Next Article in Journal
2-(2-(4-Methoxyphenyl)-4,9-dimethyl-7-oxo-7H-furo[2,3-f]chromen-3-yl)acetic Acid
Previous Article in Journal
4,4’-(Pyridin-4-ylmethylene)dibenzonitrile
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molbank
Volume 2021
Issue 4
10.3390/M1303
molbank-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

An Efficient Synthesis of Novel 3-[(Heteroaryl-2-ylimino)-methyl]-4-hydroxy-chromen-2-ones and Analogue of Tetrazole Derivatives and Their Antibacterial Activity

by
Ramiz Hoti
1,
Hamit Ismaili
1,*,
Veprim Thaçi
1,*,
Gjyle Mulliqi-Osmani
2,
Malësore Pllana-Zeqiri
1 and
Agon Bytyqi
1
1
Department of Chemistry, Faculty of Mathematical and Natural Sciences, University of Prishtina “Hasan Prishtina’’, 10000 Prishtina, Kosovo
2
Faculty of Medicine, National Institute of Public Health of Kosovo, 10000 Prishtina, Kosovo
*
Authors to whom correspondence should be addressed.
Molbank 2021, 2021(4), M1303; https://doi.org/10.3390/M1303
Submission received: 28 October 2021 / Revised: 23 November 2021 / Accepted: 27 November 2021 / Published: 2 December 2021
(This article belongs to the Section Organic Synthesis and Biosynthesis)
Browse Figures
Versions Notes

Abstract

:
Synthesis of a series of the substituted [(pyridinyl and pyrimidin-2-ylimino)-ethyl]-4-hydroxy-chromen-2-ones and their tetrazole derivates is presented in this study. By catalytic condensation of 4-hydroxy-3-acetylcoumarine 2 and 2-aminopyridines 3(a-d), 3-[(pyridin-2-ylimino)-ethyl]-4-hydroxy-chromen-2-ones 4(a-d) are synthesized in high yield. During the condensation reaction of 2 and 4-amino-2,6-dihydroxypyrimidine 3e, 3-[1-(2,6-Dihydroxy-pyrimidin-4-ylimino)-ethyl]-4-hydroxy-chromen-2-one 4e as condensation products is synthesized. In following series, by cyclization reactions of compounds 4 (a-e) with sodium azide, analogue 3-substituted pyridin-2-yl and pyrimidin-2-yl-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one 5(a-e) are synthesized the products. Structural characterization of the synthesized products is done on the basis of spectrometric data. Antibacterial activity of the compounds 4(a-e) and 5(a-e) against S. aureus, E. coli and Klebsiella was examined by measuring the inhibition zones around the disks marked with the corresponding products solution. The impact of substitutions in antimicrobial is also explored. Compounds with polar groups have shown significant antibacterial activity against these microorganisms.

