting from 3,5-bis[N-(1-hydrazinyl-1-oxo-3-phenylpropan-2-yl)]pyridinecarboxamide 4 as starting material, which was synthesized from dinicotinic acid 1. Treatment of 4 with 1,4-diaminobutane, 1,6-diaminohexane, or cycloalkanone derivatives gave the corresponding macrocyclic tetracarboxamides (5a, b) and cycloalkyl hydrazone derivatives (6a–c), respectively. Additionally, the reaction of 4 with acetophenone or acetylpyridine derivatives gave the corresponding Schiff base derivatives 7a–e and 8a–c, respectively. Also, carboxylic acid hydrazide 4 was treated with acid anhydrides in glacial acetic acid to afford the corresponding diimide tetracarboxamide derivatives 9a, b, 10, and 11, respectively. The structures of newly synthesized compounds are established by physical and spectral data evidences. Some of the synthesized compounds were screened as antimicrobial agents.

Keywords: antimicrobial agents; bis-Schiff base; linear dipeptide pyridine; macrocyclic pentaazapyridine

1 Introduction

The naturally occurring peptide derivatives were identified, and they were used in crucial roles in human physiology, ion channel ligands, including actions as hormones, growth factors, neurotransmitters, or anti-infectives [1–3]. A series of pyridine derivatives are correlated with several pharmacological properties, for example, antimycobacterial [4], anticancer [5], antiviral [6], anti-HIV [7], antifungal and antimicrobial [8], and anticonvulsant [9]. Also, some pyridinecarboxamide analogs were designed and used as PARP-1Q2 inhibitors [10], mycobacterium tuberculosis agents, [11] and as CB2 cannabinoid receptor partial agonists [12]. On the other hand, in addition, heterocyclic compounds containing an amino acid or a peptide structural moiety showed biological [13] and antibacterial activities [14]. A branched-chain amino acid (Leu, Ile, and Val) mixture has been used for treatment of hypoalbuminemia in patients with decompensated liver cirrhosis in Japan [15]. In view of this concept and in continuation to our previous work [16–24] in heterocyclic and peptide chemistry, we have synthesized some new linear dipeptide Schiff bases and macrocyclic tripeptide derivatives and we have evaluated some of them as antimicrobial agents.

2 Results and discussion

2.1 Chemistry

In this study, we report a series of linear dipeptide Schiff base derivatives by using N2,N2′-(pyridine-3,5-dicarbonyl)-di-l-phenyalaninyl hydrazide (4) as starting material, which was synthesized from 3,5-pyridinedicarboxylic acid according to a reported procedure [4] (Scheme 1).

Scheme 1: Synthetic routes to starting compound 4.
Scheme 1:

Synthetic routes to starting compound 4.

Treatment of 3,5-bis-hydrazide 4 with 1,4-diaminobutane or 1,6-diaminohexane afforded the corresponding macrocyclic tetracarboxamide derivatives 5a, b. Condensation of 4 with cycloalkanones in refluxing glacial acetic acid gave the corresponding cycloalkanyl hydrazone derivatives 6a–c. Additionally, the reaction of 4 with acetophenone or acetylpyridines gave the corresponding Schiff base derivatives 7a–e and 8a–c, respectively (Scheme 2).

Scheme 2: Synthetic routes to compounds 5a, b, 6a–c, 7a–e, and 8a–c.
Scheme 2:

Synthetic routes to compounds 5a, b, 6a–c, 7a–e, and 8a–c.

Finally, carboxylic acid hydrazide 4 was treated with acid anhydrides, namely, phthalic, tetrachloro-phthalic, 1,8-naphthaline, or 2,3-pyridinedicarboxylic acid anhydride in glacial acetic acid to afford the corresponding diimide tetracarboxamide derivatives 9a, b, 10, and 11, respectively (Scheme 3).

Scheme 3: Synthetic routes to compounds 9a, b, 10, and 11.
Scheme 3:

Synthetic routes to compounds 9a, b, 10, and 11.

2.2 Antimicrobial activity

The newly synthesized compounds 5–11 were tested for their preliminary antimicrobial activity against different microorganisms representing Gram-positive (Staphylococcus aureus, Bacillus cereus, and Bacillus subtilis), Gram-negative bacteria (Escherichia coli), fungi (Aspergillus niger) and yeast (Candida albicans).

