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Synthesis, Antibacterial Activity and DFT Calculation of Naphtopyrano, Furo and Pyrazolo [3,2,e] [1,2,4]Triazolo-[1,5-c]Pyrimidine Derivatives

  • Dhiab JabliEmail author
  • Rim Milad
  • Manef Abderrabba
  • Mohamed Lotfi Efrit
Open Access
Original Article
  • 67 Downloads

Abstract

A new series of 3N-substituted triazolo-[1,5-c]pyrimidine 7, 8 and 9 have been synthesized in good yields (78–91%) trough a facile method using substituted 2-amino-3-cyano-pyrans 1, 2-amino-3-cyano-4-methylfuran 2, 1-Phenyl-3-thiomethyl-5-aminopyrazole-4-carbonitrile 3 as building block and cyanoacetic acid hydrazide as reagent in one framework. The structure of the synthesized compounds was established on the basis of their mass, spectral data and DFT at B3LYP.

Graphic Abstract

Keywords

Naphthopyranotriazolopyrimidines phosphonates Aminopyrazole α-Fonctionalized iminoethers and pyrimidine 

1 Introduction

Pyrano, furano and pyrazolopyrimidine are priviliged structures, which attracted considerable attention in the designing of biologically active molecules. Pyranotriazolopyrimidine derivatives have attracted a great deal of interest due to their biological activities and their potential applications as pharmacological agents. Several derivatives of the pyranotriazolopyrimidine exhibit platelet anti-aggregating activity and local “inhibition of influenza, virus sialidase and mutagenic activity [1], anti-genotoxic activity [2], antimicrobial activity [3], AChE or acetylhydrolase inhibition [4], and antifungal [5, 6]”. Moreover pyranotriazolopyrimidine derivatives are well known antigenotoxic, [7] and in the agrochemical field, showing herbicidal activity [8]. Among these heterocyclic, the furopyrimidine derivatives are an important class of heterocyclic compounds in pharmaceutical discovery research such that antiphlogistic activity [9], antibacterial [5], anti-inflammatory [10], and herbicidal activities [11]. Recently, some furopyrimidines were shown to be potent VEGFR2 and EGFR [12]. Furthermore, 1,2,4-triazolopyrimidines derivatives has received considerable attention among synthetic chemists because molecules bearing this structural feature have been found to display a wide range of potent biological activities in medicinal chemistry, as antibacterial, antifungal, [13, 14] antiplatelet, antithrombotic, [15] anti-inflammatory and analgesic agents, [16] and in the agrochemical field, showing herbicidal activity [8]. According to these encouraging results and as a continuation of our interest works on heterocyclic compounds related to (pyrano, furano and pyrzolo)pyrimidines [17, 18], we wish to report herein the synthesis of new pyranotriazolopyrimidine 7, furanotriazolopyrimidine 8 and pyrazolotriazolopyrimidine 9 in the hope of obtaining compounds of diverse biological activities. Hence a facile method has been attempted by incorporating triazole and pyrimidine rings with substituted 2-amino-3-cyano-pyrans 1, 2-amino-3-cyano-4-methylfuran 2, 1-Phenyl-3-thiomethyl-5-aminopyrazole-4-carbonitrile 3, as building block in one framework (Scheme 1). Also, the compounds were investigated theoretically by density functional theory DFT and time-dependant density functional theory TD-DFT. (TDDFT) extends the basic thoughts of ground-state density-functional theory (DFT) to the treatment of excitations or more general time-dependent phenomena [19, 20].
Scheme 1

General reactions

2 Experimental Methods

2.1 General

Solvents and reagents were obtained from commercial sources and were dried and purified when necessary by standard techniques. Melting points were taken with a Kofler hot staged apparatus and are uncorrected. All reactions were monitored by thin layer chromatography (TLC) using precoated aluminium sheet silica gel Merck 60 F 254 and was visualized by UV lamp. IR spectra were carried out in the liquid state dissolved in chloroform with Perkin Elmer Paragon 1000 PC spectrometer or in solid state dispersion in KBr with a Perkin Elmer 1600 series FT-IR spectrometer. 1H and 13C NMR spectra were recorded on a Varian-Unity spectrometer at 300 MHz (300 MHz and 75 MHz, respectively) using TMS as an internal standard. Chemical shifts of protons were reported in parts per million (ppm) downfield from TMS. Coupling constants are reported in Hertz (Hz). Elemental analyses were determined using an elementar vario EI III Elemental Analyser.

2.1.1 Synthesis of Cyanoacetic Acid Hydrazide

Cyanoacetic acid hydrazide was obtained according to the published method in literature [26] by careful addition of 9.91 g (0.10 mol) of ethyl cyanoacetate to hydrazine hydrate (5.00 g, 0.10 mol) with stirring at room temperature. The formed cyanoacetic acid hydrazide was filtered, washed with Et2O, and dried (Mp: 108–110 °C. Yield: 90%).

2.1.2 Synthesis of 2-Amino-4-Aryl-3-Cyano-4H-Naphto-[2,1-b]-Pyrans 1

The required naphto[2,1-b]pyrans 1 were obtained using known experimental procedures developed previously by Messaâd et al. [21, 22]. Following this typical experiment, a mixture of 2-naphtol (0.01 mmol, 1.5 g) and arylalkylidenmalononitrile (0.01 mmol, 1.7 g) in ethanol (30 mL) was refluxed for 10 h with the presence of (0.2 equivalent) of piperidine. The solvent was evaporated to dryness under reduced pressure. The solid was collected by filtration and purified by recrystallization from toluene (Scheme 2).
Scheme 2

Synthesis of starting materials 4, 5 and 6

2.1.2.1 2-Amino-3-Cyano-4-(p-Chlorophenyl)-4H-Naphto-[2,1-b]-Pyran 1a [21, 22]

Yield: 68%; Mp: 231 °C. IR (νmax, cm−1): 3412, 3331, 2178 cm−1. 1H NMR (300 MHz, DMSO-d6 + CDCl3) δ: 7.11–7.95 (m, 10H), 6.87 (br, s, 2H), 5.09 (s, 1H).

