7th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-7), http://www.mdpi.net/ecsoc-7, 1-30 November 2003

[C001]

Substituted Pyrazine-2-carboxamides: Preparation and Their Photosynthesis-inhibiting Activity

Josef Jampilek1*, Martin Dolezal1, Zdenek Osicka1, Jiri Kunes2, Katarina Kralova3

1 Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy, Charles University, 500 05 Hradec Kralove, Czech Republic
e-mail: jamp@faf.cuni.cz, tel.: +420-49-5067375, fax: +420-49-5512423
2 Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, 500 05 Hradec Kralove, Czech Republic
3 Institute of Chemistry, Faculty of Natural Sciences, Comenius University, 842 15 Bratislava, Slovak Republic
* Author to whom correspondence should be addressed.

Abstract: Condensation of substituted pyrazine-2-carboxylic acids chlorides with ring-substituted amines yielded a series of amides of pyrazine-2-carboxylic or 6-chloropyrazine-2-carboxylic, 5-tert-butylpyrazine-2-carboxylic or 5-tert-butyl-6-chloropyrazine-2-carboxylic acids, respectively. Products were tested for their photosynthesis-inhibiting activity. The most active inhibitor of oxygen evolution rate in spinach chloroplasts was 5-tert-butyl-6-chloropyrazine-2-carboxylic acid thiazol-2-ylamide (IC50 = 0.0495 mmol dm-3).

Keywords: Substituted amides of pyrazin-2-carboxylic acid; Photosynthesis inhibition; Spinach chloroplasts

Introduction

Various compounds possessing -NHCO- moiety were found to inhibit photosynthetic electron transport [1-4]. Amides of 2-alkylpyridine-4-carboxylic [5,6], 2-alkylsulfanylpyridine-4-carboxylic [6,7] acids inhibited oxygen evolution rate in Chlorella vulgaris and their inhibitory activity depended on the lipophilicity of the compounds. Several esters of alkoxy substituted phenylcarbamic acids showed the antialgal activity against Chlorella vulgaris [8-10]. We have recently reported the synthesis of a series of amides prepared from the substituted pyrazine-2-carboxylic acids and some aminophenols [11], halogenated and alkylated anilines [12-15]. All these amides possess some antialgal, antifungal, and antimycobacterial properties [12,14,16].

The presented study is concerned in the synthesis of another series of heterocyclic amides prepared from substituted pyrazine-2-carboxylic acids and 2-aminothiazole, 2-amino-4-methyl- or 2-amino-5-methylthiazole, respectively and 2-bromoaniline or 2,6-dibromo-4-aminophenol, respectively. Thiazol-2-ylamide pyrazine-2-carboxylic acid (2a) was prepared by Kushner [17] firstly, and tested on its antimycobacterial activity only. The aim of this work is to search for the structure-activity relationships in the mentioned series, i.e. to continue in studying of the substituent variability influence on the biological activity, and to determine the importance of increased hydrophobic properties for photosynthesis-inhibiting evaluation of newly prepared substituted pyrazine-2-carboxamides.

Results and Discussion

The synthesis of amides is shown in Scheme 1. Condensation of chlorides of pyrazine-2-carboxylic [18], 6-chloropyrazine-2-carboxylic [19], 5-tert-butylpyrazine-2-carboxylic [11] or 6-chloro-5-tert-butylpyrazine-2-carboxylic [11] acids with ring-substituted anilines and 2-aminothiazoles yielded a series of 18 amides of pyrazine-2-carboxylic acids 2a-r. The melting points, yields, and the IR, 1H and 13C NMR spectral data for the all compounds prepared are given in Experimental. Calculated log P values of all derivatives studied are shown in Table 1.

Scheme 1: Synthesis of some substituted pyrazine-2-carboxamides 2a-r

Sixteen studied compounds (two compounds 2a, 2c were not tested on their inhibition activity due to their low solubility in DMSO) inhibited photosynthetic electron transport in spinach chloroplasts (see Table 1). The IC50 values varied in the range from 49.5 (2d) to 1589 µmol dm-3 (2b). The inhibitory activity of the studied compounds was relatively low, the most efficient inhibitors were compounds 2h (IC50 = 88.8 µmol dm-3) and mainly 2d (IC50 = 49.5 µmol dm-3).