The obtained results (Table 1) showed that all synthesized compounds exhibited both antibacterial and antifungal activities on all tested microbial strains, except for compounds 5a, 5b, 7a, 7e, 8a, 8c, 9, and 11, which did not showed antifungal activity against C. albicans. In terms of antifungal activities, compounds 5a, 7c, 7d, and 10 were the most active and their activities were higher than that of the positive control (fusidic acid) by about 2.6, 2.6, 5.0, and 5.0%, respectively. Regarding antibacterial activities, it can be clearly observed that compounds 6a, 6b, 7d, 8b, 10, and 11 were the highly active compounds. Among of these compounds, compound 7d was the most active one, where its activity reached 97.5, 92.5, 95.2, and 94.7% of the positive control (chloramphenicol), respectively.

Table 1:

Antimicrobial activities of some newly synthesized compounds.

CompoundInhibition zone (cm)
Gram +veGram –veFungiYeast
Staphylococcus aureusBacillus subtilisBacillus cereusEscherichia coliAspergillus nigerCandida albicans
5a1.651.461.800.661.95–
5b1.681.751.550.601.70–
6a1.801.651.960.781.480.94
6b1.851.851.920.801.560.92
6c1.761.721.580.741.800.95
7a1.561.561.500.661.68–
7b1.751.651.740.751.851.05
7c1.641.761.750.801.951.05
7d1.951.852.000.902.000.96
7e1.781.451.650.621.75–
8a1.551.851.500.651.75–
8b1.851.801.950.781.551.00
8c1.661.721.220.601.75–
91.651.651.830.641.58–
101.771.841.880.922.001.10
111.801.701.650.641.75–
Chloramphenicol2.002.002.100.95––
fusidic acid––––1.91.9

3 Experimental section

3.1 Chemistry

Melting points were determined in open glass capillary tubes with an electrothermal digital melting point apparatus (model IA9100) and were uncorrected. Elemental microanalysis for carbon, hydrogen, and nitrogen (Microanalytical Unit, National Research Center) was found within the acceptable limits of the calculated values. IR was recorded on a Nexus 670 FTIR Nicolet, Fourier transform infrared spectrometer. 1H NMR and 13C NMR spectra were run in deuterated dimethyl sulfoxide ([D6]DMSO) on Jeol 500 MHz (1H) and 125 MHz (13C) instruments. Mass spectra were run on a MAT Finnigan SSQ 7000 spectrometer, using the electron impact technique (EI). Analytical thin layer chromatography was performed on silica gel aluminum sheets, 60 F254 (E. Merck). Antimicrobial activities were evaluated in National Research Center, Dokki, Cairo, Egypt.

3.2 Synthesis of 5a, b

To a cold (–5°C) and stirred solution of the dihydrazide 4 (1 mmol) in 5 n aq. HCl (3 mL) and acetic acid (3 mL), sodium nitrite solution (10%, 0.13 g, 2 mmol) was added at the same temperature. The reaction mixture was stirred for 30 min, and then it was extracted with ether. The ethereal part was washed with water, NaHCO3, water and then dried over anhydrous sodium sulfate. The cold ethereal solution (–5°C) was then added to a cold (–5°C) dichloromethane solution of 1,4-butanediamine, or 1,6-hexanediamine (1 mmol, 10 mL of CH2Cl2). Stirring was continued for 5 h at –5°C and at room temperature for 2 h. The reaction mixture was washed with 1 n aq. HCl and water and then dried over anhydrous calcium chloride. The solvent was evaporated under reduced pressure and crystallized from ethanol-ether to afford the corresponding title compounds 5a, b, respectively.

3.2.1 Cyclo-(Nα-dinicotinoyl)-bis[l-phenylalaninyl]-1,4-butanediamine (5a)

Yield 58%; m.p. 204–206°C. – [α]D25 = –110 (c = 0.5, DMF). – IR (film): ν = 3365 (NH), 3076 (CH-Ar), 2984 (CH-aliph.), 1662, 1535, 1234 (C=O, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.40–1.48 (m, 4H, 2 CH2), 2.62–2.74 (m, 4H, 2 CH2), 3.42 (d, 4H, 2CH2), 4.05–4.10 (m, 2H, 2 CH), 6.95–7.52 (m, 10H, 2Ph-H), 8.58, 9.05 (2s, 3H, pyr-H), 8.72, 8.95 (2s, 4H, 4NH, exchangeable with D2O). – MS (EI, 70 eV): m/z (%) = 514 (12) [M]+. – C29H31N5O4 (513.58): calcd. C 67.82, H 6.08, N 13.64; found C 67.70, H 6.00, N 13.57.

