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Synthesis of chiral 3,5-bis(l-phenylalaninyl-l-leucinyl)pyridine Schiff base and their macrocyclic carboxaimide derivatives using 3,5-bis(l-phenylalaninyl)-pyridine methyl ester

  • Ahmed M. Naglah , Abd El-Galil E. Amr EMAIL logo , Randa E. Abdel-Mageid , Elsayed A. Elsayed and Osama I. Abd El-Salam
Published/Copyright: February 6, 2020
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Zeitschrift für Naturforschung B
From the journal Zeitschrift für Naturforschung B Volume 75 Issue 3

Abstract

A series of linear tetrapeptides 2–7 and cyclooctapeptedopyridine derivatives 8 and 9, were synthesized using Nα-dinicotinoyl-bis[(l-phenylalaninyl-l-leucyl)hydrazide] 2 as starting material. Acid hydrazide 2 was reacted with aromatic or heterocyclic aldehydes to give Schiff base derivatives 3 and 4, respectively. Additionally, compound 2 was reacted with dicarboxylic acid anhydrides ortetracarboxylic diacid anhydrides to give the corresponding linear diimide carboxamides 5–7, and octapeptide tetraimides 8 and 9, respectively. The synthesized products were elucidated by using spectroscopic evidences and they were evaluated for their antibacterial activity by using streptomycin as reference antibiotic drug.

Keywords: amino acids; antibacterial activity; octapeptide tetraimides; Schiff bases

1 Introduction

Pyridines and their derivatives are of interest from both the chemical and biological aspects, such as hypotensive, anticonvulsant, antiinflammatory, antimicrobial [1], [2], [3], [4], [5], anticancer [6] activities, and they have also been characterized with a broad range of biological activity [7], [8], [9], [10]. In addition, some of hetero-nitrogen derivatives proved to be biologically active, such as antimicrobial [11], anti-inflammatory [12], antihistaminic [13], antihypertensive [14], hypnotic [15], and anticonvulsant [16] activity. From our previous work, Schiff bases were synthesized [17], [18], [19], and exhibit biological activities, such as antimicrobial [20], [21], [22], [23], [24], anti-inflammatory [25], and anticonvulsant [26] activities. In view of these observations and in continuation of our previous work in pyridine chemistry [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], we synthesized some new peptide compounds containing the pyridine ring substituted with a peptide linkage and other heterocyclic nucleus and tested their antimicrobial activities.

2 Results and discussion

2.1 Chemistry

In the present work, some of newly synthesized 3,5-pyridine tetrapeptides 1–4 were obtained by using Nα-dinicotinoyl-bis[l-phenylalaninyl acid] [27], [28] as starting materials. Treatment of 1 with l-leucine methyl ester to give Nα-dinicotinoyl-bis[l-phenylalaninyl-l-leucyl]methyl ester 1, which was treated with hydrazine hydrated in refluxing methanol to give Nα-dipicolinoyl-bis[l-phenylalanyl-l-leucine]hydrazide 2. Treatment of hydrazide 2 with aromatic and heterocyclic aldehydes, namely, benzaldehyde, p-methylbenzaldehydeor pyridine-, 2-, 3- or 4-carbaldehydes in the presence of triethylamine (TEA)-diethylamine (DEA) afforded the corresponding Schiff base derivatives 3a, b, and 4a–c, respectively (Scheme 1).

Scheme 1: Synthetic routes and yields for compounds 2, 3a, b, and 4a–c.
Scheme 1:

Synthetic routes and yields for compounds 2, 3a, b, and 4a–c.

Reaction of hydrazide 2 with mono acid anhydrides, namely, phthalic, 2,3,4,5-tetrachloro-phthalic anhydride, or 2,3-pyridinedicarboxylic acid anhydride afforded the corresponding diimide derivatives 5a, b, and 6, respectively (Scheme 2).

Scheme 2: Synthetic routes and yields for compounds 5a, b, 6, and 7.
Scheme 2:

Synthetic routes and yields for compounds 5a, b, 6, and 7.

Condensation of compound 2 with 1,2,4,5-benzenetetracarboxylic acid dianhydride, or 1,4,5,8-naphthalenetetracarboxylic acid dianhydride in refluxing acetic acid, afforded the corresponding 3,5-bis[l-phenylalaninyl-l-leucyl]benzene cyclic bridged octapeptide 8 and 3,5-bis- [l-phenylalaninyl-l-leucyl]naphthalene cyclic bridged octapeptide 9, respectively (Scheme 3).

Scheme 3: Synthetic routes for compounds 8 and 9.
Scheme 3:

Synthetic routes for compounds 8 and 9.