2.1.2.2 2-Amino-3-Cyano-4-(3,4-Dichlorophenyl)-4H-Naphto-[2,1-b]-Pyran 1b [21, 22]

Yield: 72%. Mp: 219 °C. IR (νmax, cm−1): 3417, 3321, 2193 cm−1. 1H NMR (300 MHz, DMSO-d6 + CDCl3) δ: 7.40 (br, s, 2H), 7.18–8.04 (m, 9H), 5.16 (s, 1H).

2.1.3 Synthesis of 2-Amino-3-Cyano-4-Methylfuran 2

Acetol (3.7 g, 50 mmol) was dissolved in methanol (20 mL) with stirring under an atmosphere of nitrogene and a mixture of malononitrile (3.5 g, 53 mmol) and triethylamine (6.96 mL, 0 mmol) in methanol (25 mL) was added slowly drop-wise at such as rate as to maintain the reaction temperature below 0 °C. After, the reaction mixture was diluted with water (50 mL) and extracted with methylene chloride (2 × 50 mL). The organic layers were combined, dried (MgSO4) and condensed to a brown solid. Recrystalysed from ethyl acetate-hexane gave 2.

2.1.3.1 2-Amino-3-Cyano-4-Methylfuran 2 [23]

Yield: 61%. Mp: 158–159 °C. IR (νmax, cm−1): νNH2 = 3345–3451; νCN = 2210; νC=C = 1591. 1H-NMR (300 MHz, DMSO-d6) δ 6.49 (s, 1H, =CH), 5.76 (br, s, 2H, NH2), 2.12 (s, 3H, CH3). 13C-NMR (75 MHz, DMSO-d6) δ: 20.2, 24.1, 29.3, 120.4, 127.3, 129.8.

2.1.4 Synthesis of 5-Amino-3-(Methylthio)-1-Phenyl-1H-Pyrazole-4-Carbonitrile 3 [26]

To a mixture of (0.03 mol) of 2-(bis-methylsulfanylmethylene)malononitrile and (0.03 mol) of phenyl hydrazine in (20 mL) ethanol were added drop wise with stirring a solution of diethyl amine or morpholine (2 mL) in ethanol (5 mL). When addition was completed; the mixture was stirred at a temperature of 80 °C to reflux for 9 h. The heating and stirring were still left 1 h. The remaining solids were recrystallized from isopropanol to produce the pure compound 3 (Scheme 1).

2.1.4.1 1-Phenyl-3-(Methylthio)-5-Aminopyrazole-4-Carbonitrile 3

Yield: 81%. Mp: 134–136 °C, 1H-NMR (300 MHz, DMSO-d6 +CDCl3): δ: 7.36–7.68 (m, 5H, Ph), 6.21 (br s, 2H, NH2), 2.67 (s, 3H, SCH3).

2.1.5 Synthesis of Iminoethers 4, 5 and 6 [28, 29, 30]

A mixture of compounds 1, 2 and 3 (5 mmol) and excess of ethyl orthoester (10 mL) was heated under reflux for 4–10 h in the presence of few drops of glacial acetic acid. After removing liberated ethanol and excess of ethyl orthoester under vacuum, we get either a solid that was purified by recrystallization (EtOH) or an oil which was distilled under reduced pressure.

2.1.5.1 N-[1-(4-Chloro-Phenyl)-2-Cyano-1H-Benzo[f]chromen-3-yl]-Acetimidic Acid Ethyl Ester 4a

Yield: 60%; Mp 109–111 °C; IR (νmax, cm−1) 2200 (C≡N), 1658 (C=N). 1H NMR (300 MHz, DMSO-d6) δ: 7.19–7.85 (m, 10H, Ar–H); 5.32 (s, 1H), 4.31 (q, 3J = 7.2 Hz, 2H, OCH2CH3), 2.11 (s, 3H, CH3), 1.37 (t, 3J = 7.2 Hz, 3H, OCH2CH3). 13C NMR (75 MHz, DMSO-d6) δ: 16.2, 20.1, 25.3, 32.4, 102.6, 110.4, 110.4, 111.9, 111.8, 112.1, 112.8, 116.7, 120.8, 121.0, 131.6, 134.6, 137.5, 141.8, 143.9, 145.4, 148.6, 153.3, 157.3, 163.1.

2.1.5.2 N-[1-(4-Chloro-Phenyl)-2-Cyano-1H-Benzo[f]chromen-3-yl]-Propiomidic Acid Ethyl Ester 4b

Yield: 95%; Mp 108 °C; IR (νmax, cm−1) 2203 (C≡N), 1652 (C=N). 1H NMR (300 MHz, DMSO-d6 +CDCl3) δ: 7.17–7.84 (m, 9H, Ar–H); 5.32 (s, 1H), 4.31 (q, 3J = 7.2 Hz, 2H, OCH2CH3) 2.39 (q, 3J = 7.2 Hz, 2H, CH2CH3), 1.36 (t, 3J = 7.2 Hz, 3H, OCH2CH3), 1.20 (t, 3J = 7.2 Hz, 3H, CH2CH3). 13C NMR (75 MHz, DMSO-d6) δ: 17.3, 21.2, 26.4, 32.3, 102.4, 111.6, 111.6, 112.4, 112.4, 113.2, 113.8, 116.5, 121.1, 122.0, 131.4, 133.5, 138.3, 142.4, 143.9, 146.2, 148.7, 154.6, 157.3, 164.2.