3.2.2 Cyclo-(Nα-dinicotinoyl)-bis[l-phenylalaninyl]-1,6-hexanediamine (5b)

Yield 60%; m.p. 194–196°C. – [α]D25 = –96 (c = 0.5, DMF). – IR (film): ν = 3358–3312 (NH), 3080 (CH-Ar), 2975 (CH-aliph.), 1660, 1530, 1240 (C=O, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ =1.24–1.28 (m, 4H, 2 CH2), 1.38–1.44 (m, 4H, 2CH2), 2.60–1.68 (m, 4H, 2 CH2), 3.42 (d, 4H, 2CH2), 4.08–4.20 (m, 2H, 2 CH), 6.96–7.55 (m, 10H, 2Ph-H), 8.62, 9.00 (2s, 3H, pyridyl-H), 8.74, 8.95 (42s, H, 4NH, exchangeable with D2O). – MS (EI, 70 eV): m/z (%) = 542 (22) [M]+. – C31H35N5O4 (541.64): calcd. C 68.74, H 6.51, N 12.93; found C 68.62, H 6.44, N 12.85.

3.3 Synthesis of hydrazones 6a–c

To a solution of acid hydrazide 4 (1 mmol) in glacial acetic acid (30 mL), cyclopentanone, cyclohexanone, or cycloheptanone (2 mmol) was added. The reaction mixture was refluxed for 6 h and poured onto ice water; the obtained solid was filtered off, washed with water, dried, and crystallized from the proper solvents to give the corresponding Schiff base derivatives 6a–c, respectively.

3.3.1 N,N′-Bis[1-(cyclopentanyl-1-methylhydrazonyl)-2- l-phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (6a)

Yield 82%; m.p. 178–180°C (EtOH-H2O). – [α]D25 = –124 (c = 0.5, DMF). – IR (film): ν = 3446–3367 (NH), 3085 (CH-Ar), 2982 (CH-aliph.), 1661, 1521, 1314 (C=O, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.28–1.34 (m, 16H, 2 cyclopentyl-H), 3.36 (d, 4H, 2CH2), 4.62–4.73 (m, 2H, 2CH), 6.98–7.52 (m, 10H, 2Ph-H), 7.90, 8.64 (2s, 4H, 4NH, exchangeable with D2O), 8.68, 9.12 (2s, 3H, pyr-H). – 13C NMR (125 MHz, [D6]DMSO): δ = 41.35 (2C, 2CH2), 53.14 (2C, 2CH), 125.66, 127.70, 128.64, 139.44 (12C, 2Ph-C), 131.46, 141.23, 152.36 (5C, Pyr-C), 167.18 (2C, 2C=O), 176.64 (2C, 2C=O), 26.04, 36.86, 186.74 (10C, cyclopentyl-C). – MS (EI, 70 eV): m/z (%) = 622 (6) [M]+. – C35H39N7O4 (621.72): calcd. C 67.61, H 6.32, N 15.77; found C 67.52, H 6.22, N 15.69.

3.3.2 N,N′-Bis[1-(cyclohexanyl-1-methylhydrazonyl)-2-l-phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (6b)

Yield 66%; m.p. 206–208°C (AcOH-H2O). – [α]D25 = –116 (c = 0.5, DMF). – IR (film): ν = 3565–3432 (NH), 3084 (CH-Ar), 2974 (CH-aliph.), 1664, 1525, 1318 (C=O, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.25–1.36 (m, 20H, 2 cyclohexyl-H), 3.42 (d, 4H, 2CH2), 4.65–4.70 (m, 2H, 2CH), 6.96–7.54 (m, 10H, 2Ph-H), 7.96, 8.68 (2s, 4H, 4NH, exchangeable with D2O), 8.76, 9.10 (2s, 3H, Pyr-H). – 13C NMR (125 MHz, [D6]DMSO): δ = 41.36 (2C, 2CH2), 53.32 (2C, 2CH), 125.65, 127.74, 128.67, 139.48 (12C, 2Ph-C), 131.42, 141.28, 152.33 (5C, Pyr-C), 167.24 (2C, 2C=O), 176.44 (2C, 2C=O), 23.22, 26.86, 28.14, 161.33 (12C, cyclohexyl-C). – MS (EI, 70 eV): m/z (%) = 650 (22) [M]+. – C37H43N7O4 (649.78): calcd. C 68.39, H 6.67, N, 15.09; found C 68.30, H 6.60, N 15.00.