For series 2e-h and 2i-l the biological activity showed linear increase with increasing lipophilicity of the compounds within these series. In both series of anilides 2m-o and 2p-r, for the most lipophilic compounds (2o (log P = 4.63) and 2r (log P = 5.28)) significant activity decrease was observed. Substitution in the position 5' of the thiazole ring was less advantageous than in the position 4' or without a thiazole ring substitution. Results from the previous observation have exposed on the importance of phenolic moiety for the photosynthesis-inhibiting activity in the previously studied pyrazine-2-carboxamides [11,20]. However, the biological activity of compounds 2p-r was lower than that of compounds 2m-o. We assume that this activity decrease was connected with increased lipophilicity of the compounds due to the presence of two bromine atoms.

The addition of diphenylcarbazide (an artificial electron donor acting in the intermediate Z+/D+ on the donor side of photo system II [21]) to spinach chloroplasts inhibited by 2d caused complete restoration of the photosynthetic electron transport. This indicates that the primary donor of PS II (P680) was not be damaged by this compound. Previous EPR experiments with some amides of pyrazin-2-carboxylic acid showed that the site of action of these compounds in the photosynthetic apparatus of spinach chloroplasts is intermediate D2 on the donor side of photo system II [22].

Experimetal

General

All organic solvents used for the synthesis were of analytical grade. The solvents were dried and freshly distilled under argon atmosphere. TLC was performed on Silufol UV 254 plates (Kavalier, Votice, Czech Republic) in the following solvent system: acetone/toluene (1:1). The spots were detected in UV (254 nm). Melting points were determined on Boetius PHMK 05 (VEB Kombinat Nagema, Radebeul, Germany). Infrared spectra were recorded in KBr pellets on an IR-spectrometer Nicolet Impact 400. 1H and 13C NMR Spectra were recorded on a Varian Mercury – Vx BB 300 (299.95 MHz for 1H and 75.43 MHz for 13C), Varian (Palo Alto CA, USA). Chemical shifts are given relative to internal Si(CH3)4. Log P values were computed using the program CS ChemOffice Ultra ver. 7.0 (CambridgeSoft, Cambridge MA, USA).

Synthesis of amides 2a-r

A mixture of acid, i.e. pyrazine-2-carboxylic [18], 6-chloropyrazine-2-carboxylic [19], 5-tert-butylpyrazine-2-carboxylic [11] or 5-tert-butyl-6-chloropyrazine-2-carboxylic [11] acids, respectively, (50.0 mmol) and thionyl chloride (5.5 mL, 75.0 mmol) in 20 mL of dry toluene was refluxed for about 1 h. Excess of thionyl chloride was removed by repeated evaporation with dry toluene in vacuo. The crude acyl chloride dissolved in 50 mL of dry acetone was added drop wise to a stirred solution of the corresponding substituted amine (50.0 mmol) in 50 mL of dry pyridine keeping at the room temperature. After the addition was complete, stirring continued for another 30 min. The reaction mixture was then poured into 100 mL of cold water and the crude amide was collected and recrystallized from aqueous ethanol.

Pyrazine-2-carboxylic acid thiazol-2-ylamide (2a). Yield: 88 %, m.p. 187-188 °C (Ref. [17]: m.p. 187-189 °C), RF = 0.43. IR spectrum (KBr), cm-1: 3432 (N-H), 1668 (C=O). 1H NMR (300 MHz, CDCl3), δ: 11.14 (bs, 1H, NH), 9.52 (d, 1H, J = 1.79 Hz, H3), 8.86 (d, 1H, J = 1.79 Hz, H6), 8.65-8.63 (m, 1H, H5), 7.55 (d, 1H, J = 3.57 Hz, H4'), 7.09 (d, 1H, J = 3.57 Hz, H5'). 13C NMR (75 MHz, CDCl3), δ: 160.7, 157.3, 148.3, 144.9, 143.0, 142.7, 138.2, 114.3.