1. Introduction

Coumarin (2H-Chromen-2-one) derivatives are a large class of oxygen-containing heterocyclic compounds with particular importance. Many coumarins are found as ingredients of the plant world [1]. Most of them play an important role in various life processes. Some coumarins are involved in various enzymatic reactions because their benzopyran-2-one structure enables them to interact with diversity of enzymes in organisms, thereby exhibiting wide potentiality as bioactive drugs [2]. Coumarin derivatives first were known as important agents for the treatment and prevention of various diseases [3]. Some naturally occurring coumarins such as novobiocin, chlorobiocin and coumermycin are an unprecedented class of antibiotics, showing expressed activity against Gram-positive bacteria [4]. Many of the compounds being in this class exhibit various biological activities, such as antimicrobial [5,6], antifungal [7,8] and antimalarial [9]. It was reported that some coumarin analogues also exhibited antioxidant [10,11], cytotoxic [12,13] and anti-tubercular activity [14]. A significant number of substituted coumarins also show sedative, analgesic, anticoagulant [15], anti-HIV [16,17], antidiabetic [18] and hepatoprotective activity [19]. The dynamics of the anticoagulant action of warfarin in the human body has also been investigated. Several warfarin analogues are currently used as rodenticides [20]. Some synthesized chromen-2-ones reported as anticancer agents [21,22]. For this reason, many of coumarin derivatives have found widespread usage in pharmacies. On the other hand, tetrazoles and their heterocyclic analogues are useful drugs with a wide range of applications in medicine, agriculture and material sciences. Many tetrazoles are reported as important pharmacophores that demonstrate a wide range of pharmacological activities and are widely used in medicinal chemistry. Some tetrazole analogues as transporter inhibitors also are reported [23]. Many of them are reported to exhibit antihypertensive [24], anti-analgesic [25], anti-ulcer and anti-inflammatory activity [26]. The extraordinary biological importance of such derivatives on the basis of chromen-2-one has generated a constant interest in their synthesis and research. The biological activity of coumarin derivatives is conditioned by their structure. The type and potency of biological activity are conditioned by the presence of various substituents in the benzopyronic moiety. However, despite continuous efforts, the structure and biological activity relationship of these derivatives so far has not yet been sufficiently clarified. We have previously reported on the synthesis and antibacterial activity of some substituted chromen-2-one derivatives [27,28,29]. In continuation of our previous studies, in this paper our aim is to report about the synthesis of some new substituted 4-hydroxy-chromene-2-one derivatives through condensation reactions of 4-hydroxy-3-acetylcoumarin with substituted aminopyridines and aminopyrimidines, as well as some tetrazole analogues through cyclization reactions of these derivatives with sodium azide, for which so far there are no data from the literature. Following this work, their antibacterial activity against S. aureus, E. coli and Klebsiella also are screened. Based on the obtained results, we think that these compounds could find use as pharmaceutical products.