2.1.5.3 N-[2-(4-Cyano-1-(3,4-Dichloro-Phenyl)-1H-Benzo[f]chromen-3-yl]-Acetimidic Acid Ethyl Ester 4c

Yield: 60%; Mp 114–115 °C; IR (νmax, cm−1) 2214 (C≡N), 1662 (C=N). 1H NMR (300 MHz, CDCl3) δ: 7.13–7.62 (m, 10H, Ar–H), 5.23 (s, 1H), 4.13 (q, 3J = 7.2 Hz, 2H, OCH2CH3), 2.08 (s, 3H, CH3), 1.41 (t, 3J = 7.2 Hz, 3H, OCH2CH3). 13C NMR (75 MHz, CDCl3) δ: 17.8, 23.1, 27.1, 34.1, 102.5, 111.7, 111.7, 113.1, 113.1, 113.1, 113.9, 115.6, 123.2, 123.7, 132.8, 137.3, 140.0, 142.7, 144.9, 147.2, 150.2, 153.6, 158.1, 164.1.

2.1.5.4 N-[2-(4-Cyano-1-(3,4-Dichloro-Phenyl)-1H-Benzo[f]chromen-3-yl]-Propiomidic Acid Ethyl Ester 4d

Yield: 95%; Mp 116 °C; IR (νmax, cm−1) 2212 (C≡N), 1659 (C=N). 1H NMR (300 MHz, DMSO-d6 + CDCl3) δ: 7.23–7.76 (m, 9H, Ar–H); 5.17 (s, 1H), 4.23 (q, 3J = 7.2 Hz, 2H, OCH2CH3), 2.41 (q, 3J = 7.2 Hz, 2H, CH2CH3), 1.31 (t, 3J = 7.2 Hz, 3H, OCH2CH3), 1.18 (t, 3J = 7.2 Hz, 3H, CH2CH3). 13C NMR (75 MHz, DMSO-d6 +CDCl3) δ: 18.1, 23.2, 27.2, 32.5, 103.0, 110.7, 110.7, 112.3, 112.3, 112.7, 112.7, 115.6, 121.3, 121.9, 132.1, 133.4, 137.6, 144.6, 145.9, 148.2, 150.4, 154.4, 158.2, 165.7.

2.1.5.5 N-(3-Cyano-4-Methyl-Furan-2-yl)-Acetimidic Acid Ethyl Ester 5a

Yield: 82%. Mp: 87–88 °C. IR (CHCl3): 2214, 1645 cm−1. 1H-NMR (300 MHz, DMSO-d6) δ: 7.08 (s, 1H), 4.13 (q, J = 7.2 Hz, 2H, OCH2CH3), 2.13 (m, 6H, CH3), 1.37 (s, 3H). 13C-NMR (75 MHz, DMSO-d6) δ: 18.1, 22.3, 26.7, 60.3, 116.8, 125.2, 128.6, 140.1, 150.3, 165.7.

2.1.5.6 N-(3-Cyano-4-Methyl-Furan-2-yl)-Propiomidic Acid Ethyl Ester 5b

Yield: 82%. Mp: 108–109 °C. IR (CHCl3): 2214 and 1645 cm−1. 1H-NMR (300 MHz, DMSO-d6) δ: 6.76 (s, 1H), 3.87 (q, J = 7.2 Hz, 4H, CH2), 2.34 (s, 3H, CH3), 1.41 (t, 6H). 13C-NMR (75 MHz, DMSO-d6) δ: 16.6, 16.8, 22.3, 30.3, 62.6, 115.7, 123.5, 128.3, 141.3, 151.7, 165.9.

2.1.5.7 N-(4-Cyano-5-Methylsulfanyl-2-Phenyl-2H-Pyrazol-3-yl)-Acetimidic Acid Ethyl Ester 6a

Yield: 81%, Mp: 94 °C, 1H-NMR (CDCl3): δ = 7.26–7.74 (m, 5H, Ph), 4.13 (q, 2H, O–CH2–CH3), 3.31 (s, 3H, –SCH3), 3.23 (q, 3H, O–CH2–CH3). 1.31 (s, 3H, CH3).13C-NMR (75 MHz, DMSO-d6 + CDCl3): 18.35, 25.26, 42.31, 103.31, 113.2, 113.6, 113.85, 115.59, 126.7, 126.9, 137.15, 140.12; 140.7, 148.05; 151.38.

2.1.5.8 N-(4-Cyano-5-Methylsulfanyl-2-Phenyl-2H-Pyrazol-3-yl)-Propiomidic Acid Ethyl Ester 6b

Yield: 81%, Mp: 102 °C, 1H-NMR (300 MHz, DMSO-d6 + CDCl3): δ = 7.26–7.74 (m, 5H, Ph), 4.26 (q, 2H, O–CH2–CH3), 2.46–2.50 (s, 3H, –SCH3), 2.6 (s, 3H, –CH3), 2.21 (m, 2H, –CH2–CH3), 1.36 (m, 6H, –CH3). 13C-NMR (75 MHz, DMSO-d6 + CDCl3): 17.17, 18.24, 24.38, 42.52, 102.63, 113.47, 113.76, 113.87, 115.71, 125.8, 126.0, 138.23, 141.31; 141.73, 149.12; 153.21.

