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Article

Linear and Angular Heteroannulated Pyridines Tethered 6-Hydroxy-4,7-Dimethoxybenzofuran: Synthesis and Antimicrobial Activity

by
Najla A. Alshaye
1,
Al-Shimaa Badran
2 and
Magdy A. Ibrahim
2,*
1
Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
2
Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo 11711, Egypt
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(18), 4496; https://doi.org/10.3390/molecules29184496
Submission received: 11 September 2024 / Revised: 19 September 2024 / Accepted: 20 September 2024 / Published: 22 September 2024
(This article belongs to the Special Issue Synthetic Studies Aimed at Heterocyclic Organic Compounds)
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Abstract

:
2-Chloropyridine-3-carbonitrile derivative 1 was utilized as a key precursor to build a series of linear and angular annulated pyridines linked to a 6-hydroxy-4,7-dimethoxybenzofuran moiety. Reaction of substrate 1 with various hydrazines afforded pyrazolo[3,4-b]pyridines. Treatment of substrate 1 with 1,3-N,N-binucleophiles including 3-amino-1,2,4-triazole, 5-amino-1H-tetrazole, 3-amino-6-methyl-1,2,4-triazin-5(4H)-one and 2-aminobenzimidazole produced the novel angular pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrimidine, pyrido[3,2-e][1,2,4]tetrazolo[1,5-a]pyrimidine, pyrido[3′,2′:5,6] pyrimido[2,1-c][1,2,4]triazine and benzo[4,5]imidazo[1,2-a]pyrido[3,2-e]pyrimidine, respectively. Reaction of substrate 1 with 1,3-C,N-binucleophiles including cyanoacetamides and 1H-benzimidazol-2-ylacetonitrile furnished 1,8-naphthyridines and benzoimidazonaphthyridine. Moreover, reacting substrate 1 with 5-aminopyrazoles gave pyrazolo[3,4-b][1,8]naphthyridines. Finally, reaction of compound 1 with 6-aminouracils as cyclic enamines yielded pyrimido[4,5-b][1,8]naphthyridines. Some of the synthesized products showed noteworthy antimicrobial efficiency against all types of microbial strains. Structures of the produced compounds were established using analytical and spectroscopic tools.

Graphical Abstract

1. Introduction

Benzofuran scaffolds, found in numerous natural products and medications, are of great therapeutic value [1,2,3]. Some drugs containing benzofurans with potential biological activities are approved by the USFDA or EMA [4]. Benzofurans constitute a valuable class in the field of drug discovery and development due to their interesting biological characteristics [5,6]. Noteworthy, substituted benzofurans exhibit significant efficiency against various tumors and cancer cell lines [7,8,9]. Also, benzofurans tethered different heterocyclic compounds displayed significant antimicrobial efficiency against a diversity of microbial strains [9,10,11,12]. Benzofuran derivatives also possess diverse biological properties, such as antioxidant, anti-inflammatory, antipyretic neuroprotective, analgesic as well treatment potential for Alzheimer’s diseases [13,14,15,16,17]. Theoretical studies and physical applications on benzofuran derivatives including HOMO-LUMO energy, MEP map, Mulliken atomic charges, dipole moments, solvatochromic, NBO and NLO, photophysical, photochemical and optoelectronic properties were also investigated [18,19,20,21,22]. A variety of synthetic strategies were developed to prepare heterocyclic compounds including benzofuran skeletons [23,24,25,26]. However, 6-substituted khellin represents an excellent building block to synthesize benzofuran-tethered heterocyclic systems due to the availability of electron-deficient γ-pyrone moiety [27,28,29,30,31]. On the other hand, a diversity of pyridines and their annulated heterocycles are widely synthesized using variable synthetic methodology [32,33,34,35]. Pyridine-based heterocycles exhibited promising pharmacological characteristics including antiviral, antiproliferative anticancer, antimicrobial, antimycobacterial, antifungal, anti-diabetic and anti-Alzheimer as well as inhibitors for acetylcholinesterase and butyrylcholinesterase [36,37,38,39,40,41,42]. Given the chemical and biological importance of benzopyrans and pyridines scaffolds, the current work aims to synthesize some new linear and angular annulated pyridines tethered to a 6-hydroxy-4,7-dimethoxybenzofuran moiety in one molecular frame utilizing o-choropyridinecarbonitrile 1 [43] as a building block, and to explore the biological activities of the prepared compounds.