2. Results and Discussion

2.1. Chemistry

The 3-acetyl-4-hydroxycoumarin is synthesized by direct acetylation of 4-hydroxycoumarin with acetic acid in the presence of Phosphorous oxychloride as a catalyst, according to the procedure described in the literature [30]. By condensation reaction3-acety 4 hydroxycoumarin 2 and 2-amino-5-chloropyridine 3a, 3-[1-(5-Chloro-pyridin-2-ylimino)-ethyl]-4-hydroxy-chromen-2-one 4a is synthesized. Condensation reaction of compound 2 and 2-amino-3,5-dichloropyridine 3b resulted in formation of 3-[1-(3,5-Dichloro-pyridin-2-ylimino)-ethyl]-4-hydroxy-chromen-2-one 4b, whereas by condensation of 2 and 2-amino-5-bromopyridine 3c afforded 3-[1-(5-Bromo-pyridin-2-yl)-methyl]-4-hydroxy-chromen-2-one 4c. Reaction of 2 and 2-amino-3-benzyloxypyridine 3d gave 3-[1-(3-Benzyloxy-pyridin-2-ylimino)-ethyl]-4-hydroxy-chromen-2-one 4d, whereas condensation of 2 and 4-amino-2-6-dihydroxypyrimidine 3e afforded 3-[1-(2,6-Dihydroxy-pyrimidin-4-ylimino)-ethyl]-4-hydroxy-chromen-2-one 4e. In the last series of reactions, by cyclization of the product 4(a-e) with sodium azide, respective tetrazolyl analogues, 3-[1-(5-Chloro-pyridin-2-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one 5a, 3-[1-(3,5-Dichloro-pyridin-2-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one 5b, 3-[1-(5-Bromo-pyridin-2-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one 5c, 3-[1-(3-Benzyloxy-pyridin-2-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one 5d and 3-[1-(2,6-dihydroxy-pyrimidin-4-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxychromen-2-one 5e are synthesized (Scheme 1).
The synthesized products 4(a-e) and 5(a-e) are characterized on the basis of spectrometric data and their elemental analysis. In the IR spectrum of the product 4a a broad absorption mode at 3450–3100 cm−1 appeared due to ν(OH)str. Vibrations, while an absorption signal at 3071.08 cm−1 resulted from aromatic ν(CH)str. vibrations. The absorption peaks appeared at 1730.57, 1669.25 and 1612.46 cm−1 due to stretching ν(C=O), ν(C=N) and ν(C=C) of aromatic system, while the sharp peak at 765.33 cm−1 is due to aromatic δ(C-H) oop. vibrations.
In the 1H-NMR spectrum, except characteristic peaks of aromatic protons, a singlet at 8.10 ppm and a doublet at 8.05 ppm appeared due to protons of pyridine moiety, whereas a singlet at 0.95 ppm resulted from methyl protons. The 13C-NMR spectrum showed characteristic absorptions for 16 carbon atoms. On the other hand, elemental analysis supports the structure of compound 4a.
In the IR spectrum of 4b, the broad absorption band at 3440–3100 cm−1 resulted due to ν(OH)stretching vibrations. The signal appeared at 3053.62 cm−1 corresponding to ν(CH)str. of the aromatic ring, while the sharp peak at 1734.85 cm−1 is characteristic for ν(C=O)str. vibrations. Absorption modes at 1651.02 and 1610.45 cm−1 appeared due to ν(C=N) str. and ν(C=C)str. of the aromatic system. The mode at 1093.23 cm−1 is also characteristic for stretching ν(C-O-C) vibrations of the lactonic moiety, while absorptions at 867.28 and 756.94 cm−1 appeared due to ν(C-Cl) str. and aromatic δ(C-H) oop. vibrations. On the other hand, except for characteristic signals for aromatic protons, a singlet at 1.1 ppm appeared due to methyl protons. 13C-NMR spectrum also showed characteristic peaks for 16 carbon atoms and the elemental analysis is consistent with the composition of this compound.
In the IR spectrum of the compound 4d a broad absorption due to ν(OH)str. vibrations appeared at 3450–3100 cm−1 and peaks at 3067.46 and 2955.92 cm−1 are responsible for aromatic ν(CH)str. and methylene ν(CH)str. vibrations. The absorption modes at 1713.71, 1662.02 and 1610.56 cm−1 resulted from lactonic ν(C=O)str., ν(C=N)str. and ν(C=C)str. vibrations of this compound. A signal at 1043.07 cm−1 and another at 756.72 cm−1 are responsible for lactonic ν(C-O-C)str. and aromatic δ(C-H) oop. The 1H-NMR spectrum of 4d showed aromatic protons appearing at 7.42 ppm as a triplet, at 6.99 ppm as a doublet and at 6.54 ppm as a doublet of a doublet. A proton singlet resulting from methyl protons appeared at 1.2 ppm. In the 13C-NMR spectrum, methylene carbon appeared a signal at 75.2 ppm, whereas the elemental composition of product 4d is confirmed by elemental analysis.
IR spectrum of 4e showed a broad band at 3360–3000 cm−1 which is responsible for ν(OH)str. vibrations. Signals at 1725.67, 1655.24 and 1584.73 cm−1 resulted from the ν(C=O)str., ν(C=N)str. and ν(C=C)str. vibrations, whereas characteristic modes at 1051.84 and 763.31 cm−1 appeared due to lactonic ν(C-O-C)str. and bending δ(CH) oop. vibrations of the aromatic ring. The 1H-NMR spectrum of 4e, except doublets and doublet of doublets for aromatic protons, a singlet at 6.1 ppm for pyrimidine proton has appeared. The 13C-NMR spectrum of 4e showed characteristic signals for C-OH carbons appeared at 175.2 and 174.7 ppm, while C=N and C=O carbons displayed corresponding absorptions 167.4 and 160.5 ppm, respectively. Elemental analysis of this compound also confirmed their composition. Tetrazoles 5(a-e) also are characterized on the basis of spectrometric data.
In the IR spectrum of compound 5a, except others, the absorption peak at 3420.34 and 1669.84 cm−1 resulted from ν(NH)str. and ν(N=N)str. argue the presence of tetrazole ring. The 1H-NMR spectrum of 5a showed singlets at 8.2 ppm of N=C-H, at 3.2 ppm of N-H and another singlet at 1.3 ppm of methyl protons. The 13C-NMR spectrum shows for 16 carbons, among which the characteristic ones are at 161.7 ppm from C-N of pyridine, a signal at 78.9 ppm from C-tetrazole, and the other signal at 20.2 ppm due to methyl carbon.
In the IR spectrum of product 5b the characteristic signals appeared at 3391.65 and 1680.35 cm−1, which resulted from v(NH) and v(N=N)str. vibrations of the tetrazole ring, respectively. Tetrazole residue was also confirmed by the presence of a singlet at 3.5 ppm from tetrazole. Another singlet at 1.4 ppm resulted from methyl protons. Tetrazole moiety also is confirmed from characteristic modes at 76.8 ppm in the 13C-NMR spectrum, whereas absorption mode at 21,5 ppm resulted from methyl carbon.
Compound 5c exhibited absorption mode from vibrations ν(N=N)str. at 1650.31 cm−1, while in the 1H-NMR spectrum the singlets at 2.1 ppm and at 1.4 ppm appeared resulting from tetrazole and methyl protons. The 13C-NMR spectrum showed the characteristic signal for C-tetrazole at 76.1 ppm, as well as the characteristic signals for 15 other aromatic carbons.
In the IR spectrum of the 5d compound, except aromatic ν(CH)str. vibrations at 3079.55 cm−1, the ν(CH)str. mode of the methyl group at 2947.48 cm−1 are also observed, while a signal displayed at 1665.82 cm−1 resulted from ν(N=N)str. vibrations. The 1H-NMR spectrum shows the corresponding a signal at 2.2 ppm of the tetrazole proton, as well as a singlet at 1.4 ppm from the CH3 protons. Absorption mode at 78.8 ppm in the 13C-NMR spectrum argues the presence of tetrazole moiety.
A broad band in the IR spectrum of 5e displayed at 3420–3100 cm−1 has resulted from ν(OH)str. vibrations, while the peak at 3450.05 appeared due to ν(NH)str. vibrations. On the other hand, absorption mode at 1665.82 cm−1 reflects the ν(N=N)str. vibrations of the tetrazole ring. In support of confirmation of tetrazole ring is also the singlet displayed at 2.2 ppm in the 1H-NMR spectrum, as well as the signal at 78.8 ppm in the 13C-NMR spectrum. The structure of compounds 5(a-e) has also been confirmed by its elementary analysis (Table 1).