2.2 Antimicrobial testing

The newly synthesized compounds 2–9 were evaluated for their antibacterial activity against Escherichia coli, Bacillus subtilis, and Staphylococcus aureus bacteria. The evaluated compounds have shown potent antibacterial activities at a concentration 50 μg mL−1 with a bioassay technique for antibiotics [29] specified in the US Pharmacopeia. Streptomycin was used as antibacterial reference drug. The results are summarized in Table 1. The obtained results revealed that all synthesized compounds showed varying degrees of antimicrobial activities against all tested three microbial pathogens. Furthermore, it can be seen that these activities were much higher when compared with the standard streptomycin antibiotic. Against the Gram negative E. coli, the most potent prepared compound (Compound 9) showed higher antimicrobial activity by about 36.8% than the standard used antibiotic. Similarly, for Gram negative pathogens; i.e. B. subtilisand S. aureus, the most potent derivatives, 4b and 2, respectively, showed increased activities by about 20% and 21%, respectively. Generally, the order of descending activities against Gram negative pathogen can be summarized as Compound 9>4b>3b>7>2, 3a, 5a, 5b>6, 8>4c>4a. On the other hand the obtained descending order of activities against Gram positive pathogens differed depending on the tested pathogen. For B. subtilis, the order was 4b>8 >5a>9>5b>6>2>3a, 7>4c>3b>4a, while for S. aureus, the order was 2>7, 9>8>4b, 5a>3b>4c>5b, 6>3a>4a. A comparison of our results with previous results reported for antimicrobial activities of oligopeptides shows that our synthesized derivatives have potential antimicrobial activities against tested pathogens. Abd El Rahman et al. [30] obtained their highest antimicrobial activities (13.1 mm against B. subtilis) for their synthesized peptide (PEG-Gly-Tyr-Tyr-Ala-NH2) at their used concentration of 10 mg mL−1, while this peptide was not active at all against S. aureus and E. coli. It is noteworthy to mention that our results were obtained at the 50 μg mL−1 level. The difference in the obtained antimicrobial activity is generally explained due to the difference in the structure of cell membranes of each microbial cell type [31], [32]. The higher obtained activities of these compounds can be attributed to the presence of macrocyclic octapeptide ring, the Schiff base of 3-pyridine carbaldehyde and the hydrazide bond in compounds 9, 4b and 2, respectively. Generally, the antimicrobial activity of the synthesized peptides can be due to the interaction of the peptides with microbial cell membranes, and thus affecting the integrity of the cell walls [33], [34]. Furthermore, peptides have been reported to effect microbial cells intracellularly by interacting with cellular DNA or enzyme machinery [35].

Table 1:

Antibacterial activities of compounds 2–9.

Comp. No.Zones of inhibition (mm)
E. coliB. subtilisS. aureus
20.751.831.58
3a0.751.851.92
3b0.681.871.77
4a0.901.961.95
4b0.651.621.75
4c0.841.861.78
5a0.761.741.75
5b0.751.781.86
60.781.801.85
70.721.851.65
80.781.681.67
90.601.751.65
Streptomycin0.952.002.00

  1. E. coli, Escherichia coli; B. subtilis, Bacillus subtilis; S. aureus, Staphylococcus aureus.

3 Experimental section

3.1 Reagents

3,5-Pyridinedicarbonylchloride was prepared and elucidated according to literature procedures [36]. l-Leucine methyl ester, ethanol, methanol, dichloromethane, hydrazine hydrate, ethyl chloroformate, benzaldehyde, p-methylbenzaldehyde, and sodium hydroxide were all purchased from Sigma-Aldrich (Buchs, Switzerland). Melting points were determined in open glass capillary tubes with an Electro Thermal Digital melting point apparatus (Shimadzu, Tokyo, Japan), (model: IA9100) and are uncorrected. Elemental microanalysis for carbon, hydrogen and nitrogen (Microanalytical Unit, NRC) was found within the acceptable limits of the calculated values. Infrared spectra (KBr) were recorded using a Nexus 670 FTIR Nicolet, Fourier Transform infrared spectrometer (Perkin Elmer, Hopkinton, MA, USA). 1H and 13C NMR spectra were run in (DMSO-d6) using Jeol 500 MHz instruments (Tokyo, Japan). Mass spectra were run using a MAT Finnigan SSQ 7000 spectrometer (Shimadzu, Kyoto, Japan; Model: QP2010 ultra), using the electron impact technique (EI). Analytical thin layer chromatography was performed on silica gel aluminum sheets, 60 F254 (E. Merck).