2. Results and Discussion

2.1. Characterization of the Synthesized Compounds

It is known that compounds containing neighboring cyano and chloro functions are active building blocks for constructing nitrogen heterocyclic compounds [44,45]. Thus, chloropyridinecarbonitrile derivative 1 serves as an effective precursor for the synthesis of a variety of fused pyridines connected to a 6-hydroxy-4,7-dimethoxybenzofuranylcarbonyl moiety.
Reaction of substrate 1 with 3-hydrazino-5,6-diphenyl-1,2,4-triazine (2) [46] and 7-chloro-4-hydrazinoquinoline (3) [47], in refluxing DMF/TEA, afforded triazinyl/ quinolinylpyrazolo[3,4-b]pyridines 4 and 5, respectively (Scheme 1). Compounds 4 and 5 are formed via the nucleophilic addition of NH2 group to the nitrile function in substrate 1, followed by pyrazole ring closure and elimination of an HCl molecule. The mass spectra of compounds 4 and 5 confirmed their molecular formulae C32H23N7O5 and C26H18ClN5O5 showing their parent ion peaks at m/z 585 and 515, respectively. The C≡N function, detected at ṽ 2227 cm−1 in the spectrum of compound 1, disappeared in the IR spectra of products 4 and 5. The IR spectrum of products 4 and 5 presented distinctive absorption bands due to amino groups at ṽ 3368, 3293 and 3354, 3271 cm−1, respectively. Also, characteristic absorption bands corresponding to C=O and C=N were recorded at ṽ 1652/1658 and 1610/1612 cm−1. Further, the NH2 groups were detected in the 1H-NMR spectra of compounds 4 and 5 at δ 9.31 and 9.42 ppm, respectively, while the OH protons were seen at δ 12.29 and 12.52 ppm. In addition, two characteristic doublets attributable to H-3furan and H-2furan were seen in the 1H NMR spectra of compounds 4 and 5 at δ 7.08/7.13 and 7.85/7.86 ppm, respectively.
Likewise, compound 1 was permitted to react with some 1,3-N,N-binucleophiles. Thus, the novel angular pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrimidine 6 and pyrido[3,2-e][1,2,4]tetrazolo[1,5-a]pyrimidine 7 were synthesized from reacting substrate 1 with 3-amino-1,2,4-triazole and 5-amino-1H-tetrazole, respectively (Scheme 2). The mass spectra of the compounds 6 and 7 displayed their molecular ion peaks at m/z 406 and 407, coinciding with the proposed molecular formulae C19H14N6O5 and C18H13N7O5, respectively. Their IR spectra showed distinctive absorption bands at ṽ 3348, 3265/3369, 3287 (NH2) and 1649/1644 cm−1 (C=O). The 1H NMR spectra of compounds 6 and 7 revealed characteristic singlet signals due to H-4pyridine and H-2pyridine at δ 8.43/8.52 and 8.55/8.61, respectively. In addition, the amino protons were observed as D2O exchangeable signals at δ 9.50 and 9.26 ppm. The spectrum of compound 6 displayed definite singlet signal assignable to H-3triazole at δ 8.97. The carbonyl carbon in compounds 6 and 7 were observed in the downfield region in the 13C NMR spectra at δ 192.3 and 192.4 ppm, respectively, also the spectrum of compound 6 showed distinctive singlet due to C-3triazole at δ 137.3 ppm.
Similarly, treatment of substrate 3 with 3-amino-6-methyl-1,2,4-triazin-5(4H)-one (8) [48] and 2-aminobenzimidazole, in boiling DMF/TEA, yielded the novel angular annulated pyrido[3′,2′:5,6]pyrimido[2,1-c][1,2,4]triazine 9 and benzo[4,5]imidazo[1,2-a] pyrido[3,2-e]pyrimidine 10, respectively (Scheme 3). The IR spectra of compounds 9 and 10 showed distinctive absorption bands at ṽ 3372,3296/3383,3268 (NH2) and 1654/1648 cm−1 (C=O). Also, the spectrum of compound 9 presented distinguish absorption band due to C=Otriazine at ṽ 1692 cm−1. The 1H NMR spectra of compounds 9 and 10 presented D2O exchangeable signals due to amino protons at δ 9.32 and 9.52 ppm, respectively. The spectrum of compound 9 displayed an upfield signal at δ 2.18, corresponding to CH3 triazine. The 13C NMR spectrum of compound 9 showed two specific signals attributed to CH3 triazine and C=Otriazine at δ 17.3 and 166.2 ppm. The mass spectra of compounds 9 and 10 showed their molecular ion peaks at m/z 448 and 455, respectively, which coincided well with their proposed molecular formulae C21H16N6O6 and C24H17N5O5, respectively.
Next, compound 1 was permitted to react with some of 1,3-C,N-binucleophiles. Hence, reaction of compound 1 with cyanoacetamide, N-benzyl-2-cyanoacetamide and 1H-benzimidazol-2-ylacetonitrile, in boiling DMF/TEA, furnished 1,8-naphthyridine-3-carbonitriles 11, 12 and benzo[4,5]imidazo[1,2-a][1,8] naphthyridine-6-carbonitrile 13, respectively (Scheme 4). The IR spectra of compounds 11–13 showed characteristic absorption bands attributed to C≡N at ṽ 2224, 2221 and 2226 cm−1, respectively. The spectra of compounds 11 and 12 showed characteristic absorption bands due to C=Opyridine at 1681 and 1686 cm−1. The 1H NMR spectra of compounds 11–13 presented the NH2 protons as exchangeable signals at δ 9.32, 9.28 and 9.41 ppm, respectively. The NH proton in compound 11 was seen at δ 11.04 ppm. Also, the CH2 protons in compound 12 were recorded at δ 3.08 ppm. The 13C NMR spectra of compounds 11 and 12 showed characteristic signals attributed to C≡N, C=Onaphthyridine and C=Oketone at δ 116.3/116.6, 169.5/169.1 and 193.2/194.1 ppm, respectively. The spectrum of compound 12 displayed the methylene carbon as definite signal at δ 29.4. The mass spectra of compounds 11–13 exhibited their parent ion peaks at m/z 406, 496 and 479 that agree well with the suggested molecular formulae C20H14N4O6 (406.35), C27H20N4O6 (496.47) and C26H17N5O5 (479.44), respectively.
Moreover, the reaction of substrate 1 with 5-amino-2,4-dihydro-3H-pyrazol-3-one and 5-amino-3-methyl-1H-pyrazole, in boiling DMF/TEA, gave linear annulated pyrazolo[3,4-b][1,8]naphthyridines 14 and 15, respectively (Scheme 5). The IR spectrum of compound 14 showed typical absorption bands at ṽ 3376, 3338, 3296 (NH2, 2NH), 1667 (C=Opyrazole) and 1646 cm−1 (C=O). The 1H NMR spectrum of compound 15 revealed characteristic singlet signals at δ 2.42, 8.52 and 8.64 ppm attributed to CH3 pyrazole, H-4pyridine and H-2pyridine, in addition to three D2O exchangeable signals at δ 9.32 (NH2), 10.36 (NH) and 12.41 ppm (OH). The mass spectra of compounds 14 and 15 revealed their molecular ion peaks at m/z 421 and 319 that match well with the proposed molecular formulae C20H15N5O6 (421.36) and C21H17N5O5 (419.39), respectively. The carbon of C=Opyrazole was seen in the 13C NMR spectrum of compound 14 in the downfield region at δ 165.5 ppm, while the spectrum of compound 15 presented distinctive signal due to CH3 pyrazole at the upfield region δ 18.6 ppm (CH3).
Finally, compound 1 was permitted to react with some cyclic enamines namely 6-aminouracil, 6-aminothiouracil and 6-amino-1,3-dimethyluracil, in DMF containing TEA, giving pyrimido[4,5-b][1,8]naphthyridines 16–18, respectively (Scheme 6). The mass spectra of compounds 16–18 presented their molecular ion peaks at m/z 449, 465 and 477 approving their suggested formula weights 449.37 (C21H15N5O7), 465.44 (C21H15N5O6S) and 477.43 (C23H19N5O7), respectively. The amino protons were observed in 1H NMR spectra of compounds 16–18 at δ 9.58, 9.34 and 9.37 ppm, respectively. Two characteristic signals attributable to 2NCH3 protons were seen in the 1H NMR spectrum of compound 18 at δ 3.06 and 3.17 ppm. Further, the 13C NMR spectra of compounds 16 and 18 showed characteristic signals at δ 165.1/165.5 (C2 as C=Opyrimidine) and 167.4/168.1 (C4 as C=Opyrimidine), while The spectrum of compound 17 displayed specific signals due to C4 as C=Opyrimidine and C2 as C=Spyrimidine at δ 168.9 and 186.3 ppm, respectively. Also, the 13C NMR spectrum of compound 18 showed two characteristic signals at δ 28.9 and 30.0 corresponding to 2NCH3 carbons.

2.2. Antimicrobial Estimation

The synthesized products were investigated for their antimicrobial assay, in vitro, against some Gram-positive bacteria (S. aureus and B. subtilis) and Gram-negative bacteria (S. typhimurium and E. coli), as well as yeast (C. albicans) and fungus (A. fumigatus).
To assess the antimicrobial efficacy of the synthesized products, the inhibitory zones, including the disc diameter (6 mm), were evaluated (Table 1) [49]. High inhibition action referred to zone diameter >2/3 zone diameter of control, while moderate activity means zone diameter ≤2/3 and >1/3 zone diameter of reference drug. Cycloheximide is the reference drug for fungus and yeast, while Chloramphencol for Gram-positive bacteria, and Cephalothin for Gram-negative bacteria.
According to the results in Table 1 (Chart 1 and Charts S1–S5), all examined compounds had a strong inhibitory impact on the tested strains of fungus and yeast; this may due to the presence of the 6-hydroxy-4,7-dimethoxy-1-benzofuran moiety which exists in all products. Meanwhile, the inhibitory effect against the microbial strains varies according to the effect of the synthesized heterocyclic rings. Compounds 4 and 5 presented high efficiency against both types of Gram-positive and Gram-negative bacteria and this may be attributed to the presence of triazinyl/quinolinyl-pyrazolopyridine moieties linked to the benzofuranylcarbonyl fragment. Also, building angular heterocyclic systems, namely pyridotetrazolopyrimidine 7 and pyridopyrimidotriazine 9, enhanced the inhibitory effects against all tested microorganisms. On the other hand, some linear heterocyclic systems such as 1,8-naphthyridines 11, 12 and pyrimidonaphthyridines 16–18 showed high inhibition actions towards all tested bacterial strains.
As illustrated above, due to the existence of the principal scaffold, 6-hydroxy-4,7-dimethoxy-1-benzofuran moiety, all of the examined products demonstrated valuable inhibitory effects towards yeast and fungus. Furthermore, the inhibitory action towards bacterial strains was improved by the inclusion of additional heterocyclic systems, such as pyrazolopyridine, pyridotetrazolopyrimidine, pyridopyrimidotriazine, 1,8-naphthyridine and pyrimidonaphthyridine. As a result, some of the produced compounds may have excellent antimicrobial properties.

3. Materials and Methods

3.1. General Information

General. Melting point determination was performed using a digital Stuart SMP3 device (Buchi, Flawil, Switzerland). The mass spectra were measured using Shimadzu (Tokyo, Japan) GC-2010 mass spectrometer (70 eV); in gas chromatography. The 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were measured with the Mercury-400BB apparatus (vnmr1, Rheinstetten, Germany) using DMSO-d6 as the solvent and TMS (δ) as the internal standard. Using KBr disks, an FTIR Nicolet (Green Bay, WI, USA) IS10 spectrophotometer (cm−1) was used to record the infrared spectra. 2-Chloro-5-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]pyridine-3-carbonitrile (1) was prepared according to literature [43].