2.2. Antibacterial Activity of the Products 4(a-e) and 5(a-e)

In the following, this study includes results of antibacterial activity of products 4(a-e) and 5(a-e). Our research has focused on testing the antibacterial activity of these compounds against the bacteria S. aureus, E. coli and Klebsiella. Screening of antibacterial activity was done on the basis of Kirby Bayer method [30,31,32], by measuring the zones of inhibition around the standard discs that have previously been marked with solutions of the products in N,N-DMF with concentrations of 2 mg/mL, 4 mg/mL and 6 mg/mL. The bacterial cultures have incubated for 48 h at 37 °C. The biological evaluation also is based on previous studies [33,34].
The results in Figure 1, Figure 2 and Figure 3 show that compounds of series 4 and 5 showed exhibited considerable activity against these bacteria. Compounds 4b and 5e expressed the significant activity against S. aureus, while 5b and 4e were most active against E. coli, and 5b and 5e were more active against Klebsiella. These compounds expressed both bactericide and bacteriostatic activity against S. aureus. Furthermore, antibacterial activity against E. coli and Klebsiella is displayed on a large-scale as bactericide activity. In general, the bacteriostatic activity is exhibited in a large range (+4 mm), whereas bactericide activity showed in small diameter. The influence of polar groups was quite pronounced. while tetrazole moiety appeared low impact on antimicrobial activity. The impact of chlorine is particularly noted which has affected the increase of antibacterial activity. The pyrimidine hydroxyl groups 5e has shown a significant impact on the range of antibacterial activity against the bacterial culture Klebsiella. Based on these results we consider that antibacterial activity may result as a consequence of the involvement of these compounds in enzymatic reactions during bacterial reproduction. It is believed that these compounds may have caused enzymatic inhibition by binding to the active center of enzymes that participates in the cellular wall construction of these bacteria. However, the mechanism of inhibition is not yet fully studied. In general, antimicrobial activity increased by increasing the concentration of the products.