2.1.6 Synthesis of Naphtopyranotriazolopyrimidines 7

A mixture of 4 (20 mmol) and hydrazine hydrate (5 mL) in ethanol (15 mL) was refluxed during 7 h, and then left to cool. The solid obtained was collected by filtration and purified by recrystallization from toluene (Scheme 2), washed with ethanol, dried and crystallized from ethanol to give pale yellow crystals 4-iminopyranopyrimidine 7′. To a solution of compounds 7′ (10 mmol) in Toluene (50 mL) containing TsOH (0.1 g) as catalyst, was added ethyl cyanoacetate (10 mmol). The reaction mixture was heated under reflux overnight. The mixture was then poured onto ice/water and the formed solid pyranotriazolopyrimidine derivatives 7 collected by filtration and recrystallized from ethanol/water.

2.1.6.1 2-Cyanomethyl-5-Methyl-1-(4-Chloro-Phenyl)-1H-Benzo[f]Chromene[3,2e][1,2,4]Triazolo[1,5-c]Pyrimidine 7a

Yield: 77%. Mp: 202–204 °C. IR: 3081, 2972, 2211, 1656, 1630, 1587, 1571, 1453, 771, 743 cm−1. 1H-NMR (300 MHz, CDCl3 + DMSO-d6) δ: 7.56–7.37 (m, 10H), 6.42 (s, 1H), 4.18 (s, 2H), 2.54 (s, 3H). 13C NMR (75 MHz, DMSO-d6 + CDCl3) δ: C1,20.4; C2,31.6; C4,30,2; C6,102.2, C7,114.3, C8,117.6, C5,123.5, C9–C14,125.3, 127.5, 128.5, C15–C20,128.7, 130.2, 130.2, 131.2, 131.6, C21, 142.0, C22,148.0, C23,149.8, C24,156.1, C25,157.7, C26, 160,9. Anal. Calcd for (C25H15ClN5O) 436.8805: C, 68.732; H, 3.461; N, 16.031. Found: C, 68.72; H, 3.48; N, 16.01.

2.1.6.2 2-Cyanomethyl-5-Ethyl-1-(4-Chloro-Phenyl)-1H-Benzo[f]Chromene[3,2e][1,2,4]Triazolo [1,5-c]Pyrimidine 7b

Yield: 84%. Mp: 180–181 °C. IR: 3093, 2983, 2221, 1645, 1620, 1596, 1574, 1450, 771, 728 cm−1. 1H-NMR (300 MHz, CDCl3 + DMSO-d6) δ: 7.84–8.13 (m, 10H), 6.74 (s, 1H), 4.21 (s, 2H), 2.57 (s, 3H), 1.29 (t, 3H, J = 7.2). 13C NMR (75 MHz, DMSO-d6 + CDCl3) δ: C1,18.7, C2,25.1, C3,32.4, C4, 32,2;C6,102.2, C7,114.3, C8,117.6, C5,123.5, C9–C14,125.3–128.5, C15–C20,128.7–131.6, C21,141.5, C22,142.1, C23,149.2, C24,149.8, C25,155.7, C26,157.6. Anal. Calcd for (C26H18ClN5O) 450.9073: C, 69.257; H, 3.8; N, 15.532. Found: C, 69.30; H, 3.76; N, 15.49.

2.1.6.3 2-Cyanomethyl-5-Methyl-1-(3,4-Dichloro-Phenyl)-1H-Benzo[f]Chromene[3,2e][1,2,4]Triazolo [1,5-c]Pyrimidine 7c

Yield: 81%. Mp: 217–219 °C. IR: 3057, 2977, 2218, 1661, 1632, 1583, 1568, 1454, 781, 732 cm−1. 1H-NMR (300 MHz, CDCl3 + DMSO-d6) δ: 7.69–7.48 (m, 9H), 6.46 (s, 1H), 4.27 (s, 2H), 2.48 (s, 3H). 13C NMR (75 MHz, DMSO-d6 + CDCl3) δ: C1,17.1, C2,31.7, C4,29,8; C6,109.7, C7,113.5, C8,119.2, C5,120.1, C9–C14,127.6–128.1; C15–C20,132.4–137.6; C21,143.2, C22,145.1, C23,148.7, C24,154.9, C25,156.6, C26,164.5. Anal. Calcd for (C25H15Cl2N5O) 471.3256: C, 63.709; H, 2.994; N, 14.859. Found: C, 63.73; H, 3.05; N, 14.81.

2.1.6.4 2-Cyanomethyl-5-Ethyl-1-(3,4-Dichloro-Phenyl)-1H-Benzo[f]Chromene[3,2e][1, 2, 4]Triazolo[1,5-c]Pyrimidine 7d

Yield: 78%. Mp: 202–204 °C. IR: 3097, 2981, 2220, 1648, 1623, 1589, 1571, 1452, 783, 734 cm−1. 1H-NMR (300 MHz, CDCl3 + DMSO-d6) δ: 7.93–8.11 (m, 9H), 6.67 (s, 1H), 4.25 (s, 2H), 2.56 (s, 3H), 1.32 (t, 3H, J = 7.2). 13C NMR (75 MHz, DMSO-d6 + CDCl3) δ: C1,20.7, C2,26.3, C3,35.1, C4,103.3, C6,116.0, C7,118.5, C8,122.7, C5,125.4, C9–C14,127.3–128.5, C15–C20,131.2–137.0, C21,145.7, C22,147.3, C23,151.8, C24,153.7, C25,159.2, C26,164.3. Anal. Calcd for (C26H17Cl2N5O) 485.3524: C, 64.342; H, 3.323; N, 14.43. Found: C, 64.38; H, 3.29; N, 14.47.