6-Chloropyrazine-2-carboxylic acid thiazol-2-ylamide (2b). Yield: 98 %, m.p. 153-155 °C, RF = 0.65. IR spectrum (KBr), cm-1: 3435 (N-H), 1675 (C=O). 1H NMR (300 MHz, DMSO-d6), δ: 10.91 (bs, 1H, NH), 9.17 (s, 1H, H3), 7.59 (d, 1H, J = 3.57 Hz, H4'), 7.36 (d, 1H, J = 3.57 Hz, H5'), 1.50 (s, 9H, CH3). 13C NMR (75 MHz, DMSO-d6), δ: 163.6, 161.5, 158.2, 145.8, 141.7, 140.9, 137.7, 114.8, 38.8, 28.2.

5-tert-Butylpyrazine-2-carboxylic acid thiazol-2-ylamide (2c). Yield: 45 %, m.p. 131-132 °C, RF = 0.63. IR spectrum (KBr), cm-1: 3432 (N-H), 1676 (C=O). 1H NMR (300 MHz, CDCl3), δ: 11.02 (bs, 1H, NH), 9.39 (d, 1H, J = 1.37 Hz, H3), 8.66 (d, 1H, J = 1.38 Hz, H6), 7.54 (d, 1H, J = 3.58 Hz, H4'), 7.07 (d, 1H, J = 3.57 Hz, H5'), 1.45 (s, 9H, CH3). 13C NMR (75 MHz, CDCl3), δ: 168.8, 161.0, 157.4, 143.2, 139.7, 139.7, 138.1, 114.2, 37.2, 29.7.

5-tert-Butyl-6-chloropyrazine-2-carboxylic acid thiazol-2-ylamide (2d). Yield: 97 %, m.p. 148-150 °C, RF = 0.88. IR spectrum (KBr), cm-1: 3448 (N-H), 1675 (C=O). 1H NMR (300 MHz, DMSO-d6), δ: 12.49 (bs, 1H, NH), 9.17 (s, 1H, H3), 7.59 (d, 1H, J = 3.6 Hz, H4'), 7.36 (d, 1H, J = 3.6 Hz, H5'), 1.50 (s, 9H, CH3). 13C NMR (75 MHz, DMSO-d6), δ: 163.6, 161.5, 158.2, 145.8, 141.7, 140.9, 137.7, 114.8, 38.8, 28.2.

Pyrazine-2-carboxylic acid (4-methylthiazol-2-yl)amide (2e). Yield: 67 %, m.p. 144-145 °C, RF = 0.50. IR spectrum (KBr), cm-1: 3433 (N-H), 1670 (C=O). 1H NMR (300 MHz, DMSO-d6), δ: 12.27 (bs, 1H, NH), 9.20 (d, 1H, J = 1.0 Hz, H3), 8.95 (d, 1H, J = 1.0 Hz, H6), 7.88 (m, 1H, H5), 6.90 (d, 1H, J = 1.0 Hz, H5'), 2.40 (s, 3H, J = 1.0 Hz, CH3). 13C NMR (75 MHz, DMSO-d6), δ: 164.0, 163.6, 148.0, 147.8, 147.5, 145.6, 139.7, 111.2, 17.7.

6-Chloropyrazine-2-carboxylic acid (4-methylthiazol-2-yl)amide (2f). Yield: 97 %, m.p. 192-194 °C, RF = 0.74. IR spectrum (KBr), cm-1: 3434 (N-H), 1675 (C=O). 1H NMR (300 MHz, DMSO-d6), δ: 12.54 (bs, 1H, NH), 9.23 (s, 1H, H3), 9.04 (s, 1H, H5), 6.90 (d, 1H, J = 1.0 Hz, H5'), 2.30 (d, 3H, J = 1.0 Hz, CH3). 13C NMR (75 MHz, DMSO-d6), δ: 162.0, 158.3, 147.9, 147.5, 145.9, 144.5, 142.8, 109.0, 16.7.