3. Material and Methods

3.1. Materials and Basic Measurements

The new compounds are synthesized under refluxing conditions using commercial reagents of Aldrich company as precursors with pro-analysis purity. Reaction flow was monitored by TLC using Merck Kieselgel-60 (F-254) as the stationary phase and mixture of benzene, toluene, glacial acetic acid (v/v/v, 80:10:10) as mobile phase, visualization with Uv lamp. Purification of the products is done by recrystallization from ethanol. Melting points of the compounds were determined in a paraffin oil bath with an open capillary tube and are uncorrected. IR spectra are recorded in KBr discs on Shimadzu 8400xFT-IR spectrometer with 4cm−1 resolution. 1H-NMR and 13C-NMR spectra are recorded in DMSO-d6 on UNITYplus-500“NMR 1” spectrometer. Chemical shifts were reported in ppm down field from TMS as internal standard (δ0.00). Antibacterial activity of the compounds was examined on the basis of Kirby-Bayer’s method, using standard discs (d = 5.0 mm, maximum capacity10 pg). Standard discs are previously saturated with compound solutionsin N,N-DMF concentrations 2 mg/mL, 4 mg/mL and 6 mg/mL.

3.2. 3-[Pyridin-2-ylimino)-ethyl]-4-hydroxy-chromen-2-ones 4(a-e), General Procedure

3-Acetyl-4-hydroxycoumarin 2 (0.82 g, 0.004 mol) is dissolved in 15 mL ethanol and 2–3 drops of sulphuric acid is added. The mixture is stirred at room temperature and an equimolar amount of corresponding 2-aminopyridine 3a-d or 4-aminopyrimidine 3e (0.004 mol dissolved in 10 mL ethanol) is added to the mixture in small portions, then the mixture is refluxed for 6–8 h. After cooling, the mixture is concentrated in the rotary evaporator, the residue is cooled and the crystalline product is filtered off under vacuum and washed with 2 × 2 mL of ethanol. The crystalline product is dried and recrystallized from ethanol.

3.3. 3-[1-(5-Chloro-pyridin-2-ylimino)-ethyl]-4-hydroxy-chromen-2-one

4a: mp = 204–206 °C reflux time 6 h, R= 66%. IR (KBr disc, cm−1): 3450–3100, 3071.08, 1730.57, 1669.25, 1612.46, 1073.94, 765.33. 1H-NMR; (δ, ppm) 8.10 (s, 1H Pyr), 8.05 (d, 1H, Pyr), 7.76 (d, 1H, Ar), 7.64–7.61 (t, 1H, Ar), 7.40–7.36 (m, 2H, Ar), 7.12 -7.07 (t, 1H, Ar), 0.95 (s, 3H, CH3). 13C-NMR; (δ, ppm) 170.6 (C-2, Pyr.), 163.6 (C=N), 163.2 (C=N), 162.4(C=O), 159,5 (C-OH), 151.4, 149.5, 134.6, 128.8, 128.2, 125,7, 125.2, 124.8, 123.6, 121.9, 11.6.

3.4. 3-[1-(3,5-Dichloro-pyridin-2-ylimino)-ethyl]-4-hydroxy-chromen-2-one

4b: mp = 212–214 °C reflux time 6 h, R = 72%. IR (KBr disc, cm−1): 3440–3100, 3053.62, 1734.85, 1651.02, 1610.45, 1093.23, 867.28, 756.94. 1H-NMR; (δ, ppm), 8.7 (s, 1H, Pyr), 8.1 (s, 1H, Pyr), 7.5–7.3 (m, 2H, Ar), 7.2–7.0 (m, 2H, Ar), 1.1 (s, CH3). 13C-NMR; (δ, ppm) 167.9 (C-2 Pyr), 163.6 (C=N), 160.8 (C=O), 151.2, 147.8, 134.5, 128.2, 127,8, 126,4, 125.2, 124.4, 123.0, 121.5, 120.2, 111.3, 11.2.