3.2 Syntheses

3.2.1 Synthesis of Nα-dinicotinoyl-bis[l-phenylalanine-l-leucyl]methyl ester (1)

Compound 1 was prepared according to the mixed anhydride method [37] by using Nα-dinicotinoyl-bis[l-phenylalaninyl acid] [27], [28] and l-leucine methyl ester as starting materials. Yield 90%, m.p. 134°C–136°C. – [a]D25=–109 (c=0.5, DMF). – IR (film): ν=3540–3380 (br, NH), 3086 (CH–Ar), 2992 (CH-aliph.), 1754 (C=O, estr), 1653, 1534, 1256 (C=O, amide I, II and III)cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.92 (d, 12H, J=6.5 Hz, 4CH3), 1.70 (t, 4H, J=7.88 Hz, 2CH2), 2.22–2.26 (m, 2H, 2CH), 3.42 (d, 4H, J=5.2 Hz, 2CH2), 3.70 (s, 6H, 2OCH3), 4.15 (t, 2H, J=5.4 Hz, 2CH), 4.42 (t, 2H, J=4.6 Hz, 2CH), 7.12–7.64 (m, 10H, 2Ph-H), 8.35, 9.02 (2s, 3H, pyr-H), 8.72, 8.80 (2s, 4H, 4NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=17.40, 18.55 (4C, 4 CH3), 23.74 (2C, 2CH), 40.15 (2C, 2CH2), 42.54 (2C, 2CH2), 51.36 (2C, 2OCH3), 52.64, 53.13 (4C, 4 CH), 124.24, 128.30, 129.42, 138.65 (12C, 2Ph-C), 131.62, 140.18, 152.16 (5C, pyr-C), 163.75, 169.15 (4C, 4 CO-amide), 171.40 (2C, 2CO-ester). – MS (EI, 70 eV): m/z (%)=716 (42) [M]+. – C39H49N5O8 (715.85): calcd. C 65.44, H 6.90, N 9.78; found C 65.32, H 6.86, N 9.70.

3.2.2 Synthesis of Nα-dinicotinoyl-bis[l-phenylalanine- l-leucyl]hydrazide (2)

A mixture of Nα-dinicotinoyl-bis[l-phenylalanine-l-leucyl]methyl ester (1) (0.715 g, 1 mmol) and hydrazine hydrate (0.35 mL, 10 mmol) in methanol (20 mL) was refluxed for 3 h, solvent was evaporated under reduced pressure. The formed solid was washed with ether, filtered off, and crystallized from ethanol-ether to afford the corresponding title compound (2). Yield 85%, m.p. 245°C–247°C. – [a]D25=–115 (c=0.5, DMF). – IR (film): ν=3510–3375 (br, NH2, NH), 3085 (CH–Ar), 2990 (CH-aliph.), 1652, 1536, 1257 (C=O, amide I, II and III)cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.90 (d, 12H, J=6.4 Hz, 4CH3), 1.72 (t, 4H, J=7.9 Hz, 2CH2), 2.23–2.28 (m, 2H, 2CH), 3.44 (d, 4H, J=5.2 Hz, 2CH2), 4.10 (bs, 4H, 2NH2, exchangeable with D2O), 4.12 (t, 2H, J=5.4 Hz, 2CH), 4.40 (t, 2H, J=4.6 Hz, 2CH), 7.10–7.65 (m, 10H, 2Ph-H), 8.36, 9.00 (s, 3H, pyr-H), 8.70, 8.82, 9.22 (3s, 6H, 6NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=17.42, 18.60 (4C, 4 CH3), 23.78 (2C, 2CH), 40.12 (2C, 2CH2), 42.56 (2C, 2CH2), 52.65, 53.10 (4C, 4 CH), 124.23, 128.32, 129.45, 138.68 (12C, 2Ph-C), 131.60, 140.15, 152.18 (5C, pyr-C), 163.78, 169.12 (4C, 4 CO-amide), 171.45 (2C, 2CO-hydrazide). – MS (EI, 70 eV): m/z (%)=716 (32) [M]+. – C37H49N9O6 (715.86): calcd. C 62.08, H 6.90, N 17.61; found C 61.95, H 6.73, N 17.50.

3.2.3 Synthesis of Nα-dinicotinoyl-bis-[l-phenylalaninyl-l-leucyl]-p-substituted phenyl hydrazones] (3a, b)

A mixture of hydrazide derivative 2 (1 mmol) and aromatic aldehydes, namely benzaldehyde, or p-methylbenzaldehyde (2 mmol) in absolute ethanol (25 mL) in the presence of a mixture of TEA-DEA (4 mL, 2:2) was refluxed for 3–5 h. The solvent was evaporated to dryness, the obtained residue was triturated with icewater with stirring. The precipitated solid was filtered off, washed with water, and crystallized from the proper solvents to give the corresponding Nα-dinicotinoyl-bis[l-phenyl- alaninyl-l-leucyl] substituted phenypyridines (3a, b), respectively.