5-tert-Butylpyrazine-2-carboxylic acid (4-methylthiazol-2-yl)amide (2g). Yield: 33 %, m.p. 84-85 °C, RF = 0.69. IR spectrum (KBr), cm-1: 3434 (N-H), 1676 (C=O). 1H NMR (300 MHz, DMSO-d6), δ: 12.22 (bs, 1H, NH), 9.20 (d, 1H, J = 1.5 Hz, H3), 8.89 (d, 1H, J = 1.5 Hz, H6), 6.90 (d, 1H, J = 1.0 Hz, H5'), 2.30 (d, 3H, J = 1.0 Hz, CH3), 1.39 (s, 9H, CH3). 13C NMR (75 MHz, DMSO-d6), δ: 167.5, 162.3, 157.0, 147.1, 142.9, 141.4, 140.7, 109.0, 37.1, 29.6, 17.0.

5-tert-Butyl-6-chloropyrazine-2-carboxylic acid (4-methylthiazol-2-yl)amide (2h). Yield: 97 %, m.p. 118-120 °C, RF = 0.91. IR spectrum (KBr), cm-1: 3451 (N-H), 1675 (C=O). 1H NMR (300 MHz, DMSO-d6), δ: 12.47 (bs, 1H, NH), 9.15 (s, 1H, H3), 6.89 (d, 1H, J = 1.0 Hz, H5'), 2.30 (d, 3H, J = 1.0 Hz, CH3), 1.49 (s, 9H, CH3). 13C NMR (75 MHz, DMSO-d6), δ: 163.5, 161.7, 146.2, 145.8, 142.1, 141.8, 140.8, 108.9, 38.7, 28.2, 16.8.

Pyrazine-2-carboxylic acid (5-methylthiazol-2-yl)amide (2i). Yield: 66 %, m.p. 247-248 °C, RF = 0.42. IR spectrum (KBr), cm-1: 3435 (N-H), 1672 (C=O). 1H NMR (300 MHz, DMSO-d6), δ: 12.46 (bs, 1H, NH), 9.20 (d, 1H, J = 1.65 Hz, H3), 8.91 (d, 1H, J = 1.65 Hz, H6), 8.73-8.70 (m, 1H, H5), 7.28 (s, 1H, H4'), 2.38 (s, 3H, CH3). 13C NMR (75 MHz, DMSO-d6), δ: 163.0, 158.3, 148.0, 147.8, 147.5, 143.9, 136.8, 127.4, 11.5.

6-Chloropyrazine-2-carboxylic acid (5-methylthiazol-2-yl)amide (2j). Yield: 98 %, m.p. 214-215 °C, RF = 0.79. IR spectrum (KBr), cm-1: 3436 (N-H), 1672 (C=O). 1H NMR (300 MHz, DMSO-d6), δ: 12.56 (bs, 1H, NH), 9.24 (s, 1H, H3), 9.05 (s, 1H, H5), 7.27 (s, 1H, H4'), 2.39 (s, 3H, CH3). 13C NMR (75 MHz, DMSO-d6), δ: 161.7, 157.1, 147.9, 147.5, 144.5, 142.8, 134.1, 127.4, 11.5.

5-tert-Butylpyrazine-2-carboxylic acid (5-methylthiazol-2-yl)amide (2k). Yield: 33 %, m.p. 114-116 °C, RF = 0.80. IR spectrum (KBr), cm-1: 3435 (N-H), 1677 (C=O). 1H NMR (300 MHz, DMSO-d6), δ: 12.12 (bs, 1H, NH), 9.20 (s, 1H, H3), 8.88 (s, 1H, H6), 7.24 (s, 1H, H4'), 2.38 (s, 3H, J = 1.0 Hz, CH3), 1.39 (s, 9H, CH3). 13C NMR (75 MHz, DMSO-d6), δ: 167.5, 162.0, 155.8, 142.9, 141.4, 140.6, 135.2, 127.6, 37.1, 29.6, 11.4.

5-tert-Butyl-6-chloropyrazine-2-carboxylic acid (5-methylthiazol-2-yl)amide (2l). Yield: 98 %, m.p. 152-153 °C, RF = 0.85. IR spectrum (KBr), cm-1: 3453 (N-H), 1678 (C=O). 1H NMR (300 MHz, DMSO-d6), δ: 12.45 (bs, 1H, NH), 9.15 (d, 1H, J = 0.5 Hz, H3), 7.27-7.24 (m, 1H, H4'), 2.38 (d, 3H, J = 0.5 Hz, CH3), 1.49 (s, 9H, CH3). 13C NMR (75 MHz, DMSO-d6), δ: 163.4, 161.4, 156.7, 145.8, 141.8, 140.8, 134.4, 127.4, 38.7, 28.2, 11.4.