3.3.3 N,N′-Bis[1-(cycloheptanyl-1-methylhydrazonyl)-2-l-phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (6c)

Yield 72%; m.p. 232–234°C (EtOH). – [α]D25 = –112 (c = 0.5, DMF). – IR (film): ν = 3554–3428 (NH), 3090 (CH-Ar), 2978 (CH-aliph.), 1661, 1526, 1318 (C=O, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.20–1.36 (m, 24H, 2 cycloheptyl-H), 3.31 (d, 4H, 2CH2), 4.62–4.71 (m, 2H, 2CH), 6.99–7.56 (m, 10H, 2Ph-H), 7.94, 8.66 (2s, 4H, 4NH, exchangeable with D2O), 8.79, 9.18 (2s, 3H, Pyr-H). – 13C NMR (125 MHz, [D6]DMSO): δ = 41.48 (2C, 2CH2), 53.15 (2C, 2CH), 125.76, 127.54, 128.62, 139.50 (12C, 2Ph-C), 132.13, 141.18, 152.42 (5C, Pyr-C), 167.24 (2C, 2C=O), 175.98 (2C, 2C=O), 23.56, 25.42, 29.70, 183.84 (14C, cycloheptyl-C). – MS (EI, 70 eV): m/z (%) = 678 (15) [M]+. – C39H47N7O4 (677.83): calcd. C 69.10, H 6.99, N 14.46; found C 69.00, H 6.90, N 14.40.

3.4 Synthesis of compounds 7a–e and 8a–c

A mixture of 4 (1 mmol) and a substituted acetophenone (acetophenone, 4-methyl-, 4-methoxy-, 4-chloro-, 4-fluoroacetophenone) or an acetylpyridine (2-acetyl-, 3-acetyl-, 4-acetylpyridine, 2 mmol) in glacial acetic acid (30 mL) was refluxed for 4–7 h. The reaction mixture was poured into ice water, and then neutralized with 1 n aq. sodium carbonate. The obtained solid was filtered off, washed with water, dried, and crystallized from the proper solvent to give the corresponding Schiff bases 7a–e and 8a–c, respectively.

3.4.1 N,N′-Bis[(1-phenyl-1-methyl-hydrazonyl-2-l-phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (7a)

Yield 75%; m.p. 242–244°C (DMF-H2O). – [α]D25 = –98 (c = 0.5, DMF). – IR (film): ν = 3367–3342 (NH), 3078 (CH-Ar), 2990 (CH-aliph.), 1652, 1537, 1254 (CO, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.04 (s, 6H, 2CH3), 3.24 (d, 4H, 2CH2), 4.68–4.75 (m, 2H, 2CH), 7.05–7.68 (m, 20H, 4Ph-H), 8.54, 8.65 (2s, 4H, 4NH, D2O exchangeable), 8.75, 9.08 (2s, 3H, pyr-H). – 13C NMR (125 MHz, [D6]DMSO): δ = 14.43 (2C, 2CH3), 41.22 (2C, 2CH2), 53.98 (2C, 2CH), 125.56, 127.72, 128.55, 139.35 (12C, 2Ph-C), 127.82, 128.55, 130.70, 133.36 (12C, 2Ph-C), 131.72, 140.34, 151.86 (5C, pyr-C), 167.42 (2C, 2CO), 168.35 (2C, 2C=N), 176.98 (2C, 2CO, hydrazone). – MS (EI, 70 eV): m/z (%) = 694 (16) [M]+. – C41H39N7O4 (693.79): calcd. C 70.98, H 5.67, N 14.13; found C 70.90, H 5.60, N 14.05.

3.4.2 N,N′-Bis[1-(4-methylphenyl-1-methylhydrazonyl)-2-l-phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (7b)

Yield 68%; m.p. 226–228°C (AcOH-H2O). – [α]D25 = –105 (c = 0.5, DMF). – IR (film): ν = 3388–3335 (NH), 3082 (CH-Ar), 2985 (CH-aliph.), 1653, 1534, 1252 (CO, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.00 (s, 6H, 2CH3), 2.23 (s, 6H, 2CH3), 3.26 (d, 4H, 2CH2), 4.65–4.72 (m, 2H, 2CH), 7.12–7.72 (m, 18H, 4Ph-H), 8.65, 8.78 (2s, 4H, 4NH, D2O exchangeable), 8.72, 9.12 (2s, 3H, pyr-H). – 13C NMR (125 MHz, [D6]DMSO): δ = 14.22, 23.45 (4C, 4CH3), 41.25 (2C, 2CH2), 54.10 (2C, 2CH), 125.62, 127.70, 128.58, 139.45 (12C, 2Ph-C), 128.74, 129.08, 130.86, 140.35 (12C, 2Ph-C), 131.84, 140.38, 151.85 (5C, pyr-C), 167.36 (2C, 2CO), 168.45 (2C, 2C=N), 176.95 (2C, 2CO, hydrazone). – MS (EI, 70 eV): m/z (%) = 722 (8) [M]+. – C43H43N7O4 (721.84): calcd. C 71.55, H 6.00, N 13.58; found C 71.48, H 5.92, N 13.50.