3.2.3.1 Nα-Dinicotinoyl-bis-[l-phenylalaninyl-l-leucyl]phenylhydrazone (3a)

Yield 65%, m.p. 198°C –200°C (dioxane-ether). – [a]D25=–98 (c=0.5, DMF). – IR (film): ν=3490–3355 (NH), 3092 (CH–Ar), 2978 (CH-aliph.), 1656, 1535, 1252 (C=O, amide I, II and III)cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.96 (d, 12H, J=6.5 Hz, 4CH3), 1.75 (t, 4H, J=7.4 Hz, 2CH2), 2.25–2.32 (m, 2H, 2CH), 3.42 (d, 4H, J=7.9 Hz, 2CH2), 4.16 (t, 2H, J=5.5 Hz, 2CH), 4.45 (t, 2H, J=4.5 Hz, 2CH), 7.00–7.68 (m, 22H, 20Ar-H+2CH=N), 8.36, 9.14 (2s, 3H, pyr-H), 8.70, 8.82, 9.26 (3s, 6H, 6NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=18.68, 19.25 (4C, 4 CH3), 22.47 (2C, 2CH), 40.16 (2C, 2CH2), 42.46 (2C, CH2), 52.40, 53.30 (4C, 4 CH), 125.87, 127.46, 128.34, 128.50, 129.08, 131.08, 133.25, 138.66 (24C, 4Ph-C), 131.65, 140.35, 152.46 (5C, pyr-C), 143.16 (2C, 2C=N), 163.92, 169.42 (4C, 4 CO-amide), 178.42 (2C, 2CO-hydrazone). – MS (EI, 70 eV): m/z (%)=892 (25) [M]+. – C51H57N9O6 (892.07): calcd. C 68.67, H 6.44, N 14.13; found C 68.54, H 6.35, N 14.08.

3.2.3.2 Nα-Dinicotinoyl-bis-[l-phenylalaninyl-l-leucyl]-p-methylphenylhydrazone (3b)

Yield 78%, m.p. 132°C–234°C (DMF-H2O). – [a]D25=–125 (c=0.5, DMF). – IR (film): ν=3460–3348 (NH), 3090 (CH–Ar), 2982 (CH-aliph.), 1654, 1536, 1250 (C=O, amide I, II and III)cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.98 (d, 12H, J=6.6 Hz, 4CH3), 1.72 (t, 4H, J=7.3 Hz, 2CH2), 2.21–2.34 (m, 8H, 2CH+2 CH3), 3.46 (d, 4H, J=7.9 Hz, 2CH2), 4.18 (t, 2H, J=5.4 Hz, 2CH), 4.40 (t, 2H, J=4.6 Hz, 2CH), 6.98–7.56 (m, 20H, 18Ar-H+2CH=N), 8.45, 9.18 (s, 3H, pyr-H), 8.65, 8.85, 9.24 (3s, 6H, 6NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=18.65, 19.30, 24.18 (6C, 6 CH3), 23.45 (2C, 2CH), 40.22 (2C, 2CH2), 42.48 (2C, CH2), 52.45, 53.45 (4C, 4CH), 125.85, 127.66, 128.54, 128.95, 129.18, 130.48, 139.45, 140.64 (24C, 4Ph-C), 131.62, 140.50, 152.56 (5C, pyr-C), 142.90 (2C, 2C=N), 164.14, 169.55 (4C, 4 CO-amide), 178.68 (2C, 2CO-hydrazone). – MS (EI, 70 eV): m/z (%)=920 (15) [M]+. – C53H61N9O6 (920.13): calcd. C 69.18, H 6.68, N 13.70; found C 69.05, H 6.58, N 13.64.

3.2.4 Synthesis of Nα-dinicotinoyl-bis[(l-phenylalaninyl-l-leucyl)]-pyridyl hydrazones] (4a–c)

A mixture of 2 (0.715 g, 1 mmol) and pyridinecarbaldehye, namely, pyridine 2-, 3-, or 4-carbaldehydes (2 mmol) in glacial acetic acid (30 mL) was refluxed for 3–5 h. The solvent was concentratedto dryness, the obtained residue was triturated with water. The formed precipitate was filtered off, washed with water, dried, and crystallized from the proper solvents to give 3,5-bisSchiff bases 4a–c, respectively.