2.1.7 Synthesis of 2-Cyanomethyl-Methylfuro[3,2-e][1,2,4]Triazolo[1,5-c]Pyrimidine 8 and 9

The method of preparation of these furotriazolopyranopyrimidines 8 and or 9 is the following. To a mixture of dry toluene (200 mL), Iminoether 5 or 6 (2.96 g, 10 mmol) and Para-toluene sulfonic acid (0.1 g) as catalyst was added cyanoacetic acid hydrazide (10 mmol). The mixture was heated under reflux in a Dean–Stark apparatus with removal of water and ethanol formed during 21–27 h. Evaporation of most of toluene left a residue which was dissolved in 20 mL of saturated solution of sodium bicarbonate and then extracted twice with 25 mL of chloroform. The organic layers was washed with 25 mL of saturated sodium chloride solution and then with 30 mL of distilled water and then dried over MgSO4. After removal of chloroform, the solid obtained was filtered and recrystallized from ethanol.

2.1.7.1 (5,9-Dimethyl-Furo[3,2,e][1,2,4]Triazolo[1,5-c]Pyrimidin-2-yl)-Acetonitrile 8a

Yield: 67%. Mp: 145 °C. IR: 3076, 2987; 2221; 1651, 1621. 1H-NMR (300 MHz, DMSO-d6) δ: 2.96 (s, 3H, CH3); 4.74 (s, 2H, CH2); 6.45 (s, 1H). 13C-NMR (75 MHz, DMSO-d6) δ: C1,20.7, C2,22.5, C3,23,1; C5, 114,8; C7,117.1; C6,120.8, C8,138.2, C9,141.9, C10,148.8, C11,157.3, C12,164. Anal. Calcd for (C11H9N5O) 227.2261: C, 58.145; H, 3.992; N, 30.822. Found: C, 58.08; H, 4.12; N, 30.71.

2.1.7.2 (5-Ethyl-9-Methyl-Furo[3,2,e][1,2,4]Triazolo[1,5-c]Pyrimidin-2-yl)-Acetonitrile 8b

Yield: 65%. Mp: 167 °C. IR: 3083, 3000; 2223; 1646, 1627. 1H-NMR (300 MHz, DMSO-d6) δ: 1.42 (t, 3H, CH3), 3.37 (q, 2H, CH2); 4.76 (s, 2H, CH2); 6.73 (s, 1H). 13C-NMR (75 MHz, DMSO-d6) δ: C1,20.7, C2,22.1, C3,22,5; C4,26,4 C5, 116,1; C7,117.4; C6,120.3, C8,139.5, C9,143.2, C10,150.8, C11,158.7, C12,168,6. Anal. Calcd for (C12H11N5O) 241.2529: C, 59.743; H, 4.596; N, 29.03. Found: C, 59.78; H, 4.51; N, 29.21.

2.1.7.3 (5-Methyl-9-Methylsulfanyl-7H-Pyrazolo[4,3-e][1,2,4]Triazolo[1,5,c]Pyrimidin-2-yl)-Acetonitrile 9a

Yield: 76%. Mp: 246–248 °C. IR: 3093, 2984; 2223; 1646, 1627. 1H-NMR (300 MHz, DMSO-d6 + CDCl3) δ: 2.40 (s, 3H, CH3), 3.23 (s, 3H, S-CH3), 3.58 (s, 2H), 7.35–7.76 (m, 5H, Ar–H, J = 7.2 Hz). 13C-NMR (75 MHz, DMSO-d6 + CDCl3) δ: C1,17.3, C2,21.6, C3,22.2, C5,114.8, C6,120.7, C7–C12,123.6–130.5, C13,140.2, C14,142.3, C15,147.4, C16,161.6, C17,165.8. Anal. Calcd for (C16H13N7S) 335.3937: C, 57.299; H, 3.907; N, 29.234. Found: C, 57.30; H, 4.08; N, 29.26.

2.1.7.4 (5-Ethyl-9-Methylsulfanyl-7H-Pyrazolo[4,3-e][1,2,4]Triazolo[1,5,c]Pyrimidin-2-yl)-Acetonitrile 9b

Yield: 70%. Mp: 253–255 °C. IR: 3081, 2991; 2218; 1652, 1632. 1H-NMR (300 MHz, DMSO-d6 + CDCl3) δ: 1.26 (t, 3H, J = 7.2), 3.18 (s, 3H, SCH3), 2.65 (q, 2H, J = 7.2), 3.67 (s, 2H), 7.35 (d, 5H, Ar–H, J = 7.2 Hz). 13C-NMR (75 MHz, DMSO-d6 + CDCl3) δ: C1,18.5, C2,21.3, C3,23.7, C4, 31,2; C5,113.9, C6,118.7, C7–C12,124.3–131.7, C13,142.6, C14,144.1, C15,148.7, C16,163.4, C17,168.1. Anal. Calcd for (C17H15N7S) 349.4205: C, 58.436; H, 4.327; N, 28.06. Found: C, 58.44; H, 4.28; N, 28.19.