3.4.3 N,N′-Bis[1-(4-methoxylphenyl-1-methylhydrazonyl)-2-l-phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (7c)

Yield 78%; m.p. 268–270°C (dioxane). – [α]D25 = –78 (c = 0.5, DMF). – IR (film): ν = 3374–3328 (NH), 3080 (CH-Ar), 2988 (CH-aliph.), 1654, 1535, 1255 (CO, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.12 (s, 6H, 2CH3), 3.32 (d, 4H, 2CH2), 2.68 (s, 6H, 2OCH3), 4.62–4.68 (m, 2H, 2CH), 6.95–7.65 (m, 18H, 4Ph-H), 8.68, 8.82 (2s, 4H, 4NH, D2O exchangeable), 8.74, 9.10 (2s, 3H, pyr-H). – 13C NMR (125 MHz, [D6]DMSO): δ = 14.36 (2C, 2CH3), 41.34 (2C, 2CH2), 54.18 (2C, 2CH), 55.32 (2C, 2OCH3), 125.65, 127.73, 128.54, 139.42 (12C, 2Ph-C), 113.95, 125.78, 129.94, 162.48 (12C, 2Ph-C), 131.76, 140.42, 151.80 (5C, pyr-C), 167.43 (2C, 2CO), 168.35 (2C, 2C=N), 176.88 (2C, 2CO, hydrazone). – MS (EI, 70 eV): m/z (%) = 754 (12) [M]+. – C43H43N7O6 (753.84): calcd. C 68.51, H 5.75, N 13.01; found C 68.40, H 5.70, N 12.90.

3.4.4 N,N′-Bis[1-(4-chlorophenyl-1-methylhydrazonyl)-2-l-phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (7d)

Yield 64%; m.p. 234–236°C (AcOH). – [α]D25 = –86 (c = 0.5, DMF). – IR (film): ν = 3398–3354 (NH), 3085 (CH-Ar), 2978 (CH-aliph.), 1654, 1535, 1252 (CO, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.10 (s, 6H, 2CH3), 3.26 (d, 4H, 2CH2), 4.65–4.70 (m, 2H, 2CH), 7.15–7.72 (m, 18H, 4Ph-H), 8.52, 8.68 (2s, 4H, 4NH, D2O exchangeable), 8.76, 9.14 (2s, 3H, pyr-H). – 13C NMR (125 MHz, [D6]DMSO): δ = 14.52 (2C, 2CH3), 41.28 (2C, 2CH2), 53.85 (2C, 2CH), 125.64, 127.70, 128.62, 139.38 (12C, 2Ph-C), 128.82, 129.55, 131.65, 136.35 (12C, 2Ph-C), 131.80, 140.40, 151.82 (5C, pyr-C), 167.45 (2C, 2CO), 168.48 (2C, 2C=N), 176.86 (2C, 2CO, hydrazone). – MS (EI, 70 eV): m/z (%) = 763 (32) [M]+. – C41H37Cl2N7O4 (762.68): calcd. C 64.57, H 4.89, Cl 9.30, N 12.86; found C 64.50, H 4.80, Cl 9.22, N 12.80.

3.4.5 N,N′-Bis[1-(4-fluorophenyl-1-methylhydrazonyl)-2-l-phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (7e)

Yield 70%; m.p. 216–218°C (AcOH). – [α]D25 = –116 (c = 0.5, DMF). – IR (film): ν = 3378–3342 (NH), 3080 (CH-Ar), 2972 (CH-aliph.), 1652, 1533, 1254 (CO, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.15 (s, 6H, 2CH3), 3.24 (d, 4H, 2CH2), 4.68–4.72 (m, 2H, 2CH), 7.10–7.75 (m, 18H, 4Ph-H), 8.68, 8.70 (2s, 4H, 4NH, D2O exchangeable), 8.75, 9.10 (2s, 3H, pyr-H). – 13C NMR (125 MHz, [D6]DMSO): δ = 14.56 (2C, 2CH3), 41.32 (2C, 2CH2), 53.88 (2C, 2CH), 125.58, 127.64, 128.60, 139.44 (12C, 2Ph-C), 114.65, 128.62, 129.68, 164.78 (12C, 2Ph-C), 131.76, 140.38, 151.80 (5C, pyr-C), 167.41 (2C, 2CO), 168.52 (2C, 2C=N), 176.82 (2C, 2CO, hydrazone). – MS (EI, 70 eV): m/z (%) = 730 (25) [M]+. – C41H37F2N7O4 (729.77): calcd. C 67.48, H 5.11, N 13.44; found C 67.40, H 5.05, N 13.40.