3.2.4.1 Nα-Dinicotinoyl-bis[l-phenylalaninyl-l-leucyl]- 2-pyridylpyridine] (4a)

Yield 60%, m.p. 224°C–226°C (DMF-H2O). – [a]D25=–112 (c=0.5, DMF). – IR (film): ν=3450–3354 (NH), 3092 (CH–Ar), 2986 (CH-aliph.), 1654, 1534, 1252 (C=O, amide I, II and III)cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.90 (d, 12H, J=6.3 Hz, 4CH3), 1.78 (t, 4H, J=7.3 Hz, 2CH2), 2.26–2.32 (m, 2H, 2CH), 3.52 (d, 4H, J=8.10Hz, 2CH2), 4.25 (t, 2H, J=5.3 Hz, 2CH), 4.54 (t, 2H, J=4.5 Hz, 2CH), 6.98–7.72 (m, 12H, 2Ph-H+2CH=N), 7.80–8.50 (m, 10H, pyr-H), 9.12 (s, 1H, pyr-H), 8.72, 8.86, 9.22 (3s, 6H, 6NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=17.98, 18.60 (4C, 4 CH3), 23.76 (2C, 2CH), 40.26 (2C, 2CH2), 42.42 (2C, CH2), 52.57, 53.38 (4C, 4CH), 124.24, 128.30, 129.32, 138.64 (12C, 2Ph-C), 139.80 (2C, 2C=N), 122.90, 126.00, 131.66, 135.85, 140.24, 148.66, 152.25, 154.48 (15C, 3pyr-C), 163.86, 169.40 (4C, 4 CO-amide), 178.64 (2C, 2CO-hydrazone). – MS (EI, 70 eV): m/z (%)=895 (6) [M+1]+. – C49H55N11O6 (894.05): calcd. C 65.83, H 6.20, N 17.23; found C 65.72, H 6.12, N 17.18.

3.2.4.2 Nα-Dinicotinoyl-bis[l-phenylalaninyl-l-leucyl]- 3-pyridylpyridine] (4b)

Yield 58%, m.p. 208°C–210°C (AcOH-H2O). – [a]D25=–132 (c=0.5, DMF). – IR (film): ν=3467–3350 (NH), 3075 (CH–Ar), 2990 (CH-aliph.), 1652, 1536, 1252 (C=O, amide I, II and III)cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.96 (d, 12H, J=6.4 Hz, 4CH3), 1.75 (t, 4H, J=7.4 Hz, 2CH2), 2.18–2.36 (m, 2H, 2CH), 3.48 (d, 4H, J=8. 0 Hz, 2CH2), 4.18 (t, 2H, J=5.6Hz, 2CH), 4.52 (t, 2H, J=4.6Hz, 2CH), 6.96–7.68 (m, 12H, 2Ph-H+2CH=N), 7.76–8.62 (m, 8H, pyr-H), 9.05, 9.20 (2s, 3H, pyr-H), 8.76, 8.85, 9.28 (3s, 6H, 6NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=17.98, 18.88 (4C, 4 CH3), 23.98 (2C, 2CH), 40.32 (2C, 2CH2), 42.65 (2C, CH2), 52.45, 53.65 (4C, 4 CH), 124.32, 128.45, 129.52, 138.65 (12C, 2Ph-C), 123.44, 126.00, 131.65, 136.46, 140.34, 150.80, 151.20, 152.20 (15C, 3 pyr-C), 142.95 (2C, 2C=N), 164.08, 169.48 (4C, 4 CO-amide), 178.74 (2C, 2CO-hydrazone). – MS (EI, 70 eV): m/z (%)=894 (18) [M]+. – C49H55N11O6 (894.05): calcd. C 65.83, H 6.20, N 17.23; found C 65.74, H 6.15, N 17.16.

3.2.4.3 Nα-Dinicotinoyl-bis[l-phenylalaninyl-l-leucyl]- 4-pyridylpyridine] (4c)

Yield 75%, m.p. 196°C–198°C (EtOH-H2O). – [a]D25=–140 (c=0.5, DMF). – IR (film): ν=3466–3348 (NH), 3080 (CH–Ar), 2986 (CH-aliph.), 1655, 1535, 1255 (C=O, amide I, II and III)cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.98 (d, 12H, J=6.3 Hz, 4CH3), 1.77 (t, 4H, J=7.5 Hz, 2CH2), 2.20–2.35 (m, 2H, 2CH), 3.46 (d, 4H, J=8.0 Hz, 2CH2), 4.22 (t, 2H, J=5.6 Hz, 2CH), 4.54 (t, 2H, J=4.6 Hz, 2CH), 6.97–7.51 (m, 12H, 2Ph-H+2CH=N), 8.10 (d, 4H, J=6.25 Hz,pyr-H), 8.78 (d, 4H, J=6.25 Hz,Pyr-H), 8.60, 9.00 (2s, 3H, pyr-H-4), 8.72, 8.89, 9.26 (3s, 6H, 6NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=17.90, 18.98 (4C, 4 CH3), 23.82 (2C, 2CH), 41.04 (2C, 2CH2), 42.60 (2C, CH2), 52.55, 53.65 (4C, 4 CH), 124.22, 128.40, 129.46, 138.60 (12C, 2Ph-C), 143.12 (2C, 2C=N), 123.95, 132.90, 139.02, 144.20, 149.18, 150.94 (15C, 3 pyr-C), 163.86, 169.12 (4C, 4 CO-amide), 177.82 (2C, 2CO-hydrazone). – MS (EI, 70 eV): m/z (%)=892(15) [M–2]+. – C49H55N11O6 (894.06): calcd. C 65.83, H 6.20, N 17.23; found C 65.75, H 6.16, N 17.15.