6-Chloropyrazine-2-carboxylic acid (2-bromophenyl)amide (2m). Yield: 24 %, m.p. 118-119 °C. IR spectrum (KBr), cm-1: 3436 (N-H), 1701 (C=O). 1H NMR (300 MHz, CDCl3), δ: 10.11 (bs, 1H, NH), 9.39 (d, 1H, J = 0.55 Hz, H3), 8.83 (d, 1H, J = 0.55 Hz, H5), 8.55 (dd, 1H, J = 1.65 Hz, H6'), 7.61 (dd, 1H, J = 7.97 Hz, J = 1.37 Hz, H3'), 7.43-7.35 (m,1H, H5'). 13C NMR (75 MHz, CDCl3), δ: 159.5, 147.8, 147.6, 143.8, 142.1, 135.0, 132.6, 128.5, 126.0, 121.6,114.1.

5-tert-Butylpyrazine-2-carboxylic acid (2-bromophenyl)amide (2n). Yield: 20 %, m.p. 83-84 °C. IR spectrum (KBr), cm-1: 3439 (N-H), 1693 (C=O). 1H NMR (300 MHz, CDCl3), δ: 10.35 (bs, 1H, NH), 9.39 (d, 1H, J = 1.37 Hz, H3), 8.71 (d, 1H, J = 1.65 Hz, H6), 8.62 (dd, 1H, J = 8.24 Hz, J = 1.65 Hz, H6'), 7.59 (dd, 1H, J = 8.25 Hz, J = 1.65 Hz, H3'), 7.42-7.34 (m, 1H, H4'), 7.03 (dt, 1H, J = 7.42 Hz, J = 1.65 Hz, H5'), 1.45 (s, 9H, CH3). 13C NMR (75 MHz, CDCl3), δ: 168.0, 161.3, 143.0, 141.3, 139.4, 135.5, 132.5, 128.4, 125.4, 121.4, 113.8, 37.1, 29.7.

5-tert-Butyl-6-chloropyrazine-2-carboxylic acid (2-bromophenyl)amide (2o). Yield: 17 %, m.p. 116-117 °C. IR spectrum (KBr), cm-1: 3435 (N-H), 1701 (C=O). 1H NMR (300 MHz, CDCl3), δ: 10.11 (bs, 1H, NH), 9.39 (s, 1H, H3), 8.83 (s, 1H, H5), 8.55 (dd, 1H, J = 8.24 Hz, J = 1.37 Hz, H6'), 7.61 (dd, 1H, J = 8.24 Hz, J = 1.37 Hz, H3'), 7.43-7.35 (m, 1H, H4'), 7.09-7.03 (m, 1H, H5'). 13C NMR (75 MHz, CDCl3), δ: 159.8, 148.0, 147.9, 144.1, 142.3, 135.2, 132.8, 128.7, 126.2, 121.8, 114.4, 37.0, 29.7.

6-Chloropyrazine-2-carboxylic acid (3,5-dibromo-4-hydroxyphenyl)amide (2p). Yield: 14 %, m.p. 191-193 °C. IR spectrum (KBr), cm-1: 3432 (N-H), 1685 (C=O). 1H NMR (300 MHz, CDCl3), δ: 10.74 (bs, 1H, NH), 9.86 (bs, 1H, OH), 9.20 (d, 1H, J = 0.55 Hz, H3), 9.05 (d, 1H, J = 0.5 Hz, H5), 8.13 (s, 2H, H2', H6'). 13C NMR (75 MHz, CDCl3), δ: 160.8, 147.8, 147.8, 147.1, 144.8, 142.5, 132.4, 124.7, 111.8.