2.2 Antibacterial Screening for Furo, Pyrano, and Pyrazolo[3,2,e][1,2,4]Triazolo-[1,5-c]Pyrimidine 7, 8 and 9

Compounds 7a–c, 8a–b and 9a–b were examined for their antibacterial activity with paper disc (ϕ5 mm) method as described by [33, 34, 35] and compared with that of Tetracycline (TE30, 54882, 30 µg), considered as reference. Strains used as test organisms in this study were; Salmonella typhimurium (ATCC14028: Source Département de génétique, Faculté de biologie, Université de Seville, Seville 41080, Espagne) Pseudomonas aeruginosa (Centre technique de l’agroalimentaire de Tunis) Escherichia coli (JW 1772) and Staphylococcus aureus (Centre technique de l’agroalimentaire de Tunis). Briefly, Tested compounds 7a–c, 8a–b and 9a–b were dissolved in a DMSO at different concentrations (1–54 M) as well as reference antibiotics TE30 (21 mg/mL). Paper discs were soaked in each compound solution for 3–5 min a then transferred into the surface of growth media seeded with the test organism. After an incubation period (24 h at 35 °C), the diameters of the inhibition zones around the discs were measured (mm). Standard blank with no added test compounds was also analyzed. The obtained results are summarized in Tables 2 and 3. Table 3 summarizes the TE30 diameter of the inhibition zones against studied bacteria strains in a dimethylsulfoxide (DMSO).

3 Results and Discussion

3.1 Synthesis

The synthetic route of the triazolopyrimidines 7, 8, and 9 is outlined in the Schemes 2, 3 and 4. “2-Amino-3-cyano-4-methylfuran 1, 2-amino-3-cyano-pyrans 2, 1-Phenyl-3-thiomethyl-5-aminopyrazole-4-carbonitrile 3” were selected as our primary starting material for this synthesis and were prepared by methods taken from the literature [21, 22, 23], the reactivity of the cyanoacetic acid hydrazone has been already reported by the present authors [24, 28]. Compound 1, 2 and 3 reacted with excess of ethyl orthoester to yield iminoethers 4, 5 and 6 (Scheme 2), which were known to react with compounds containing –NH2 moiety such as hydrazides [4, 25, 26, 27, 28, 29].
Scheme 3

Synthetic route for the title compounds 7, 8 and 9

Scheme 4

A plausible mechanism for the formation of triazolopyrimidines 7, 8 and 9

In fact these precursors possess two reactive sites, a cyano group and an imidic carbon. These groups render them susceptible to react with cyanoacetic acid hydrazide in refluxing toluene with catalytic amount of p-toluenesulfonic acid to afford triazolopyrimidines 7, 8 and 9. From the mechanistic view point and as shown in Scheme 1, tow plausible pathways and different intermediates and products could be expected. Indeed, the bis electrophilic character of iminoether 4 would allow a successive two nucleophilic additions of –NH2 group or of NH2–NH– moiety on the imidic carbon and the cyano group, which would give by intracyclisation via elimination of water to compound 7, and which was isolated in some cases when ethanol was used as solvent or amidopyranopyrimidines 7′. Based on spectral data, the reaction was proceeded to produce pyranotriazolopyrimidine derivatives 7 rather than amidopyranopyrimidines 7′. But iminoethers 5 and 6 would allow a successive two nucleophilic additions of –NH2 group or two nitrogen of NH2–NH– moiety on the imidic carbon and the cyano group, which would give respectively their intermediate (furano and pyrazolo)triazepines 8′, 9′ and/or their isomers 8″, 9″ that can be evolved by intramolecular cyclization via elimination of water to compounds furo(pyrazolo)triazolopyrimidine derivatives 8 and 9 (Scheme 3, Fig. 1, Table 1).
Table 1

Prepared synthesized triazolopyrimidines 7, 8 and 9

*Yield calculated using the reaction of scheme (2)

A plausible mechanism for the formation of triazolopyrimidines 7, 8 and 9 is depicted in Scheme 4. The transformation is believed to proceed via the nucleophilic attack of –NH2 group on the imidic carbon and the cyano group, giving rise to an imine intermediate. A subsequent intramolecular cyclization through the nucleophilic attack of the imino group on the carbonyl of the amide group, leads to the final.

4 DFT Study

4.1 Computational Method

Gaussian 09 has been employed for all the theoretical calculations [30]. Geometries of the molecules 7′, 8′ and 9′ were optimized using the DFT at B3LYP level [31, 32, 33, 34] along with 631G (d, p) basis set. The molecule 7′ was calculated without –Cl in order to reduce the computational calcul. Stable minima of Ground state S0 geometries were confirmed by the absence of imaginary frequencies in the subsequent vibrational frequency calculations. The vibrational spectra of the compounds studied were calculated at the B3LYP/631G(d, p) optimized geometries. The torsional barriers around the N7–N6–C4–C3 and N19–N20–C21–C22 dihedral angle have been investigated with B3LYP/321G(d) for both compound 8′ and 9′ respectively (Figures). UV–Vis spectral was investigated at TD-B3LYP/631G(d, p) [19, 20]. All calculations were performed in the gas phase.

4.2 Molecular Geometry

Naphtopyrano, furo and pyrazolotriazolopyrimidine derivatives 7, 8 and 9 can theoretically exist in form conformational isomers represented below (Fig. 2) and make appear different types of intramolecular hydrogen bonds.

It should be noted that the analysis spectra of compounds 7′, 8 and 9 carried out in CDCl3 have a single isomer alone; one of the three conformations is preferred. In order to determine the most stable conformation under which these compounds exist, a theoretical study carried out on compounds 7′, 8 and 9 using the Gaussian 09 program carried out at the DFT (Functional Density Theory) level with the functional B3LYP29 was undertaken.