3.2. Biological Method

On medium potato dextrose agar (PDA), which comprised an infusion of 200 g potatoes, 6 g dextrose, and 15 g agar, the antimicrobial activity test was conducted. Filter paper disks of uniform size (6 mm in diameter, with three disks for each chemical) were carefully placed on an inoculated agar surface after being impregnated with an equivalent volume (10 µL) of dissolved compounds at concentrations of 500 and 1000 mg/mL in dimethylformamide (DMF). Following 36 h of incubation at 27 °C for bacteria and 48 h at 24 °C for fungi. The average diameter of the bacterial and fungal inhibitory zones surrounding the disks, measured in millimeters at concentrations of 500 and 1000 mg/mL, was recorded for each investigated compound [49].
3-Amino-1-(5,6-diphenyl-1,2,4-triazin-3-yl)-5-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]-1H-pyrazolo[3,4-b]pyridne (4)
A mixture of compound 1 (0.72 g, 2 mmol) and 3-hydrazinyl-5,6-diphenyl-1,2,4-triazine (2) (0.58 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the pale-yellow crystals deposited were filtered and recrystallized from AcOH, mp > 300 °C, yield (0.88 g, 75%). IR (KBr, cm−1): 3413 (OH), 3368, 3293 (NH2), 1652 (C=O), 1610 (C=N), 1581 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 3.86 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 7.08 (d, 1H, J = 2.0 Hz, H-3furan), 7.44–7.52 (m, 10H, Ar-H), 7.85 (d, 1H, J = 2.0 Hz, H-2furan), 8.42 (s, 1H, H-4pyridine), 8.48 (s, 1H, H-2pyridine), 9.31 (s, 2H, NH2 exchangeable with D2O), 12.29 (s, 1H, OH exchangeable with D2O). 13C NMR (75 MHz, DMSO-d6, δ): 58.7 (OMe), 59.8 (OMe), 102.3 (C3a′), 104.0 (C3′), 108.2 (C3a), 112.4 (C5′), 121.4 (Ar-C), 122.1 (Ar-C), 123.8 (C7′), 124.7 (Ar-C), 125.2 (Ar-C), 127.6 (Ar-C), 129.1 (C4′), 129.8 (Ar-C), 131.4 (Ar-C), 132.8 (C5), 135.7 (Ar-C), 138.2 (C-7a), 139.0 (C-5triazine), 139.9 (C-6triazine), 140.2 (C-3triazine), 143.2 (C-3), 144.5 (C-4), 147.2 (C-2′), 148.1 (C-6), 149.1 (C6′), 151.6 (C7a′), 189.7 (C=Oketone). Mass spectrum, m/z (Ir %): 585 (M+, 46), 555 (24), 452 (37), 353 (16), 324 (20), 220 (71), 178 (100), 159 (13), 133 (10), 117 (16), 93 (25), 77 (48), 64 (21). Anal. Calcd for C32H23N7O5 (585.57): C, 65.64; H, 3.96; N, 16.74%. Found: C, 65.37; H, 3.88; N, 16.64%.
3-Amino-1-(7-chloroquinolin-4-yl)-5-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]-1H-pyrazolo[3,4-b]pyridne (5)
A mixture of compound 1 (0.72 g, 2 mmol) and 7-chloro-4-hydrazinylquinoline (3) (0.38 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the orange-yellow crystals so formed were filtered and recrystallized from AcOH, mp > 300 °C, yield (0.79 g, 78%). IR (KBr, cm−1): 3408 (OH), 3354, 3271 (NH2), 1658 (C=O), 1612 (C=N), 1588 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 3.87 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 7.13 (d, 1H, J = 2.0 Hz, H-3furan), 7.52–7.56 (m, 3H, H-3quinoline, H-5quinoline and H-6quinoline), 7.86 (d, 1H, J = 2.0 Hz, H-2furan), 8.04 (s, 1H, H-8quinoline), 8.18 (d, 1H, J = 7.6 Hz, H-2quinoline), 8.53 (s, 1H, H-4pyridine), 8.69 (s, 1H, H-2pyridine), 9.42 (s, 2H, NH2 exchangeable with D2O), 12.52 (s, 1H, OH exchangeable with D2O). 13C NMR (75 MHz, DMSO-d6, δ): 58.5 (OMe), 59.3 (OMe), 102.5 (C3a′), 106.4 (C3′), 109.3 (C3a), 112.5 (C5′), 122.0 (Ar-C), 122.6 (Ar-C), 123.3 (Ar-C), 123.7 (C7′), 124.6 (Ar-C), 125.1 (Ar-C), 126.4 (Ar-C), 127.8 (Ar-C), 128.6 (C4′), 134.5 (C8aquinoline), 139.5 (C-7a), 140.5 (C4quinoline), 143.4 (C2 quinoline), 144.5 (C-4), 145.2 (C-3), 147.4 (C-2′), 148.2 (C-6), 150.5 (C6′), 152.6 (C7a′), 192.2 (C=Oketone). Mass spectrum, m/z (Ir %): 515/517 (M+/M+2, 100/33), 354 (68), 312 (32), 221 (54), 162/164 (69/23), 134 (11), 117 (19), 94 (42), 77 (26), 64 (15). Anal. Calcd for C26H18ClN5O5 (515.90): C, 60.53; H, 3.52; N, 13.57%. Found: C, 60.41; H, 3.39; N, 13.52%.
5-Amino-3-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]pyrido[3,2-e] [1,2,4]triazolo[4,3-a]pyrimidine (6)
A mixture of compound 1 (0.72 g, 2 mmol) and 3-amino-1,2,4-triazole (0.16 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the yellow crystals deposited were filtered and recrystallized from iso-butanol, mp > 300 °C, yield (0.59 g, 72%). IR (KBr, cm−1): 3406 (OH), 3348, 3265 (NH2), 1649 (C=O), 1615 (C=N), 1594 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 3.84 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 7.11 (d, 1H, J = 2.0 Hz, H-3furan), 7.92 (d, 1H, J = 2.0 Hz, H-2furan), 8.43 (s, 1H, H-4pyridine), 8.55 (s, 1H, H-2pyridine), 8.97 (s, 1H, H-3triazole), 9.50 (s, 2H, NH2 exchangeable with D2O), 12.33 (s, 1H, OH exchangeable with D2O). 13C NMR (100 MHz, DMSO-d6, δ): 58.0 (OCH3), 59.2 (OCH3), 102.3 (C5′), 104.3 (C4a), 106.7 (C3′), 109.3 (C3a′), 122.4 (C7′), 128.2 (C3), 129.6 (C4′), 137.3 (C9), 138.4 (C4), 139.3 (C2), 144.9 (C5), 145.2 (C2′), 148.5 (C10a), 149.7 (C6a), 151.6 (C6′), 152.8 (C7a′), 192.3 (C=Oketone). Mass spectrum, m/z (Ir %): 406 (M+, 100), 350 (67), 320 (39), 288 (32), 221 (51), 185 (24), 148 (28), 134 (15), 118 (11), 94 (47), 77 (33), 64 (10). Anal. Calcd for C19H14N6O5 (406.35): C, 56.16; H, 3.47; N, 20.68%. Found: C, 55.96; H, 3.44; N, 20.39%.
5-Amino-7-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]pyrido[3,2-e] [1,2,4]tetrazolo[1,5-a]pyrimidine (7)
A mixture of compound 1 (0.72 g, 2 mmol) and 5-amino-1H-tetrazole (0.16 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the yellow crystals so formed were filtered and recrystallized from iso-butanol, mp > 300 °C, yield (0.57 g, 70%). IR (KBr, cm−1): 3403 (OH), 3369, 3287 (NH2), 1644 (C=O), 1611 (C=N), 1590 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 3.86 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 7.19 (d, 1H, J = 2.0 Hz, H-3furan), 7.95 (d, 1H, J = 2.0 Hz, H-2furan), 8.52 (s, 1H, H-4pyridine), 8.61 (s, 1H, H-2pyridine), 9.26 (s, 2H, NH2 exchangeable with D2O), 12.40 (s, 1H, OH exchangeable with D2O). 13C NMR (100 MHz, DMSO-d6, δ): 58.5 (OCH3), 59.1 (OCH3), 101.8 (C5′), 105.1 (C4a), 106.2 (C3′), 110.3 (C3a′), 123.1 (C7′), 128.5 (C3), 129.8 (C4′), 138.5 (C4), 138.8 (C2), 144.2 (C5), 145.1 (C2′), 148.1 (C10a), 149.2 (C6a), 151.1 (C6′), 152.7 (C7a′), 192.4 (C=Oketone). Mass spectrum, m/z (Ir %): 407 (M+, 48), 349 (30), 304 (25), 274 (19), 221 (36), 192 (16), 171 (14), 159 (22), 133 (18), 117 (14), 93 (100), 77 (64), 64 (24). Anal. Calcd for C18H13N7O5 (407.34): C, 53.07; H, 3.22; N, 24.07%. Found: C, 52.83; H, 3.14; N, 23.95%.
5-Amino-3-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]-9-methyl-10H-pyrido[3′,2′:5,6]pyrimido[2,1-c][1,2,4]triazin-10-one (9)