3.2.5 Synthesis of Nα-dinicotinoyl-bis[(l-phenylalaninyl-l-leucyl) substituted aromatic or heterocyclic bisimide derivatives 5–7

A mixture of 2 (0.715 g, 1 mmol) and mono acid hydride derivatives, namely, phthalic, tetrachlorophthalic, 2,3-pyridinedicarboxylic, or 1,8-naphthaline dicarboxylic acid anhydrides (2 mmol) was refluxed inglacial acetic acid (50 mL) for 4–6 h. The reaction mixture was poured into ice-water, the obtained precipitate was collected by filtration, washed with water, dried, and crystallized from the proper solvents to give bisimidehexacarboxamide derivatives 5a, b, 6, and 7, respectively.

3.2.5.1 Nα-dinicotinoyl-bis[(l-phenylalaninyl-l-leucyl)-N-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-imide] (5a)

Yield 72%, m.p. 236°C–238°C. – [a]D25=–110 (c=0.5, DMF). – IR (film): ν=3455–3345 (NH), 3082 (C–Harom), 2986 (C–Haliph), 1652, 1534, 1254 (C=O, amide I, II and III) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.96 (d, 12H, J=6.4 Hz, 4CH3), 1.74 (t, 4H, J=7.9 Hz, 2CH2), 2.24–2.30 (m, 2H, 2CH), 3.40 (d, 4H, J=5.2 Hz, 2CH2), 4.24 (t, 2H, J=5.4 Hz, 2CH), 4.54 (t, 2H, J=4.6 Hz, 2CH), 7.00–7.98 (m, 18H, 4Ph-H), 8.40, 9.08 (2s, 3H, pyr-H), 8.65, 8.82, 9.22 (3s, 6H, 6NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=17.36, 18.52 (4C, 4 CH3), 23.78 (2C, 2CH), 40.10 (2C, 2CH2), 42.27 (2C, CH2), 52.45, 53.06 (4C, 4 CH), 124.15, 127.23, 128.24, 129.35, 131.86, 132.18, 138.72 (24C, 4Ph-C), 131.60, 140.12, 152.08 (5C, pyr-C), 164.64 (4C, 4 CO-imide), 163.82, 169.42, 170.10 (6C, 6 CO-amide). – MS (EI, 70 eV): m/z (%)=976 (24) [M]+. – C53H53N9O10 (976.06): calcd. C 65.22, H 5.47, N 12.92; found C 65.05, H 5.38, N 12.86.

3.2.5.2 Nα-dinicotinoyl-bis[(l-phenylalaninyl-l-leucyl)-N-(4,5,6,7-tetrachloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)imide] (5b)

Yield 78%, m.p. 256°C–258°C. – [a]D25=–125 (c=0.5, DMF). – IR (film): ν=3460–3318 (NH), 3085 (C–Harom), 2992 (C–Haliph), 1650, 1532, 1254 (C=O, amide I, II and III)cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.95 (d, 12H, J=6.4 Hz, 4CH3), 1.73 (t, 4H, J=7.8 Hz, 2CH2), 2.25–2.35 (m, 2H, 2CH), 3.42 (d, 4H, J=5.3 Hz, 2CH2), 4.30 (t, 2H, J=5.4 Hz, 2CH), 4.48 (t, 2H, J=4.5 Hz, 2CH), 6.95–7.56 (m, 10H, 2Ph-H), 8.35, 9.14 (2s, 3H, pyr-H), 8.70, 8.78, 9.18 (3s, 6H, 6NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=17.45, 18.56 (4C, 4 CH3), 23.82 (2C, 2CH), 40.16 (2C, 2CH2), 42.32 (2C, CH2), 52.50, 53.17 (4C, 4 CH), 124.24, 128.02, 128.44, 129.46, 132.74, 138.12, 138.68 (24C, 4Ph-C), 131.53, 140.20, 152.32 (5C, pyr-C), 164.76 (4C, 4 CO-imide), 163.84, 169.45, 170.15 (6C, 6 CO-amide). – MS (EI, 70 eV): m/z (%)=1251 (6) [M–1]+. – C53H45Cl8N9O10 (1251.07): calcd. C 50.86, H 3.62, Cl 22.66, N 10.07; found C 50.70, H 3.56, Cl 22.58, N 10.01.