According to Brown’s criterion, there are three classes of hydrogen bonds. Very strong, strong and weak depending on the distances and angles shown in the Table 2.
Table 2

Classes of hydrogen bonds

Classes

Distances and angles

Very strong

H–A≡D–H

Strong H…A > D–H

Weak

H…A ≫ D–H

d (H…A) (Ǻ)

1.2–1.5

1.5–2.2

> 2.5

ϴ (D–H…A) (°)

175–180

130–180

90–180

The existence of hydrogen bonding for these compounds is due to the presence of adjacent amide group, amino group and nitrile group in the aromatic ring. To know the impact of hydrogen bonding in defining conformational flexibility of the molecule, B3LYP/3–21G(d) calculations were carried out by applying rotations (Fig. 3).

The stable molecule corresponds to minimum energy using potential energy scan [35]. The relative energy of the three molecules was calculated at B3LYP/6–31G (d). It was found that the molecule 9′ was the most stable. The energies of the others were − 3,645,013.145 and − 2,231,583.532 kJ mol−1 for molecule 7′ and 8′, respectively (Table 3).
Table 3

The relative energies of compounds 7′, 8′ and 9′

B3LYP 6-31G(d,p)

Molecule 7′II

Molecule 8′III

Molecule 9′III

Energy/kJ mol−1

− 3,645,013.145

− 2,231,583.532

− 3,873,610.11

The torsional barrier of molecule 8′ showed that C4=O5 and N6–H16 were on the same side (Fig. 4). This result leads to the formation of intramolecular hydrogen O5…H16–N6.

The torsional barrier of molecule 9′ showed that N19–N20–C21–C22 dihedral angle was 2.57 Å (Fig. 5).

The fully optimized molecular structures of molecules 7′ and 8′ with atomic numbering, calculated at B3LYP/6–31G (d,p) level of the theory, are shown in Fig. 1. Selected calculated bond distances are given in Table 3. As seen from Table 4. Two intramolecular hydrogen O5…H16–N6 and N6…H15–N14 for molecules were found. The presence of intramolecular Hydrogen significantly lowers the energy of the system and stabilizes the molecule. The stabilization of molecule is matched with the shortening of O5…H16–N6 and N6…H15–N14 distance. From the results of Table 3, it was observed that the calculated C4=O5 and H15–N14 bond distances of the molecule 9′ reduced. This result showed that –S–CH3 was responsible for the reduced of C4=O5 and H15–N14 bond distances.
Fig. 1

Triazolopyrimidines 7, 8 and 9

Fig. 2

different types of intramolecular hydrogen bonds of triazolopyrimidines 7, 8 and 9

Fig. 3

Optimized structure at B3LYP/6-31G(d,p)

Fig. 4

Torsional barrier of molecule 8′ around the N–N–C–C dihedral angle at B3LYP/3–21G(d)

Fig. 5

Torsional barrier of molecule 9′ around the N–N–C–C dihedral angle at B3LYP/3–21G(d)

Table 4

Geometrical parameters of molecule 7′, 8′ and 9′

Bond length (A°)

Molecule-7′II

Molecule-8′III

Molecule-9′VI

N1…H15

5.413

5.397

5.435

N1…H16

5.551

5.556

5.539

O5…H16

2.44

2.450

2.448

N6…H15

2.375

2.38

2.343

O5…H15

3.275

3.316

3.311

S18…H15

  

4.562

C4=O5

1.210

1.211

1.210

N6–H16

1.015

1.015

1.015

H15–N14

1.019

1.020

1.019

4.3 Electronic Structure and UV Spectrum

TDB3LYP/631G (d,p) based on B3LYP/631G(d,p) geometries was used to determine the low lying excited state of the molecule. Excitation energy, oscillator strength, and the main components of the ground state S0 → excited state S1transition energy of each system are summarized in Table 5. The lowest excited states of the investigated structures is characterized by π → π* transition from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO). The π → π* transition was observed for two molecule and caused by C=O in amide group. The excitation energies decrease from 4.178 eV for the molecule 8′ to 3.689 eV for the molecule 9′. The main absorption peak of molecule 8′ is blue-shifted with respect to the one of molecule 9′ and 7′ (Fig. 6).
Table 5

Calculated maximum absorption wavelength (λ), excitation energies (E), oscillator strength (f) of molecule 7′, 8′ and 9′ by the TD-DFT method

 

Calculated wavelength

Energy (eV)

Oscillator strength

Transition

Molecule 7′

336.49

3.684

0.0167

H → L (97.13%)

Molecule 8′

296.71

4.178

0.1997

H → L (97.82%)

Molecule 9′

336.06

3.689

0.1066

H → L (97.016%)

Fig. 6

Calculated UV–Vis spectra of different molecules at TD-DFT

4.4 The Frontier Molecular Orbitals of Molecules 7′, 8′ and 9′

The interested orbital in molecules are the frontier molecular orbital, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). Specific molecular orbital MO localization can be introduced by donor–acceptor molecules, while (LUMO) is localized on the acceptor unit and the (HOMO) is localized on the donor unit (Fig. 7).
Fig. 7

B3LYP-calculated wave functions of the frontier molecular orbitals of molecules 7′, 8′ and 9′

The stabilization in (LUMO) is more pronounced than the stabilization in (HOMO), so that molecule 7′ and 9′ have smaller (HOMO–LUMO) gaps as compared to the molecule 8′ (Table 6).
Table 6

Calculated HOMO, LUMO and energy gap EL-H in eV at B3LYP/6–31G(d)

 