3.4.6 N,N′-Bis[1-(2-pyridyl-1-methylhydrazonyl)-2-l-phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (8a)

Yield 65%; m.p. 217–219°C (AcOH-H2O). – [α]D25 = –92 (c = 0.5, DMF). – IR (film): ν = 3454–3324 (NH), 3088 (CH-Ar), 2974 (CH-aliph.), 1655, 1534, 1253 (C=O, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 0.99 (s, 6H, 2CH3), 3.62 (d, 4H, 2CH2), 4.64–4.70 (m, 2H, 2CH), 7.02–7.60 (m, 10H, 2Ph-H), 7.75–8.56 (m, 6H, 2-pyridyl-H), 8.65, 8.92 (2s, 4H, 4NH, D2O exchangeable), 8.80 (s, 2H, pyridyl-H), 8.75, 9.08 (2s, 3H, 3,5-pyridyl-H). – 13C NMR (125 MHz, [D6]DMSO): δ = 13.65 (2C, 2 CH3), 41.82 (2C, 2CH2), 53.74 (2C, 2CH), 125.35, 127.62, 128.55, 139.58 (12C, 2Ph-C), 122.88, 126.12, 131.68, 135.84, 140.32, 148.65, 152.28, 154.48 (15C, 3 pyr-C), 144.98 (2C, 2C=N), 167.72 (2C, 2CO), 176.85 (2C, 2CO, hydrazone). – MS (EI, 70 eV): m/z (%) = 696 (10) [M]+. – C39H37N9O4 (695.76): calcd. C 67.32, H 5.36, N 18.12; found C 67.21, H 5.30, N 18.05.

3.4.7 N,N′-Bis[1-(3-pyridyl-1-methylhydrazonyl)-2-l-phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (8b)

Yield 55%; m.p. 241–243°C (EtOH). – [α]D25 = –75 (c = 0.5, DMF). – IR (film): ν = 3415–3332 (NH), 3075 (CH-Ar), 2982 (CH-aliph.), 1652, 1534, 1255 (CO, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.05 (s, 6H, 2CH3), 3.75 (d, 4H, 2CH2), 4.60–4.66 (m, 2H, 2CH), 7.00–7.58 (m, 10H, 2Ph-H), 7.70–8.50 (m, 6H, pyridyl-H), 8.65, 8.86 (2s, 4H, 4NH, D2O exchangeable), 8.75, 9.10 (2s, 3H, 3,5-pyridyl-H), 9.18 (s, 2H, pyridyl-H-2). – 13C NMR (125 MHz, [D6]DMSO): δ = 12.98 (2C, 2CH3), 41.68 (2C, 2CH2), 53.84 (2C, 2CH), 125.64, 127.58, 128.72, 139.67 (12C, 2Ph-C), 122.56, 125.52, 136.92, 150.75, 151.24 (10C, 3-Pyridyl-C), 131.48, 140.65, 152.32 (5C, 3,5-pyridyl-C), 167.05 (2C, 2CO), 168.42 (2C, 2C=N), 176.78 (2C, 2CO, hydrazone). – MS (EI, 70 eV): m/z (%) = 696 (35) [M]+. – C39H37N9O4 (695.76): calcd. C 67.32, H 5.36, N 18.12; found C 67.20, H 5.28, N 18.05.

3.4.8 N,N′-Bis[1-(4-pyridyl-1-methylhydrazonyl)-2-l-phenylalaninyl]-3,5-(diaminocarbonyl)pyridine (8c)

Yield 62%; m.p. 255–257°C (MeOH). – [α]D25 = –102 (c = 0.5, DMF). – IR (film): ν = 3410–3330 (NH), 3078 (CH-Ar), 2986 (CH-aliph.), 1653, 1532, 1251 (CO, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 0.98 (s, 6H, 2CH3), 3.78 (d, 4H, 2CH2), 4.62–4.65 (m, 2H, 2CH), 6.98–7.46 (m, 10H, 2Ph-H), 7.78, 8.70 (d, 8H, pyridyl-H), 8.68, 8.88 (2s, 4H, 4NH, D2O exchangeable), 8.78, 9.12 (2s, 3H, 3,5-pyridyl-H). – 13C NMR (125 MHz, [D6]DMSO): δ = 13.12 (2C, 2CH3), 41.60 (2C, 2CH2), 53.80 (2C, 2CH), 125.60, 127.50, 128.65, 139.60 (12C, 2Ph-C), 123.65, 136.52, 148.65 (10C, pyridyl-C), 131.55, 140.32, 152.44 (5C, 3,5-pyridyl-C), 167.00 (2C, 2CO), 168.30 (2C, 2C=N), 176.84 (2C, 2CO, hydrazone). – MS (EI, 70 eV): m/z (%) = 696 (16) [M]+. – C39H37N9O4 (695.76): calcd. C 67.32, H 5.36, N 18.12; found C 67.18, H 5.24, N 18.08.