3.5. 3-[1-(5-Bromo-pyridin-2-ylimino)-ethyl]-4-hydroxy-chromen-2-one

4c: mp = 125–127 °C reflux time 7 h, R = 75%. IR (KBr disc, cm−1): 3500–3110, 3068.35, 1739.44, 1683.37, 1022.41. 1H-NMR; (δ, ppm), 8.75–8.8.73 (s, 1H Pyr), 8.18–8.14 (d, 1H, Pyr), 7.74–7.71 (t, 1H, Ar), 7.68–7.66 (d, 1H, Ar), 7.41–7.37 (m, 2H, Ar), 7.24 -7.21 (t, 1H, Ar), 1.20 (s, 3H, CH3). 13C-NMR; (δ, ppm) 169.4 (C-2, Pyr.), 164.2 (C=N), 163.0 (C=N), 161.2 (C=O), 152.5, 150.1, 149.3, 137.0, 129.6, 128.2, 126.7, 125.3, 124.1, 123.5, 120.8, 10.8.

3.6. 3-[1-(3-Benzyloxy-pyridin-2-ylimino)-ethyl]-4-hydroxy-chromen-2-one

4d: mp = 305–307 °C reflux time 6 h, R = 38%. IR (KBr disc, cm−1): 3450–3100, 3067.46, 2955.92, 1713.71, 1662.02, 1610.56, 1043.07, 756.72. 1H-NMR; (δ, ppm), 8.3 (s, 1H, N=C-H, Pyr.), 7.74–7.73 (d, 1H), 7.68–7.67 (d, 1H), 7.42–7.41 (t, 1H), 6.99–6.97 (d, 1H), 6.87–6.70 (m), 6.54–6.51 (dd, 1H), 5.06 (s, 2H), 1.2 (s, 3H, CH3). 13C-NMR; (δ, ppm) 164.5 (C=N), 161.8 (C=O), 156.6, 151.2, 150,5, 146.7, 139.5, 129.8, 128.2, 127.6, 127,1, 126.7, 126,2, 125.9, 125.3, 123.4, 122.5, 121.6, 120.3, 110.6, 75.2, (O-CH2).

3.7. 3-[1-(2,6-Dihydroxy-pyrimidin-4-ylimino)-ethyl]-chromen-2-one

4e: mp =302–304 °C reflux time 8 h, R = 62%. IR (KBr disc, cm−1):3360–3000, 1725.67, 1655.24, 1584.73, 1051.84, 763.31. 1H-NMR; (δ, ppm), 7.75 (d, 1H, Ar), 7.54 (dd, 1H), 7.24 (dd, 1H), 7.18 (d, 1H, Ar), 6.1 (s, 1H, Pyrim), 5.4 (s, 2H), 1.12 (s, 3H, CH3). 13C-NMR; (δ, ppm) 175.2 (C-OH), 174.7 (C-OH), 167.4 (C-N), 165.2, 162.8, 160.5 (C=O), 148.6, 149.6, 129.7, 128.5, 126.5, 125.9, 121.6, 92.6, 12.4 (CH3).

3.8. 3-[Pyridin-2-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-ones 5(a-e), general procedure

The mixture of compound 4(a-e) (0.002 mol) and 0.2 g (0.003 mol) of sodium azide dissolved in 15 mL tetrahydrofuran refluxed for 6–8 h. The mixture is cooled in an ice bath and concentrated, then the crystalline product is filtered off under reduced pressure, then washed with 2 × 1 mL of ethanol and dried in the air. Compounds 5(a-e) were purified by recrystallization from ethanol.

3.9. 3-[1-(5-Chloro-pyridin-2-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one

5a:mp = 211–213 °C, R = 65%, IR (KBr disc, cm−1): 3450–3100, 3420.34, 3051.48, 2983.65, 1708,77, 1669.84, 1612.27, 1603.57, 1082.38, 897.25, 758.84. 1H-NMR; (δ, ppm), 8.2 (s, 1H, N = C-H), 7.6–7.4 (m, 3H, Ar), 7.3–7.2 (m, 2H, Pyr), 3.2 (s, 1H), 1.3 (s, 3H, CH3). 13C-NMR; (δ, ppm) 166.1 C-OH, 162.8(C=O), 161.7 (C-N, Pyr.), 151,4, 148.3, 145.7, 139,2, 129.2, 128.3, 127.2, 126.6, 122.5, 121.0, 95.2, 78.9 (C-Tetraz.), 20.2 (CH3). Please see Figure S2.