HOMO

LUMO

EL-H

Molecule 7′

− 5.880

− 1.6035

4,2765

Molecule 8′

− 6.0385

− 1.4005

4638

Molecule 9′

− 5.941

− 1.697

4244

4.5 Infrared Spectroscopy

ATR-FTIR spectra of compounds 8′ and 9′ are presented in Fig. 8. They show the presence of two characteristic bands of the NH of the amin group and a broad band centered at 3344 and 3246 cm−1 associated with the 2 × N–H stretching vibration, and an intense band at around 1680 cm−1 assigned to the vibration of the C=O group. The spectra exhibited also a decrease of the intensities of the bands at 1450 cm−1, 1498 cm−1 and 1607 cm−1 attributed to the C=C groups in the benzene ring. The CN stretching was observed at 2219 cm−1. The imine (CH=N) vibration corresponding to Schiff base formation was newly observed at 1622 cm−1 [28].
Fig. 8

ATR-FTIR spectra of compounds 8′ and 9′

The experimental results were combined with theoretical data which describes molecular features. In computational studies, DFT method was also used to compute geometrical parameters, (HOMO) and (LUMO) energy levels by DFT/B3LYP basis set in Gaussian 09 (Fig. 9) [36].
Fig. 9

ATR-FTIR spectra of compounds 8′ and 9′

5 Biological Activity

All the title compounds derivatives 7a–c, 8a–b and 9a–b were tested for their antibacterial activity Gram positive and Gram negative against four types of Bacteria and was measured by measuring the zone of inhibition in disc diffusion method (Table 7).
Table 7

Prepared synthesized of compounds 7(a,c), 8(a,b) and 9(a,b)

The antibacterial activity was tested with the disc methods according to against Staphylococcus Pseudomonas, Escherichiacoli and Salmonella. This test is summarized by a resistance study of different compounds and standard antibiotic Tetracycline TE30. The colony diameter was noted after 3 days of incubation at 25 °C. Control received the same volume of sterilized distilled water. Bacteria growth was measured by averaging the three diameters taken at right angles for each colony. Percentage growth inhibition (%) of bacteria colonies was calculated according to the following formula [37] Growth inhibition (%) = [(Growth in control − Growth in treatment)/Growth in control] × 100: significant inhibition zone (IZ) results was taken in a range of lyses more than 10 mm and the minimum inhibitory concentrations (MIC) has been calculated. The highest active products were represented by the minimum inhibitory concentrations (MIC) (Fig. 10).
Fig. 10

Figures discs containing products synthesized by different concentrations

Results recorded in Table 8 showed the inhibition-diameter of compounds 7a–c, 8a–b and 9a–b and reference TE30. Our results show that furano, pyrano, and pyrazolotriazolopyrimidine exhibited a moderate antibacterial activity against both Gram-positive and Gram-negative bacteria [38]. Importantly, pyranotriazolopyrimidine, 8a did not show any significant antibacterial activity against all used strains (> 36 mg/mL) and no lyses plaque was observed with all concentrations used. Accordingly, compound 8b inactivate Staphylococcus and Salmonella with a high MIC (34.46 mg/mL) whereas compound 9a and 9b seems to be more effective with a low MIC and a good IZ. With regard to the mechanism of antibacterial activity, one can speculate that compound 8b is not able to diffuse intracellular and to inhibit bacterial peptidoglycan. We note that adding a CH3 or CH2–CH3 in the fragment R decreases the activity. Furthermore, we noted that pyrazolotriazolopyrimidine 9a and 9b showed an inhibition zone at about 5 and 6.5 mm against Staphylococus. This result may be probably related to the presence of the phenyl group. Interestingly, compound 7a and 7c showed the highest inhibition zone at around 16 mm against Staphylococus and Pseudomonas. This result may be attributed to the presence of dihydronaphtho group [39, 40, 41, 42, 43] in the R ring. It is important to mention that all tested compounds, except 7a and 7c showed a low antibacterial activity in comparison to TE30 as can be noticed from Table 3.
Table 8

Antibacterial activity of compounds 7(a,c), 8(a,b) and 9(a,b) as inhibition diameter or IZ Diameters (mm) and minimal inhibition concentration MIC (mg/mL)

 

Gram+

Gram−

Staphylococcus

Pseudomonas

Escherichia

Salmonella

(mg/mL)

(mm)

(mg/mL)

(mm)

(mg/mL)

(mm)

(mg/mL)

(mm)

7a

16.74

15.56

16.74

14.78

 

7c

18.53

16.13

18.53

15.11

 

8a

36.67

3.52

36.67

2.63

36.67

1.57

8b

34.46

4.06

34.46

3.83

34.46

3.14

9a

18.92

5

18.92

5

9b

16.52

6.5

16.52

6.5

TE30 (30 µg)

21

26

21

21

21

24

21

22

6 Conclusions

In conclusion, a new series of naphtopyrano, furo and pyrazolo[3,2,e][1,2,4]triazolo-[1,5-c]pyrimidine 7a–c, 8a–b and 9a–b were synthesized and the structure was characterized on the basis of their infrared (IR), NMR spectral data. All the title compounds were tested for their antibacterial activity against four types of Bacteria. According to the results obtained, compounds 7a–c, 8a–b and 9a–b exhibited a moderate in vitro antibacterial activity compared to the TE30 reference. Naphtotriazolopyrimidine 7a and 7c showed the highest antibacterial activity. This can be attributed to the dihydronaphtho group.

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© The Author(s) 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Dhiab Jabli
    • 1
    Email author
  • Rim Milad
    • 2
  • Manef Abderrabba
    • 2
  • Mohamed Lotfi Efrit
    • 1
  1. 1.Laboratory of Selective Organic and Heterocyclic Synthesis-Biological Activity Evaluation, Department of Chemistry, Faculty of SciencesEl Manar UniversityTunisTunisia
  2. 2.Laboratoire Matériaux, Molécules et applicationsInstitut Préparatoire aux Etudes Scientifiques et TechniquesLa MarsaTunisia

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