3.5 Synthesis of 9–11

A mixture of 4 (1 mmol) and dicarboxylic acid anhydride derivatives (phthalic anhydride, tetrachlorophthalic anhydride, 1,8-naphthalenedicarboxylic acid anhydride, or 2,3-pyridinedicarboxylic acid anhydride, 2 mmol) was refluxed in glacial acetic acid (50 mL) for 6 h. The reaction mixture was poured into ice water; the obtained precipitate was collected by filtration, washed with water, dried, and crystallized from DMF-H2O to give the corresponding bisimide hexacarboxamide derivatives 9–11, respectively.

3.5.1 Nα-Dinicotinoyl-bis(l-phenylalaninyl-isoindoline-1,3-dione-imide) (9)

Yield 72%; m.p. 256–258°C. – [α]D25 = –117 (c = 0.5, DMF). – IR (film): ν = 3398–3343 (NH), 3078 (CH-Ar), 2986 (CH-aliph.), 1653, 1533, 1254 (C=O, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 3.40 (d, 4H, 2CH2), 4.56–4.63 (m, 2H, 2CH), 7.08–8.05 (m, 18H, 4Ph-H), 8.45, 9.00 (2s, 3H, pyr-H), 8.64, 8.75 (2s, 4H, 4NH, D2O exchangeable). – 13C NMR (125 MHz, [D6]DMSO): δ = 40.84 (2C, 2CH2), 53.03 (2C, 2 CH), 124.34, 127.42, 128.22, 138.86 (12C, 2Ph-C), 127.24, 131.22, 131.86, (12C, 2 Phth-C), 131.65, 140.14, 152.13 (5C, pyr-C), 164.56 (4C, 4 CO-imide), 167.12, 170.15 (4C, 4 CO-amide). – MS (EI, 70 eV): m/z (%) = 750 (14) [M]+. – C41H31N7O8 (749.72): calcd. C 65.68, H 4.17, N 13.08; found C 65.60, H 4.10, N 13.00.

3.5.2 Nα-Dinicotinoyl-bis(l-phenylalaninylbenzo[de]isoquinoline-1,3(2H)-dione-imide) (10)

Yield 65%; m.p. 264–266°C. – [α]D25 = –68 (c = 0.5, DMF). – IR (film): ν = 3416–3332 (NH), 3073 (CH-Ar), 2987 (CH-aliph.), 1655, 1535, 1255 (C=O, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 3.40 (d, 4H, 2CH2), 4.45–4.52 (m, 2H, 2CH), 7.12–7.86 (m, 22H, Ar-H), 8.57, 9.02 (2s, 3H, pyr-H), 8.60, 8.78 (2s, 4H, 4NH, exchangeable with D2O). – 13C NMR (125 MHz, [D6]DMSO): δ = 41.45 (2C, 2CH2), 53.12 (2C, 2 CH), 122.12, 124.65, 127.95, 130.10, 136.86, 137.35 (20C, naphthyl-C), 125.60, 127.54, 128.54, 139.68 (12C, 2Ph-C), 131.62, 140.18, 152.17 (5C, pyr-C), 158.55 (4C, 4 CO-imide), 167.24, 170.26 (4C, 4 CO-amide). – MS (EI, 70 eV): m/z (%) = 850 (8) [M]+. – C49H35N7O8 (849.84): calcd. C 69.25, H 4.15, N 11.54; found C 69.12, H 4.05, N 11.43.

3.5.3 Nα-Dinicotinoyl-bis[l-phenylalaninylpyrrolo[3,4-b]pyridine-5,7-dione-imide] (11)

Yield 68%; m.p. 234–236°C. – [α]D25 = –96 (c = 0.5, DMF). – IR (film): ν = 3445–3313 (NH), 3083 (CH-Ar), 2992 (CH-aliph.), 1653, 1535, 1252 (C=O, amide I, II, and III) cm–1. – 1H NMR (500 MHz, [D6]DMSO): δ = 3.45 (d, 4H, 2CH2), 4.50–4.61 (m, 2H, 2CH), 6.94–7.48 (m, 10H, 2Ph-H), 8.62, 9.05 (2s, 3H, pyr-H), 7.96–8.32 (m, 4H, pyr-H), 8.95 (t, 2H, pyr-H), 8.68, 8.75 (2s, 4H, 4NH, exchangeable with D2O). – 13C NMR (125 MHz, [D6]DMSO): δ = 42.28 (2C, CH2), 52.87 (2C, 2 CH), 124.32, 128.36, 129.43, 138.76 (12C, 2Ph-C), 127.21, 128.05, 131.66, 137.94, 140.12, 145.12, 152.10, 152.56 (15C, pyr-C), 164.63, 164.95 (4C, 4 CO-Imide), 169.48, 170.34 (4C, 4 CO-amide). – MS (EI, 70 eV): m/z (%) = 752 (20) [M]+. – C39H29N9O8 (751.70): calcd. C 62.31, H 3.89, N 16.77; found C 62.20, H 3.80, N 16.70.