A mixture of compound 1 (0.72 g, 2 mmol) and 3-amino-6-methyl-1,2,4-triazin-5(4H)-one (8) (0.25 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the pale-brown crystals so formed were filtered and recrystallized from AcOH/H2O, mp > 300 °C, yield (0.62 g, 69%). IR (KBr, cm−1): 3405 (OH), 3372, 3296 (NH2), 1692 (C=Otriazine), 1654 (C=O), 1604 (C=N), 1587 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 2.18 (s, 3H, CH3 triazine), 3.82 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 7.25 (d, 1H, J = 2.4 Hz, H-3furan), 7.85 (d, 1H, J = 2.4 Hz, H-2furan), 8.49 (s, 1H, H-4pyridine), 8.58 (s, 1H, H-2pyridine), 9.32 (s, 2H, NH2 exchangeable with D2O), 12.40 (s, 1H, OH exchangeable with D2O). 13C NMR (100 MHz, DMSO-d6, δ): 17.3 (CH3), 58.8 (OCH3), 59.3 (OCH3), 103.4 (C5′), 104.9 (C4a), 106.6 (C3′), 110.2 (C3a′), 123.0 (C7′), 129.3 (C4′), 130.0 (C3), 135.4 (C9), 138.5 (C4), 139.1 (C2), 143.6 (C5), 145.0 (C11a), 146.2 (C2′), 148.5 (C6a), 150.5 (C6′), 152.7 (C7a′), 166.2 (C=Otriazine), 193.6 (C=Oketone). Mass spectrum, m/z (Ir %): 448 (M+, 68), 418 (100), 388 (32), 346 (29), 227 (17), 194 (15), 159 (17), 133 (22), 118 (13), 92 (36), 77 (32), 64 (14). Anal. Calcd for C21H16N6O6 (448.39): C, 56.25; H, 3.60; N, 18.74%. Found: C, 56.03; H, 3.47; N, 18.65%.
5-Amino-3-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]benzo[4,5] imidazo[1,2-a]pyrido[3,2-e]pyrimidine (10)
A mixture of compound 1 (0.72 g, 2 mmol) and 2-aminobenzimidazole (0.27 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the yellow crystals deposited were filtered and recrystallized from AcOH, mp > 300 °C, yield (0.65 g, 71%). IR (KBr, cm−1): 3417 (OH), 3383, 3268 (NH2), 1648 (C=O), 1607 (C=N), 1582 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 3.84 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 7.15 (d, 1H, J = 2.4 Hz, H-3furan), 7.37–7.43 (m, 2H, Ar-H), 7.48–7.53 (m, 2H, Ar-H), 7.86 (d, 1H, J = 2.4 Hz, H-2furan), 8.42 (s, 1H, H-4pyridine), 8.53 (s, 1H, H-2pyridine), 9.52 (s, 2H, NH2 exchangeable with D2O), 12.33 (s, 1H, OH exchangeable with D2O). 13C NMR (100 MHz, DMSO-d6, δ): 58.5 (OCH3), 59.7 (OCH3), 102.1 (C5′), 104.8 (C4a), 106.2 (C3′), 110.5 (C3a′), 120.3 (Ar-C), 121.1 (Ar-C), 122.8 (C7′), 124.1 (Ar-C), 125.2 (Ar-C), 126.1 (Ar-C), 129.6 (C4′), 130.3 (C3), 134.3 (Ar-C), 138.3 (C4), 139.7 (C2), 142.9 (C-13a), 144.7 (C5), 146.3 (C2′), 148.1 (C6a), 150.3 (C6′), 151.9 (C7a′), 192.3 (C=Oketone). Mass spectrum, m/z (Ir %): 455 (M+, 100), 395 (59), 340 (46), 234 (21), 220 (35), 190 (24), 161 (32), 134 (26), 117 (10), 94 (56), 77 (42), 65 (17). Anal. Calcd for C24H17N5O5 (455.42): C, 63.29; H, 3.76; N, 15.38%. Found: C, 63.14; H, 3.52; N, 15.31%.
4-Amino-6-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (11)
A mixture of compound 1 (0.72 g, 2 mmol) and cyanoacetamide (0.16 g, 2 mmol) in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the yellow crystals so formed were filtered and recrystallized from DMF/H2O, mp > 300 °C, yield (0.59 g, 73%). IR (KBr, cm−1): 3411 (OH), 3385, 3316, 3274 (NH2, NH), 2224 (C≡N), 1681 (C=Opyridine), 1650 (C=O), 1608 (C=N), 1584 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 3.89 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 7.23 (d, 1H, J = 2.4 Hz, H-3furan), 7.91 (d, 1H, J = 2.4 Hz, H-2furan), 8.46 (s, 1H, H-4pyridine), 8.52 (s, 1H, H-2pyridine), 9.32 (s, 2H, NH2 exchangeable with D2O), 11.04 (s, 1H, NH exchangeable with D2O), 12.64 (s, 1H, OH exchangeable with D2O). 13C NMR (100 MHz, DMSO-d6, δ): 59.0 (OCH3), 60.2 (OCH3), 87.1 (C3), 102.7 (C5′), 105.8 (C3′), 111.2 (C3a′), 116.3 (C≡N), 122.8 (C7′), 123.2 (C4a), 128.4 (C6), 129.8 (C4′), 138.2 (C5), 140.0 (C7), 144.7 (C4), 146.1 (C2′), 148.8 (C8a), 150.8 (C6′), 152.3 (C7a′), 169.5 (C2 as C=Onaphthyridine), 193.2 (C=Oketone). Mass spectrum, m/z (Ir %): 406 (M+, 100), 340 (25), 256 (20), 221 (49), 172 (38), 133 (14), 117 (23), 93 (46), 77 (28), 64 (13). Anal. Calcd for C20H14N4O6 (406.35): C, 59.12; H, 3.47; N, 13.79%. Found: C, 59.06; H, 3.30; N, 13.58%.
4-Amino-1-benzyl-6-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (12)
A mixture of compound 1 (0.72 g, 2 mmol) and N-benzylcyanoacetamide (0.32 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the yellow crystals deposited were filtered and recrystallized from AcOH, mp > 300 °C, yield (0.68 g, 68%). IR (KBr, cm−1): 3415 (OH), 3371, 3288 (NH2), 2221 (C≡N), 1686 (C=Opyridine), 1657 (C=O), 1613 (C=N), 1579 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 3.08 (s, 2H, CH2), 3.83 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 7.18 (d, 1H, J = 2.0 Hz, H-3furan), 7.54–7.66 (m, 5H, Ar-H), 7.93 (d, 1H, J = 2.4 Hz, H-2furan), 8.42 (s, 1H, H-4pyridine), 8.50 (s, 1H, H-2pyridine), 9.28 (s, 2H, NH2 exchangeable with D2O), 12.32 (s, 1H, OH exchangeable with D2O). 13C NMR (100 MHz, DMSO-d6, δ): 29.4 (NCH2), 58.3 (OCH3), 59.5 (OCH3), 88.4 (C3), 103.5 (C5′), 106.2 (C3′), 111.4 (C3a′), 116.6 (C≡N), 123.1 (C7′), 125.3 (C4a), 125.6 (Ar-C), 127.0 (Ar-C), 128.6 (C6), 129.2 (C4′), 130.6 (Ar-C), 134.1 (Ar-C), 138.6 (C5), 139.2 (C7), 144.5 (C4), 146.6 (C2′), 149.2 (C8a), 150.8 (C6′), 152.5 (C7a′), 169.1 (C2 as C=Onaphthyridine), 194.1 (C=Oketone). Mass spectrum, m/z (Ir %): 496 (M+, 59), 466 (52), 375 (46), 309 (47), 242 (32), 220 (64), 194 (26), 159 (21), 134 (15), 118 (16), 91 (100), 77 (57), 64 (23). Anal. Calcd for C27H20N4O6 (496.47): C, 65.32; H, 4.06; N, 11.29%. Found: C, 65.14; H, 4.01; N, 11.15%.
5-Amino-3-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]-benzo[4,5]imidazo[1,2-a][1,8]naphthyridine-6-carbonitrile (13)
A mixture of compound 1 (0.72 g, 2 mmol) and 1H-benzimidazol-2-ylacetonitrile (0.31 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the pale-brown crystals deposited were filtered and recrystallized from DMF, mp > 300 °C, yield (0.71 g, 74%). IR (KBr, cm−1): 3404 (OH), 3361, 3279 (NH2), 2226 (C≡N), 1651 (C=O), 1612 (C=N), 1576 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 3.86 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 7.13 (d, 1H, J = 2.0 Hz, H-3furan), 7.37–7.42 (m, 4H, Ar-H), 7.88 (d, 1H, J = 2.0 Hz, H-2furan), 8.39 (s, 1H, H-4pyridine), 8.57 (s, 1H, H-2pyridine), 9.41 (s, 2H, NH2 exchangeable with D2O), 12.33 (s, 1H, OH exchangeable with D2O). 13C NMR (75 MHz, DMSO-d6, δ): 59.1 (OMe), 60.2 (OMe), 87.3 (C-6), 102.9 (C3a′), 105.8 (C3′), 108.6 (C-9), 112.5 (C5′), 113.1 (C-7a), 117.2 (C≡N), 120.7 (Ar-C), 122.8 (C7′), 124.1 (Ar-C), 124.7 (Ar-C), 128.9 (Ar-C), 129.8 (C4′), 130.7 (Ar-C), 132.2 (Ar-C), 138.7 (C-11a), 142.3 (C-8), 143.2 (C-10), 145.1 (C-7), 147.2 (C2′), 148.0 (C-5a), 151.9 (C6′), 152.4 (C7a′), 191.3 (C=Oketone). Mass spectrum, m/z (Ir %): 479 (M+, 100), 419 (64), 353 (47), 313 (43), 258 (24), 221 (36), 192 (18), 161 (15), 133 (12), 117 (19), 94 (68), 77 (44), 64 (19). Anal. Calcd for C26H17N5O5 (479.44): C, 65.13; H, 3.57; N, 14.61%. Found: C, 64.96; H, 3.40; N, 14.39%.
4-Amino-6-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]-1,2-dihydro-3H-pyrazolo[3,4-b][1,8]naphthyridin-3-one (14)