3.2.5.3 Nα-dinicotinoyl-bis[(l-phenylalaninyl-l-leucyl)-N-(5,7-dioxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)imide] (6)

Yield 75%, m.p. 218°C–220°C. – [a]D25=–98 (c=0.5, DMF). – IR (film): ν=3450–3345 (NH), 3090 (C–Harom), 2988 (C–Haliph), 1652, 1540, 1255 (C=O, amide I, II and III)cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.94 (d, 12H, J=6.2 Hz, 4CH3), 1.72 (t, 4H, J=7.7 Hz, 2CH2), 2.20–2.32 (m, 2H, 2CH), 3.44 (d, 4H, J=5.4 Hz, 2CH2), 4.26 (t, 2H, J=5.6 Hz, 2CH), 4.50 (t, 2H, J=4.5 Hz, 2CH), 6.96–7.48 (m, 10H, 2Ph-H), 8.48, 9.05 (2s, 3H, pyr-H), 7.98 (t, 2H, J=7.6 Hz, pyr-H), 8.54 (d, 2H, J=7.9 Hz, pyr-H), 8.95 (d, 2H, J=7.8 Hz, pyr-H), 8.65, 8.75, 9.14 (3s, 6H, 6NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=18.00, 18.85 (4C, 4 CH3), 24.00 (2C, 2CH), 39.84 (2C, 2CH2), 42.30 (2C, CH2), 52.48, 53.00 (4C, 4 CH), 124.25, 128.24, 129.32, 138.62 (12C, 2Ph-C), 127.16, 128.04, 131.64, 138.00, 140.22, 145.00, 152.10, 152.50 (15C, pyr-C), 164.54, 165.10 (4C, 4 CO-imide), 163.80, 169.46, 170.15 (6C, 6 CO-amide). – MS (EI, 70 eV): m/z (%)=978 (10) [M]+. – C51H51N11O10 (978.04): calcd. C 62.63, H 5.26, N 15.75; found C 62.50, H 5.18, N 15.66.

3.2.5.4 Nα-dinicotinoyl-bis[(l-phenylalaninyl-l-leucyl)-N-(1,3-dioxo-1H-benzo[de]iso-quinolin-2(3H)-yl)imide] (7)

Yield 74%, m.p. 254°C–256°C. – IR (film): ν=3468–3350 (NH), 3090 (C–Harom), 2988 (C–Haliph), 1652, 1532, 1252 (C=O, amide I, II and III)cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.86 (d, 12H, J=6.5 Hz, 4CH3), 1.73 t (4H, J=7.4 Hz, 2CH2), 2.18–2.26 m (2H, 2CH), 3.45 d (4H, J=5.6 Hz, 2CH2), 4.32 (t, 2H, J=5.7 Hz, 2CH), 4.50 (t, 2H, J=4.6 Hz, 2CH), 7.00–7.95 (m, 22H, Ar-H), 8.40, 9.05 (2s, 3H, pyr-H), 8.60, 8.72, 9.12 (3s, 6H, 6NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=18.00, 18.72 (4C, 4 CH3), 23.70 (2C, 2CH), 40.12 (2C, 2CH2), 41.20 (2C, 2CH2), 52.72, 53.15 (4C, 4 CH), 123.55, 125.19, 128.35, 130.38, 137.14, 137.80 (20C, naphtha-C), 124.20, 128.15, 129.32, 138.75 (12C, 2Ph-C), 131.48, 140.18, 152.00 (5C, pyr-C), 164.70, 169.84, 171.30 (6C, 6 CO-amide), 168.85 (4C, 4CO-imide). – MS (EI, 70 eV): m/z (%)=1075 (8) [M–1]+. – C61H57N9O10 (1075.42): calcd. C 68.08, H 5.34, N 11.71; found C 67.96, H 5.23, N 11.60.

3.2.6 Synthesis of cyclo[(Nα-dinicotinoyl)-bis(l-phenylalaninyl-l-leucyl)benzene or naphthalene tetraimide] derivatives (8) and (9)

The same procedure for synthesis of compounds 5–7 by using 1,4,5,8-naphthylenetracarboxylic dianhydride or 1,2,4,5-benzenetetracarboxylic dianhydride (as anhydride derivatives) (1 mmol) and compound 2 (1 mmol) in refluxing glacial acetic acid.