3.6 Antimicrobial activity

The antimicrobial activities of the synthesized compounds were determined by the agar diffusion method as recommended by the National Committee for Clinical Laboratory Standards [25]. The concentrations of the tested compounds (10 μg mL–1) were used according to modified Kirby–Bauer’s disk diffusion method [26]. The degree of inhibition is measured in comparison with that of Chloramphenicol and fusidic acid taken as standards.

4 Conclusions

In the present work, a series of tetracarboxamide and macrocyclic tripeptides have been prepared starting from 3,5-bis[N-(1-hydrazinyl-1-oxo-3-phenylpropan-2-yl)]pyridinecarboxamide as starting material. Some of the synthesized compounds were screened as antimicrobial agents.

Acknowledgments

The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group project no. RGP-172.

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Received: 2016-1-16
Accepted: 2016-2-9
Published Online: 2016-5-12
Published in Print: 2016-7-1

©2016 by De Gruyter

Articles in the same Issue

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  2. In this Issue
  3. Review
  4. Cerium intermetallics with TiNiSi-type structure
  5. Synthesis of novel pyrazole derivatives using organophosphorus, stibine, and arsine reagents and their antitumor activities
  6. A highly efficient CuI nanoparticles-catalyzed synthesis of tetrahydrochromenediones and dihydropyrano[c]chromenediones under grinding
  7. Supramolecular architecture based on high-lacunary sandwich-type building blocks: synthesis, characterization, and properties
  8. Preparation and conformation of 3,4-anhydro-1,2-O-isopropylidene-5-O-mesyl-β-d-tagatopyranose and methyl 4-chloro-4-deoxy-1,3,5-tri-O-mesyl-β-d-fructopyranoside
  9. Chromium(III) complexes with 1,2,4-diazaphospholide and 2,6-bis(N-1,2,4-diazaphosphol-1-yl) pyridine ligands: synthesis, X-ray structural characterization, EPR spectroscopy analysis, and magnetic susceptibility studies
  10. Synthesis and antimicrobial activity of some linear dipeptide pyridine and macrocyclic pentaazapyridine candidates
  11. Studies on the synthesis and properties of 1,1,1-trinitroprop-2-yl urea, carbamate and nitrocarbamate
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https://doi.org/10.1515/znb-2016-0018
Keywords for this article
antimicrobial agents; bis-Schiff base; linear dipeptide pyridine; macrocyclic pentaazapyridine

Articles in the same Issue

  1. Frontmatter
  2. In this Issue
  3. Review
  4. Cerium intermetallics with TiNiSi-type structure
  5. Synthesis of novel pyrazole derivatives using organophosphorus, stibine, and arsine reagents and their antitumor activities
  6. A highly efficient CuI nanoparticles-catalyzed synthesis of tetrahydrochromenediones and dihydropyrano[c]chromenediones under grinding
  7. Supramolecular architecture based on high-lacunary sandwich-type building blocks: synthesis, characterization, and properties
  8. Preparation and conformation of 3,4-anhydro-1,2-O-isopropylidene-5-O-mesyl-β-d-tagatopyranose and methyl 4-chloro-4-deoxy-1,3,5-tri-O-mesyl-β-d-fructopyranoside
  9. Chromium(III) complexes with 1,2,4-diazaphospholide and 2,6-bis(N-1,2,4-diazaphosphol-1-yl) pyridine ligands: synthesis, X-ray structural characterization, EPR spectroscopy analysis, and magnetic susceptibility studies
  10. Synthesis and antimicrobial activity of some linear dipeptide pyridine and macrocyclic pentaazapyridine candidates
  11. Studies on the synthesis and properties of 1,1,1-trinitroprop-2-yl urea, carbamate and nitrocarbamate
  12. Gold nanocrystal arrays as electrocatalysts for the oxidation of methanol and ethanol
  13. Syntheses, single-crystal structures, vibrational spectra and DSC/TG analyses of orthorhombic and trigonal Ag[N(CN)2]
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