A mixture of compound 1 (0.72 g, 2 mmol) and 5-amino-2,4-dihydro-3H-pyrazol-3-one (0.20 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the pale-brown crystals deposited were filtered and recrystallized from DMF, mp > 300 °C, yield (0.64 g, 76%). IR (KBr, cm−1): 3407 (OH), 3376, 3338, 3296 (NH2, 2NH), 1667 (C=Opyrazole), 1646 (C=O), 1605 (C=N), 1582 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 3.87 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 7.16 (d, 1H, J = 2.0 Hz, H-3furan), 7.93 (d, 1H, J = 2.0 Hz, H-2furan), 8.50 (s, 1H, H-4pyridine), 8.69 (s, 1H, H-2pyridine), 9.39 (s, 2H, NH2 exchangeable with D2O), 10.44 (s, 1H, NH exchangeable with D2O), 11.28 (s, 1H, NH exchangeable with D2O), 12.48 (s, 1H, OH exchangeable with D2O). 13C NMR (100 MHz, DMSO-d6, δ): 59.4 (OCH3), 59.9 (OCH3), 103.4 (C5′), 105.5 (C3a), 106.7 (C3′), 111.6 (C3a′), 112.4 (C5a), 122.6 (C7′), 128.3 (C6), 129.2 (C4′), 137.4 (C5), 138.1 (C7), 143.0 (C9a), 145.2 (C4), 146.2 (C2′), 148.4 (C8a), 150.7 (C6′), 152.5 (C7a′), 165.5 (C=Opyrazolone), 192.0 (C=Oketone). Mass spectrum, m/z (Ir %): 421 (M+, 100), 378 (47), 318 (56), 278 (27), 221 (38), 201 (41), 172 (30), 157 (14), 133 (17), 118 (21), 93 (48), 77 (36), 65 (12). Anal. Calcd for C20H15N5O6 (421.36): C, 57.01; H, 3.59; N, 16.62%. Found: C, 56.86; H, 3.47; N, 16.50%.
4-Amino-6-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]-3-methyl-1H-pyrazolo[3,4-b][1,8]naphthyridine (15)
A mixture of compound 1 (0.72 g, 2 mmol) and 5-amino-3-methyl-1H-pyrazole (0.20 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the yellow crystals so formed were filtered and recrystallized from DMF/H2O, mp > 300 °C, yield (0.66 g, 79%). IR (KBr, cm−1): 3412 (OH), 3359, 3281 (NH2), 1648 (C=O), 1617 (C=N), 1589 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 2.42 (s, 3H, CH3 pyrazole), 3.92 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 7.22 (d, 1H, J = 2.4 Hz, H-3furan), 7.96 (d, 1H, J = 2.4 Hz, H-2furan), 8.52 (s, 1H, H-4pyridine), 8.64 (s, 1H, H-2pyridine), 9.32 (s, 2H, NH2 exchangeable with D2O), 10.36 (s, 1H, NH exchangeable with D2O), 12.41 (s, 1H, OH exchangeable with D2O). 13C NMR (100 MHz, DMSO-d6, δ): 18.6 (CH3), 59.2 (OCH3), 60.0 (OCH3), 102.8 (C5′), 105.7 (C3a), 106.1 (C3′), 111.5 (C3a′), 113.4 (C5a), 122.4 (C7′), 125.4 (C6), 129.6 (C4′), 135.3 (C3), 137.2 (C6), 138.1 (C8), 142.6 (C9a), 143.0 (C4), 145.9 (C2′), 148.5 (C8a), 150.8 (C6′), 153.1 (C7a′), 191.6 (C=Oketone). Mass spectrum, m/z (Ir %): 419 (M+, 68), 389 (100), 319 (42), 278 (37), 220 (51), 198 (24), 157 (20), 133 (26), 118 (27), 92 (39), 77 (28), 64 (17). Anal. Calcd for C21H17N5O5 (419.39): C, 60.14; H, 4.09; N, 16.70%. Found: C, 59.93; H, 3.84; N, 16.59%.
5-Amino-7-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl] pyrimido[4,5-b][1,8]naphthyridine-2,4(1H,3H)-dione (16)
A mixture of compound 1 (0.72 g, 2 mmol) and 6-amino-2,3-dihydro pyrimidin-2,4(1H,3H)-dione (0.27 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the yellow crystals deposited were filtered and recrystallized from AcOH/H2O, mp > 300 °C, yield (0.67 g, 75%). IR (KBr, cm−1): 3407 (OH), 3384, 3297, 3227 (NH2, 2NH), 1679 (2C=Opyrimidine), 1656 (C=O), 1614 (C=N), 1583 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 3.92 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 7.13 (d, 1H, J = 2.4 Hz, H-3furan), 7.88 (d, 1H, J = 2.4 Hz, H-2furan), 8.34 (s, 1H, H-4pyridine), 8.72 (s, 1H, H-2pyridine), 9.58 (s, 2H, NH2 exchangeable with D2O), 10.33 (s, 1H, NH exchangeable with D2O), 10.70 (s, 1H, NH exchangeable with D2O), 12.45 (s, 1H, OH exchangeable with D2O). 13C NMR (100 MHz, DMSO-d6, δ): 58.7 (OCH3), 59.6 (OCH3), 102.5 (C5′), 104.0 (C4a), 107.4 (C3′), 109.2 (C3a′), 111.2 (C5a), 122.9 (C7′), 127.6 (C3), 129.3 (C4′), 137.8 (C6), 139.1 (C8), 144.3 (C10a), 144.9 (C5), 147.4 (C2′), 148.1 (C9a), 150.5 (C6′), 152.7 (C7a′), 165.1 (C2 as C=Opyrimidine), 167.4 (C4 as C=Opyrimidine), 192.8 (C=Oketone). Mass spectrum, m/z (Ir %): 449 (M+, 100), 391 (68), 346 (39), 305 (43), 262 (52), 229 (41), 185 (38), 157 (19), 134 (25), 117 (16), 94 (31), 77 (28), 64 (10). Anal. Calcd for C21H15N5O7 (449.37): C, 56.13; H, 3.36; N, 15.58%. Found: C, 56.02; H, 3.21; N, 15.37%.
5-Amino-7-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]-2-thioxo-2,3-dihydropyrimido[4,5-b][1,8]naphthyridin-4(1H)-one (17)
A mixture of compound 1 (0.72 g, 2 mmol) and 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.29 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL), was heated under reflux for 4 h. After cooling, the canary yellow crystals so formed were filtered and recrystallized from AcOH, mp > 300 °C, yield (0.73 g, 78%). IR (KBr, cm−1): 3401 (OH), 3370, 3284, 3216 (NH2, 2NH), 1673 (C=Opyrimidine), 1652 (C=O), 1619 (C=N), 1587 (C=C), 1226 (C=S). 1H NMR (400 MHz, DMSO-d6, δ): 3.90 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 7.08 (d, 1H, J = 2.8 Hz, H-3furan), 7.87 (d, 1H, J = 2.8 Hz, H-2furan), 8.53 (s, 1H, H-4pyridine), 8.67 (s, 1H, H-2pyridine), 9.34 (s, 2H, NH2 exchangeable with D2O), 11.42 (s, 1H, NH exchangeable with D2O), 11.78 (s, 1H, NH exchangeable with D2O), 12.64 (s, 1H, OH exchangeable with D2O). 13C NMR (100 MHz, DMSO-d6, δ): 58.5 (OCH3), 59.7 (OCH3), 103.4 (C5′), 105.3 (C4a), 107.2 (C3′), 109.5 (C3a′), 112.4 (C5a), 123.1 (C7′), 126.9 (C3), 128.7 (C4′), 136.4 (C6), 137.6 (C8), 142.1 (C10a), 143.2 (C5), 146.3 (C2′), 147.8 (C9a), 151.2 (C6′), 152.5 (C7a′), 168.9 (C4 as C=Opyrimidine), 186.3 (C2 as C=Spyrimidine), 194.8 (C=Oketone). Mass spectrum, m/z (Ir %): 465 (M+, 78), 407 (58), 348 (61), 318 (55), 263 (47), 221 (56), 173 (16), 159 (26), 133 (29), 118 (32), 92 (100), 77 (46), 64 (13). Anal. Calcd for C21H15N5O6S (465.44): C, 54.19; H, 3.25; N, 15.05; S, 6.89%. Found: C, 53.85; H, 3.17; N, 14.93; S, 6.81%.
5-Amino-7-[(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl]1,3-dimethyl-pyrimido[4,5-b][1,8]naphthyridine-2,4(1H,3H)-dione (18)
A mixture of compound 1 (0.72 g, 2 mmol) and 6-amino-1,3-dimethylpyrimidine- 2,4(1H,3H)-dione (0.31 g, 2 mmol), in DMF (10 mL) containing TEA (0.1 mL) was heated under reflux for 4 h. After cooling, the pale-yellow crystals so formed were filtered and recrystallized from AcOH/H2O, mp > 300 °C, yield (0.74 g, 77%). IR (KBr, cm−1): 3402 (OH), 3376, 3283 (NH2), 1676 (2C=Opyrimidine), 1658 (C=O), 1610 (C=N), 1588 (C=C). 1H NMR (400 MHz, DMSO-d6, δ): 3.06 (s, 3H, NCH3), 3.17 (s, 3H, NCH3), 3.92 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 7.25 (d, 1H, J = 2.0 Hz, H-3furan), 7.97 (d, 1H, J = 2.0 Hz, H-2furan), 8.52 (s, 1H, H-4pyridine), 8.68 (s, 1H, H-2pyridine), 9.37 (s, 2H, NH2 exchangeable with D2O), 12.52 (s, 1H, OH exchangeable with D2O). 13C NMR (100 MHz, DMSO-d6, δ): 28.9 (NCH3), 30.0 (NCH3), 58.9 (OCH3), 59.7 (OCH3), 102.6 (C5′), 103.9 (C4a), 106.7 (C3′), 109.8 (C3a′), 111.1 (C5a), 123.2 (C7′), 126.8 (C3), 129.0 (C4′), 137.1 (C6), 139.3 (C8), 143.6 (C10a), 144.7 (C5), 146.2 (C2′), 148.3 (C9a), 151.2 (C6′), 151.8 (C7a′), 165.5 (C2 as C=Opyrimidine), 168.1 (C4 as C=Opyrimidine), 192.7 (C=Oketone). Mass spectrum, m/z (Ir %): 477 (M+, 100), 416 (72), 375 (64), 333 (47), 256 (58), 221 (65), 194 (37), 173 (46), 158 (25), 133 (29), 118 (21), 94 (22), 77 (18), 64 (9). Anal. Calcd for C23H19N5O7 (477.43): C, 57.86; H, 4.01; N, 14.67%. Found: C, 57.64; H, 3.95; N, 14.48%.