5-tert-Butylpyrazine-2-carboxylic acid (3,5-dibromo-4-hydroxyphenyl)amide (2q). Yield: 24 %, m.p. 206-208 °C. IR spectrum (KBr), cm-1: 3432 (N-H), 1695 (C=O). 1H NMR (300 MHz, CDCl3), δ: 9.38 (d, 1H, J = 0.55 Hz, H3), 9.29 (bs, 1H, NH), 8.83 (d, 1H, J = 0.55 Hz, H5), 7.96 (s, 2H, H2', H6'), 5.84 (s, 1H, OH), 1.48 (s, 9H, CH3). 13C NMR (300 MHz, CDCl3), δ: 168.7, 161.5, 161.1, 143.3, 139.3, 139.1, 137.5, 123.4, 117.8, 37.4, 29.9.

5-tert-Butyl-6-chloropyrazine-2-carboxylic acid (3,5-dibromo-4-hydroxyphenyl)amide (2r). Yield: 20 %, m.p. 216-217 °C. IR spectrum (KBr), cm-1: 3432 (N-H), 1685 (C=O). 1H NMR (300 MHz, CDCl3), δ: 9.31 (bs, 1H, NH), 9.24 (d, 1H, J = 0.55 Hz, H3), 8.03 (s, 2H, H2', H6'), 5.71 (s, 1H, OH), 1.49 (s, 9H, CH3). 13C NMR (75 MHz, CDCl3), δ: 161.2, 159.0, 147.8, 144.8, 142.7, 139.8, 132.2, 124.7, 112.1, 31.7, 29.7.

Study of inhibition of oxygen evolution rate in spinach chloroplasts

The inhibition of oxygen evolution rate (OER) in spinach chloroplasts by the studied compounds was investigated spectrophotometrically (Specord UV VIS, Zeiss, Jena) in the presence of an electron acceptor 2,6-dichlorophenol-indophenol, using method described in Ref. [23]. The compounds were dissolved in DMSO because of their low water solubility. The used DMSO volume fractions (up to 5 vol. %) did not affect the oxygen evolution. The inhibitory efficiency of the studied compounds has been expressed by IC50 values, i.e. by molar concentration of the compounds causing 50 % decrease in the oxygen evolution relative to the untreated control. Comparable IC50 value for a selective herbicide atrazine [24] is about 1.0 µmol.dm-3.

Table 1: OER inhibition in spinach chloroplasts (IC50) and calculated lipophilicity (log P) of compounds 2a-r in comparison with standard (atrazine).
Compound X R1 R2 Log P IC50 (mmol.dm-3)
2a H H H 0.31 a
2b Cl H H 1.21 1.589
2c H (CH3)3C H 2.44 a
2d Cl (CH3)3C H 3.34 0.0495
2e H H 4-CH3 1.01 0.5828
2f Cl H 4-CH3 1.91 0.4855
2g H (CH3)3C 4-CH3 3.14 0.1806
2h Cl (CH3)3C 4-CH3 4.04 0.0888
2i H H 5-CH3 0.65 0.8622
2j Cl H 5-CH3 1.55 0.4537
2k H (CH3)3C 5-CH3 2.77 0.3114
2l Cl (CH3)3C 5-CH3 3.67 0.2190
2m Cl H 2-Br 2.94 0.3338
2n H (CH3)3C 2-Br 3.51 0.1707
2o Cl (CH3)3C 2-Br 4.63 0.3154
2p Cl H 3,5-Br, 4-OH 3.59 0.9952
2q H (CH3)3C 3,5-Br, 4-OH 4.16 0.4043
2r Cl (CH3)3C 3,5-Br, 4-OH 5.28 0.5903
atrazine --- --- --- 1.03 0.001
a not tested due to their low solubility in DMSO

Acknowledgements. This study was supported by the Ministry of Education of the Czech Republic (FRVS 2998/G6/2003, FRVS 2997/G6/2003 and MSM 111600001) and by the Slovak Scientific Grant Agency VEGA (No. 1/0089/03). We also thank Mrs. J. Zizkova, and Mr. T. Vojtisek from the Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Czech Republic, for their technical assistance and Dr. D. Mikulasova from the Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic, for her assistance in the preparation of chloroplasts.

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