3.2.6.1 Cyclo(Nα-dinicotinoyl)-bis[(l-phenylalaninyl-l-leucyl)benzene tetraimide] derivatives (8)

Yield 65%, m.p. 242°C–244°C. – [a]D25=–115 (c=0.5, DMF). – IR (film): ν=3460–3340 (NH), 3087 (C–Harom), 2985 (C–Haliph), 1653, 1534, 1252 (C=O, amide I, II and III)cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.96 (d, 24H, J=6.4 Hz, 8CH3), 1.72 (t, 8H, J=7.5 Hz, 4CH2), 2.10–2.18 (m, 4H, 4CH), 3.46 (d, 8H, J=5.6 Hz, 4CH2), 4.26 (t, 4H, J=5.6 Hz, 4CH), 4.54 (t, 4H, J=4.7 Hz, 4CH), 7.00–7.78 (m, 20H, 4Ph-H), 8.72 (s, 4H, Ar-H), 8.42, 9.02 (s, 6H, 2pyr-H), 8.64, 8.80, 9.10 (3s, 12H, 12NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=17.95, 18.66 (8C, 8 CH3), 23.72 (4C, 4CH), 40.30 (4C, 4CH2), 41.48 (4C, 4CH2), 53.55, 57.25 (8C, 8 CH), 124.95, 135.25 (12C, benzene-C), 124.36, 128.46, 129.54, 138.70 (24C, 4Ph-C), 131.48, 140.24, 152.38 (10C, 2pyr-C), 164.75, 173.35, 174.15 (12C, 12 CO-amide), 164.66 (8C, 8 CO-imide). – MS (EI, 70 eV): m/z (%)=1795(14) [M–1]+. – C94H94N18O20 (1795.67): calcd. C 62.87, H 5.28, N 14.04; found C 62.75, H 5.18, N 13.94.

3.2.6.2 Cyclo(Nα-dinicotinoyl)-bis[(l-phenylalaninyl-l-leucyl)naphthalene tetraimide] derivatives (9)

Yield 60%, m.p. 278°C–280°C. – [a]D25=–132 (c=0.5, DMF). – IR (film): ν=3460–3312 (NH), 3090 (C–Harom), 2984 (C–Haliph), 1652, 1534, 1250 (C=O, amide I, II and III)cm−1. – 1H NMR (500 MHz, DMSO-d6): δ=0.89 (d, 24H, J=6.6 Hz, 8CH3), 1.70 (t, 8H, J=7.6 Hz, 4CH2), 2.12–2.16 (m, 4H, 4CH), 3.45 (d, 8H, J=5.5 Hz, 4CH2), 4.32 (t, 4H, J=5.4 Hz, 4CH), 4.52 (t, 4H, J=4.6 Hz, 4CH), 6.95–7.64 (m, 20H, 4Ph-H), 8.10–8.15 (m, 8H, naphtha-H), 8.48, 9.10 (2s, 6H, 2pyr-H), 8.62, 8.80, 9.15 (3s, 12H, 12NH, exchangeable with D2O). – 13C NMR (125 MHz, DMSO-d6): δ=17.98, 18.40 (8C, 8 CH3), 23.70 (4C, 4CH), 40.15 (4C, 4CH2), 41.36 (4C, 4CH2), 52.75, 53.25 (8C, 8 CH), 119.95, 135.18, 139.72 (20C, naphtha-C), 124.25, 128.22, 129.35, 138.72 (24C, 4Ph-C), 131.30, 140.12, 152.15 (10C, 2pyr-C), 164.65, 169.75, 171.30 (12C, 12 CO-amide), 158.80 (8C, 8CO-imide). – MS (EI, 70 eV): m/z (%)=1896(12) [M]+. – C102H98N18O20 (1896.01): calcd. C 64.62, H 5.21, N 13.30; found C 64.48, H 5.16, N 13.26.

Acknowledgments

The authors are grateful to King Saud University for funding the work through Researchers Supporting Project (Project No. RSP-2019-066).

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Received: 2019-09-04
Accepted: 2019-12-01
Published Online: 2020-02-06
Published in Print: 2020-02-25

©2020 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/znb-2019-0146
Keywords for this article
amino acids; antibacterial activity; octapeptide tetraimides; Schiff bases

Articles in the same Issue

  1. Frontmatter
  2. In this Issue
  3. The di(thiourea)gold(I) complex [Au{S=C(NH2)2}2][SO3Me] as a precursor for the convenient preparation of gold nanoparticles
  4. Synthesis of chiral 3,5-bis(l-phenylalaninyl-l-leucinyl)pyridine Schiff base and their macrocyclic carboxaimide derivatives using 3,5-bis(l-phenylalaninyl)-pyridine methyl ester
  5. Utilization of 1-phenylimidazo[1,5-a]quinoline as partner in 1,4-dipolar cycloaddition reactions
  6. One-pot multi-component process for the synthesis of 4-azaphenanthrene-3,10-dione, 1,8-dioxo-octahydroxanthene and tetrahydrobenzo[b]pyran derivatives catalyzed by the deep eutectic solvent choline chloride-oxalic acid
  7. A novel three-dimensional copper aspartate coordination compound with efficient photoluminescence
  8. A binuclear Cd(II) complex containing bridging pyrimidine-based ligands
  9. Structures and phase transitions of (BrCH2CH2NH3)2CdBr4 and (BrCH2CH2CH2NH3)2CdBr4 as investigated by 81Br NQR, DTA, and single-crystal X-ray diffraction
  10. Single-crystal investigation of the compound SmNi5.2Mn6.8
  11. Serendipitous formation of K15NaSn5F36
  12. Derivatives of the triaminoguanidinium ion, 6. Aminal-forming reactions with aldehydes and ketones
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