4. Conclusions

In the current study, the recently synthesized 2-chloro-5-[(6-hydroxy-4,7- dimethoxy-1-benzofuran-5-yl)carbonyl]pyridine-3-carbonitrile (1) was efficiently utilized as a building block for the construction of various heterocyclic systems. Linear and angular annulated pyridines linked to the (6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)carbonyl were efficiently synthesized through the reaction of starting precursor 1 with binucleophilic reagents. All the synthesized compounds showed a remarkable effect against yeast and fungus strains, while compounds 4, 5, 7, 9, 11, 12 and 16–18 exhibited significant inhibitory effects against all tested microorganisms.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29184496/s1. Supporting Materials: (A) Copies of 1H-NMR, 13C-NMR and mass spectral data for the synthesized compounds and (B) Antimicrobial efficiency of the synthesized compounds with respected to references drugs.

Author Contributions

N.A.A. Investigation, Methodology, Formal analysis, Writing—review and editing; A.-S.B. Investigation, Methodology, Formal analysis, Writing—review and editing. M.A.I. Investigation, Methodology, Formal analysis, Writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Princess Nourah bint Abdulrahman University grant number (PNURSP2024R403).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

The authors thank the support from Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2024R403), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Qiu, Y.; Yang, X.; Xu, J.; Liu, B.; Li, X. Benzofuran ε-caprolactam glucosides, amides and phenylpropanoid derivatives with anti-inflammatory activity from Oxybaphus himalaicus. Phytochemistry 2021, 191, 112905. [Google Scholar] [CrossRef] [PubMed]
  2. Xu, F.; Zhang, L.; Zhou, C.; Mo, J.; Shen, S.; Zhang, T.; Li, J.; Lin, L.; Wu, R.; Gan, L. Alkyl-benzofuran dimers from Eupatorium chinense with insulin-sensitizing and anti-inflammatory activities. Bioorg. Chem. 2021, 113, 105030. [Google Scholar] [CrossRef] [PubMed]
  3. Su, T.; Pu, M.-C.; Tang, D.-K.; Long, J.-C.; Yuan, F.-Y.; Yin, A.-P.; Wu, S.-Q.; Yin, S.; Tang, G.-H. New benzofuran neolignans with neuroprotective activity from Phyllanthodendron breynioides. Nat. Prod. Res. 2023, 37, 3798–3805. [Google Scholar] [CrossRef]
  4. Radadiya, A.; Shah, A. Bioactive benzofuran derivatives: An insight on lead developments, radioligands and advances of the last decade. Eur. J. Med. Chem. 2015, 97, 356–376. [Google Scholar] [CrossRef]
  5. Liang, X.; Zhao, H.; Du, J.; Li, X.; Li, K.; Zhao, Z.; Bi, W.; Zhang, X.; Yu, D.; Zhang, J.; et al. Discovery of benzofuran-2-carboxylic acid derivatives as lymphoid tyrosine phosphatase (LYP) inhibitors for cancer immunotherapy. Eur. J. Med. Chem. 2023, 258, 115599. [Google Scholar] [CrossRef] [PubMed]
  6. Liu, Y.; Wu, Z.; Li, M.; Gao, H.; Wan, C.; Mao, Z. Anticancer evaluation of benzofuran derivatives linked to dipiperazine moiety, Bioorg. Med. Chem. Lett. 2023, 91, 129378. [Google Scholar] [CrossRef]
  7. Patel, P.; Shakya, R.; Vishakha; Asati, V.; Kurmi, B.D.; Verma, S.K.; Gupta, G.D.; Rajak, H. Furan and benzofuran derivatives as privileged scaffolds as anticancer agents: SAR and docking studies (2010 to till date). J. Mol. Struct. 2024, 1299, 137098. [Google Scholar] [CrossRef]
  8. Schumacher, T.J.; Sah, N.; Palle, K.; Rumbley, J.; Mereddy, V.R. Synthesis and biological evaluation of benzofuran piperazine derivatives as potential anticancer agents. Bioorg. Med. Chem. Lett. 2023, 93, 129425. [Google Scholar] [CrossRef]
  9. Patil, J.V.; Umar, S.; Soni, R.; Soman, S.S.; Balakrishnan, S. Design, synthesis and anticancer activity of amide derivatives of substituted 3-methyl-benzofuran-2-carboxylic acid. Synth. Commun. 2023, 53, 217–233. [Google Scholar] [CrossRef]
  10. Riyahi, Z.; Asadi, P.; Hassanzadeh, F.; Khodamoradi, E.; Gonzalez, A.; Abdolmaleki, M.K. Synthesis of novel conjugated benzofuran-triazine derivatives: Antimicrobial and in-silico molecular docking studies. Heliyon 2023, 9, e18759. [Google Scholar] [CrossRef]
  11. Kilbile, J.T.; Ansari, S.A.; Gadekar, S.S.; Krishna, V.S.; Damale, M.G.; Kashid, B.B.; Sangshetti, J.N.; Sapkal, S.B. Design, synthesis, and molecular docking study of N-(arylsulfonyl)-l-proline-piperazine hybrids tethered with pyrazole/benzofuran moiety as antimicrobial agents. Synth. Commun. 2024, 54, 567–582. [Google Scholar] [CrossRef]
  12. Ashok, D.; Reddy, M.R.; Thara, G.; Dharavath, R.; Ramakrishna, K.; Nagaraju, N.; Gundu, S.; Sarasija, M. A new library of 1,2,3-triazole based benzofuran scaffolds: Synthesis and biological evaluation as potential antimicrobial agents. J. Heterocycl. Chem. 2022, 59, 1376–1384. [Google Scholar] [CrossRef]
  13. Kenchappa, R.; Yadav, D.B. Synthesis, analgesic and anti-inflammatory activity of benzofuran pyrazole heterocycles, Chem. Data Collect. 2020, 28, 100453. [Google Scholar] [CrossRef]
  14. Xie, Y.-S.; Kumar, D.; Bodduri, V.D.V.; Tarani, P.S.; Zhao, B.-X.; Miao, J.-Y.; Jang, K.; Shin, D.-S. Microwave-assisted parallel synthesis of benzofuran-2-carboxamide derivatives bearing anti-inflammatory, analgesic and antipyretic agents. Tetrahedron Lett. 2014, 55, 2796–2800. [Google Scholar] [CrossRef]
  15. Nagumo, M.; Ninomiya, M.; Oshima, N.; Itoh, T.; Tanaka, K.; Nishina, A.; Koketsu, M. Comparative analysis of stilbene and benzofuran neolignan derivatives as acetylcholinesterase inhibitors with neuroprotective and anti-inflammatory activities Bioorg. Med. Chem. Lett. 2019, 29, 2475–2479. [Google Scholar] [CrossRef]
  16. Yang, Z.; Luo, G.; Ying, Y.; Li, H.; Wan, Y.; Xu, G.; Li, M.; Xian, Y.; Feng, Y.; Fang, Y. Novel 2,6-disubstituted benzofuran-3-one analogues improve cerebral ischemia/reperfusion injury via neuroprotective and antioxidative effects. Bioorg. Chem. 2023, 132, 106346. [Google Scholar] [CrossRef] [PubMed]
  17. Abd El-Karim, S.S.; Anwar, M.M.; Ahmed, N.S.; Syam, Y.M.; Elseginy, S.A.; Aly, H.F.; Younis, E.A.; Khalil, W.K.B.; Ahmed, K.A.; Mohammed, F.F.; et al. Discovery of novel benzofuran-based derivatives as acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease: Design, synthesis, biological evaluation, molecular docking and 3D-QSAR investigation. Eur. J. Med. Chem. 2023, 260, 115766. [Google Scholar] [CrossRef]
  18. Diana, R.; Schibeci, M.; Arciello, A.; Sessa, L.; Concilio, S.; Piotto, S.; Caruso, U.; Panunzi, B. Two series of benzofuran and benzodifuran chelating chromophores with DR/NIR emission and anticancer activity. Dyes Pigments 2024, 224, 112034. [Google Scholar] [CrossRef]
  19. Yao, W.; Wang, J.; Zhong, A.; Li, J.; Yang, J. Combined KOH/BEt3 Catalyst for Selective Deaminative Hydroboration of Aromatic Carboxamides for Construction of Luminophores. Org. Lett. 2020, 22, 8086–8090. [Google Scholar] [CrossRef]
  20. Abdel Halim, S.; Ibrahim, M.A. Synthesis, spectral analysis, quantum studies, NLO, and thermodynamic properties of the novel 5-(6-hydroxy-4-methoxy-1-benzofuran-5-ylcarbonyl)-6-amino-3-methyl-1H-pyrazolo[3,4-b]pyridine (HMBPP). RSC Adv. 2022, 12, 13135. [Google Scholar] [CrossRef]
  21. Abdel Halim, S.; Ibrahim, M.A. Quantum computational, Spectroscopic investigations on benzofuranylcarbonylpyrazolopyridine by DFT/TD-DFT: Synthesis, Structure, NBO and NLO research. J. Mol. Struct. 2023, 1293, 136201. [Google Scholar] [CrossRef]
  22. Shang, H.; Zhou, W.; Wu, X.; Xiao, J.; Song, Y. Synthesis, Photophysics and Optical Limiting Properties of Functionalized Benzofuran Derivatives. Asian J. Org. Chem. 2023, 12, 139–144. [Google Scholar] [CrossRef]
  23. Zhang, Q.; Nie, H.; Zhang, K.; Huang, H.; Song, C. A novel base-promoted intramolecular cyclization approach for the synthesis of benzofurans, benzothiophenes and indoles. Tetrahedron 2022, 116, 132815. [Google Scholar] [CrossRef]
  24. Mundhe, P.; Bhanwala, N.; Saini, S.M.; Sumanth, G.; Shivaprasad, K.; Shende, S.U.; Reddy, K.; Chandrashekharappa, S. Domino synthesis of novel 3-alkenyl benzofuran derivatives-base mediated condensation cascade reaction. Tetrahedron 2023, 132, 133265. [Google Scholar] [CrossRef]
  25. Mutovska, M.; Skabeev, A.; Konstantinov, K.; Cabanetos, C.; Stoyanov, S.; Zagranyarski, Y. One-pot synthesis of fused-rings heterocyclic systems based on symmetrically benzofuran annulated 1,8-naphthalimides. Dyes Pigments 2023, 220, 111701. [Google Scholar] [CrossRef]
  26. Yao, W.; Wang, J.; Zhong, A.; Wang, S.; Shao, Y. Transition-metal-free catalytic hydroboration reduction of amides to amines. Org. Chem. Front. 2020, 7, 3515–3520. [Google Scholar] [CrossRef]
  27. Ibrahim, M.A.; El-Gohary, N.M. Chemical behavior of 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carboxaldehyde towards carbon nucleophilic reagents. J. Heterocycl. Chem. 2020, 57, 2815–2830. [Google Scholar] [CrossRef]
  28. Assiri, M.A.; Ali, T.E.; Ibrahim, M.A.; Badran, A.; Yahia, I.S. the chemical behavior of (2E)-3-(4,9-dimethoxy-5-oxo-5H- furo[3,2-g]chromen-6-yl)acrylonitrile towards Some Carbon Nucleophiles. Polycycl. Aromat. Compd. 2021, 41, 1357–1368. [Google Scholar] [CrossRef]
  29. Alshaye, N.A.; Ibrahim, M.A. Utility of 4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile for construction of some novel heteroannulated furochromenopyridines. Polycycl. Aromat. Compd. 2024, 44, 562–576. [Google Scholar] [CrossRef]
  30. Ali, T.E.; Assiri, M.A.; Ibrahim, M.A.; Yahia, I.S. Nucleophilic Reactivity of a Novel 3-Chloro-3-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)prop-2-enal. Russ. J. Org. Chem. 2020, 56, 845–855. [Google Scholar] [CrossRef]
  31. Ibrahim, M.A.; Allehyani, E.S. Reactivity of 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile towards some nitrogen nucleophilic reagents. Heterocycles 2020, 100, 2091–2107. [Google Scholar] [CrossRef]
  32. Yoon, H.R.; Balupuri, A.; Lee, J.; Lee, C.; Son, D.-H.; Jeoung, R.G.; Kim, K.; Choi, S.; Kang, N.S. Design, synthesis of new 3H-imidazo[4,5-b]pyridine derivatives and evaluation of their inhibitory properties as mixed lineage kinase 3 inhibitors. Bioorg. Med. Chem. Lett. 2024, 101, 129652. [Google Scholar] [CrossRef] [PubMed]
  33. Roby, O.; Kadiri, F.Z.; Loukhmi, Z.; Moutaouakil, M.; Tighadouini, S.; Saddik, R.; Aboulmouhajir, A. Synthesis of new set of imidazo[1,2-a]pyridine-Schiff bases derivatives as potential antimicrobial agents: Experimental and theoretical approaches. J. Mol. Struct. 2023, 1292, 136186. [Google Scholar] [CrossRef]
  34. Feng, X.; Wang, J.; Liu, D.; Shi, H.; Lu, W.; Shi, D. Multicomponent Strategy to Pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine Derivatives under Microwave Irradiation. J. Org. Chem. 2023, 88, 6682–6690. [Google Scholar] [CrossRef]
  35. Jiang, W.; Cheng, W.; Zhang, T.; Lu, T.; Wang, J.; Yan, Y.; Tang, X.; Wang, X. Synthesis and antifungal activity evaluation of novel pyridine derivatives as potential succinate dehydrogenase inhibitors. J. Mol. Struct. 2023, 1292, 136186. [Google Scholar] [CrossRef]
  36. Kassab, R.M.; Ibrahim, M.H.; Rushdi, A.; Almehmadi, S.J.; Zaki, M.E.A.; Al-Hussain, S.A.; Muhammad, Z.A.; Farghaly, T.A. Comprehensive study for synthesis, antiviral activity, docking and ADME study for the new fluorinated hydrazonal and indeno[1,2-b]pyridine derivatives. J. Mol. Struct. 2024, 1305, 137752. [Google Scholar] [CrossRef]
  37. Zailaee, R.A.; Zailaie, S.A.; Sobahy, T.M.; Al-Amshany, Z.M.; Al-Footy, K.O.; El-Shishtawy, R.M. Synthesis and antitumorigenesis effect of novel 2-amino -3-cyano pyridine derivatives containing sulfonamide moiety against breast cancer. J. Mol. Struct. 2024, 1301, 137309. [Google Scholar] [CrossRef]
  38. Lin, M.-Y.; Ji, T.-Y.; Zheng, M.; Chen, Y.-Y.; Xu, S.-Y.; You, W.-W.; Zhao, P.-L. Efficient synthesis and evaluation of novel 6-arylamino-[1,2,4]triazolo[4,3-a]pyridine derivatives as antiproliferative agents. Bioorg. Med. Chem. Lett. 2022, 75, 128978. [Google Scholar] [CrossRef] [PubMed]
  39. Mohamed, H.A.; Ammar, Y.A.; Elhagali, G.A.M.; Eyada, H.A.; Aboul-Magd, D.S.; Ragab, A. Discovery a novel of thiazolo[3,2-a]pyridine and pyrazolo[3,4-d]thiazole derivatives as DNA gyrase inhibitors; design, synthesis, antimicrobial activity, and some in-silico ADMET with molecular docking study. J. Mol. Struct. 2023, 1287, 135671. [Google Scholar] [CrossRef]
  40. Gong, C.; Zhou, Y.; Zhou, Q.; Meng, K.; Sun, Z.; Zeng, W.; Qin, Y.; Luo, X.; Xue, W. Novel flavonoid derivatives containing 1,2,4-triazolo[4,3-a]pyridine as potential antifungal agents: Design, synthesis, and biological evaluation. J. Saudi Chem. Soc. 2024, 28, 101797. [Google Scholar] [CrossRef]
  41. Abdelazeem, N.M.; Aboulthan, W.M.; Hassan, A.S.; Almehizia, A.A.; Naglah, A.M.; Alkahtani, H.M. Synthesis, in silico ADMET prediction analysis, and pharmacological evaluation of sulfonamide derivatives tethered with pyrazole or pyridine as anti-diabetic and anti-Alzheimer’s agents. Saudi Pharm. J. 2024, 32, 102025. [Google Scholar] [CrossRef] [PubMed]
  42. Hussain, R.; Khan, S.; Khan, Y.; Iqbal, T.; Anwar, S.; Aziz, T.; Alharbi, M. Development of promising acetylcholinesterase and butyrylcholinesterase inhibitors: Synthesis, in vitro and in silico approaches of pyridine derived fused bis-oxadiazole and bis-thiadiazole derivatives. J. Mol. Struct. 2024, 1310, 138228. [Google Scholar] [CrossRef]
  43. Alshaye, N.A.; Ibrahim, M.A. Synthesis and antimicrobial evaluation of 6-hydroxy-4,7-dimethoxybenzofuranylcarbonyl Tethered annulated pyridines. Synth. Commun. 2024, 54, 815–825. [Google Scholar] [CrossRef]
  44. El-Sayed, O.A.; Aboul-Enein, H.Y. Synthesis and antimicrobial activity of novel pyrazolo[3,4-b]quinoline derivatives. Arch. Pharm. 2001, 334, 117–120. [Google Scholar] [CrossRef]
  45. Deki, M.S.; Deki, B.R.; Deki, V.S.; Deki, S.V. Synthesis and structure of novel 3,4-annelated coumarin derivatives. J. Heterocycl. Chem. 2008, 45, 295–298. [Google Scholar] [CrossRef]
  46. Laakso, P.V.; Robinson, R.; Vandrewala, H.P. Studies in the triazine series including a new synthesis of 1:2:4-triazines. Tetrahedron 1957, 1, 103–118. [Google Scholar] [CrossRef]
  47. Al-Shaalan, N.H. Synthesis, Characterization and Biological Activities of Cu(II), Co(II), Mn(II), Fe(II), and UO2(VI) Complexes with a New Schiff Base Hydrazone: O-Hydroxyacetophenone-7-chloro-4-quinoline Hydrazone. Molecules 2011, 16, 8629–8645. [Google Scholar] [CrossRef]
  48. Oskooie, H.A.; Heravi, M.M.; Nazari, N.N.A. Synthesis of some nitrogen heterocycles under microwave irradiation in solventless system. Heterocycl. Commun. 2005, 11, 101–104. [Google Scholar] [CrossRef]
  49. Gould, J.C.; Bowie, J.M. The Determination of Bacterial Sensitivity to Antibiotics. Edinb. Med. J. 1952, 59, 178–199. [Google Scholar]
Molecules 29 04496 sch001
Scheme 1. Formation of pyrazolo[3,4-b]pyridines 4 and 5.
Scheme 1. Formation of pyrazolo[3,4-b]pyridines 4 and 5.
Molecules 29 04496 sch001
Molecules 29 04496 sch002
Scheme 2. Formation of pyridotriazolopyrimidine 6 and pyridotetrazolopyrimidine 7.
Scheme 2. Formation of pyridotriazolopyrimidine 6 and pyridotetrazolopyrimidine 7.
Molecules 29 04496 sch002
Molecules 29 04496 sch003
Scheme 3. Formation of angular pyridopyrimidotriazine 9 and benzoimidazopyrido-pyrimidine 10.
Scheme 3. Formation of angular pyridopyrimidotriazine 9 and benzoimidazopyrido-pyrimidine 10.
Molecules 29 04496 sch003
Molecules 29 04496 sch004
Scheme 4. Formation of naphthyridines 11, 12 and benzoimidazonaphthyridine 13.
Scheme 4. Formation of naphthyridines 11, 12 and benzoimidazonaphthyridine 13.
Molecules 29 04496 sch004
Molecules 29 04496 sch005
Scheme 5. Formation of pyrazolo[3,4-b][1,8]naphthyridines 14 and 15.
Scheme 5. Formation of pyrazolo[3,4-b][1,8]naphthyridines 14 and 15.
Molecules 29 04496 sch005
Molecules 29 04496 sch006
Scheme 6. Formation of pyrimido[4,5-b][1,8]naphthyridines 16–18.
Scheme 6. Formation of pyrimido[4,5-b][1,8]naphthyridines 16–18.
Molecules 29 04496 sch006
Molecules 29 04496 ch001
Chart 1. The antibacterial efficiency of synthesized compounds against S. aureus.
Chart 1. The antibacterial efficiency of synthesized compounds against S. aureus.
Molecules 29 04496 ch001
Table 1. Antimicrobial estimation, in vitro, for the prepared compounds 1–18 by disc diffusion measurement.
Table 1. Antimicrobial estimation, in vitro, for the prepared compounds 1–18 by disc diffusion measurement.
No.Zone Diameter (mm) * (% with Respect to Reference Drug)
Gram-Positive BacteriaGram-Negative BacteriaYeasts and Fungi
Compd. No.S. aureusB. subtilisS. typhimuriumE. coliC. albicansA. fumigatus
1000
μg/mL		500
μg/mL		1000
μg/mL		500
μg/mL		1000
μg/mL		500
μg/mL		1000
μg/mL		500
μg/mL		1000
μg/mL		500
μg/mL		1000
μg/mL		500
μg/mL
140%38%49%48%53%50%45%44%69%71%70%73%
477%77%69%72%69%68%71%74%86%75%73%77%
583%81%77%76%75%68%74%70%80%75%70%69%
646%50%51%52%47%46%39%41%71%64%77%73%
780%77%74%76%75%71%74%70%86%79%77%81%
986%88%83%84%75%71%68%74%83%75%73%73%
1057%58%49%48%42%39%45%52%71%68%73%77%
1180%81%71%72%78%75%68%70%77%71%68%69%
1271%69%69%72%72%71%74%78%74%68%78%77%
1349%42%46%40%53%43%42%41%69%71%70%69%
1454%54%43%44%58%50%47%44%74%71%77%81%
1551%50%49%48%50%46%39%41%77%75%68%73%
1677%77%74%72%78%68%66%67%74%71%77%81%
1789%85%71%72%72%64%71%70%77%75%68%73%
1883%83%80%76%75%71%68%71%71%68%77%77%
S100%100%100%100%100%100%100%100%100%100%100%100%
* Calculated from 3 times. S: Standard antibiotics, which are Cycloheximide for fungus and yeast, Chloramphencol for Gram-positive bacteria, and Cephalothin for Gram-negative bacteria.
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Alshaye, N.A.; Badran, A.-S.; Ibrahim, M.A. Linear and Angular Heteroannulated Pyridines Tethered 6-Hydroxy-4,7-Dimethoxybenzofuran: Synthesis and Antimicrobial Activity. Molecules 2024, 29, 4496. https://doi.org/10.3390/molecules29184496

AMA Style

Alshaye NA, Badran A-S, Ibrahim MA. Linear and Angular Heteroannulated Pyridines Tethered 6-Hydroxy-4,7-Dimethoxybenzofuran: Synthesis and Antimicrobial Activity. Molecules. 2024; 29(18):4496. https://doi.org/10.3390/molecules29184496

Chicago/Turabian Style

Alshaye, Najla A., Al-Shimaa Badran, and Magdy A. Ibrahim. 2024. "Linear and Angular Heteroannulated Pyridines Tethered 6-Hydroxy-4,7-Dimethoxybenzofuran: Synthesis and Antimicrobial Activity" Molecules 29, no. 18: 4496. https://doi.org/10.3390/molecules29184496

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