3.10. 3-[1-(3,5-Dichloro-pyridin-2-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one

5b: mp = 208–211 °C, R = 73%, IR (KBr disc, cm−1): 3420–3080, 3391.65, 3072.93, 2982.75, 1708,68, 1680.35, 1624.59, 1607.2, 1054.64, 912.42, 760.36. 1H-NMR; (δ, ppm), 8.2 (s, 1H, N=C-H), 7.8 (s, 1H), 7.5–7.2 (m, 4H, Ar), 3.5, 1.4 (s, 3H, CH3). 13C-NMR; (δ, ppm) 163.9 (C-OH), 161.2 (C=O), 157.4 (C-N, Pyr.), 149,8, 138,3, 129.5, 128.4, 127,3, 127.0, 126,3, 125.2, 123.7, 122.7, 108.4, 76.8 (C-Tetraz.), 21.5 (CH3). Please see Figure S3.

3.11. 3-[1-(5-Bromo-pyridin-2-yl)-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one

5c: mp = 120–122 °C, R = 70%, IR (KBr disc, cm−1): 3450–3100, 3068.38, 2974.38, 1711,46, 1650.31, 1602.26, 1600.31, 1049.39, 796.82, 764.32. 1H-NMR; (δ, ppm) 8.2 (s, 1H, N=C-H), 7.8 (d, 1H), 7.5–7.7 (m, 3H, Ar), 7.1 (d, 1H), 3.5 (s, 1H). 1.4 (s, 3H,), 13C-NMR; (δ, ppm) 166.4 (C-OH), 162.1 (C=O), 160.5 (C-N, Pyr.), 148.8, 145.6, 137,8, 129.2, 128.6, 127,3, 127.0, 125,1, 122.7, 120.8, 109.6, 76.1 (C-Tetraz.), 21.3 (CH3).

3.12. 3-[1-(3-Benzyloxy-pyridin-2-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one

5d: mp = 224–226 °C, R = 67%, IR (KBr disc, cm−1): 3420–3100, 3055.28, 2957.72, 1711.34, 1694,32, 1616.38, 1233.86, 1120.1, 762.53. 1H-NMR; (δ, ppm)7.9 (d, 1H), 7.5–7.8 (m, 4H, Ar), 7.3–7.1 (m, 5H), 7.0 (d, 1H), 6.8 (dd, 1H), 5.4 (s, 2H, OCH2), 3.4 (s, 1H,), 1.4 (s, 3H, CH3). 13C-NMR; (δ, ppm) 165.4 (C-OH), 163.8 (C=O), 152.4 (C-N, Pyr.), 148.3, 144.8, 143.4, 131.5, 130.4, 129.3, 128,7, 127,6, 127.0, 126.5, 126.0, 125.6, 124.2, 122.7, 122.2, 120.8, 109.6, 96.5, 77.4 (C-Tetraz.), 19.8 (CH3). Please see Figure S4.

3.13. 3-[1-(2,6-Dihydroxy-pyrimidin-4-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one

5e: mp = 223–225 °C, R = 45%, IR (KBr disc, cm−1): 3450.05, 3420–3100, 3079.55, 2947.48, 1727.86, 1665.82, 1660.24, 1054.26, 986.29, 761.25. 1H-NMR; (δ, ppm)7.6–7.4 (m, 2H, Ar), 7.2–7.0 (m, 2H, Ar), 5.2 (s, 2H,), 4.5 (s, 1H), 3.5 (s, 1H), 2.2 (s, 1H), 1.4 (s, 3H, CH3). 13C-NMR; (δ, ppm) 172.6, 165.5, 163.4 (C=O), 161.0 (C-N, Pyr.), 151.2, 129.2, 128.8, 127.3, 126.2, 125.5, 122.6, 121.2, 102,4, 78.8 (C-Tetraz.), 21.3 (CH3). Please see Figure S5.
Antibacterial activity is screened by measuring the zones of inhibition around the standard discs saturated with solutions of the products in N,N-DMF with concentrations of 2 mg/mL, 4 mg/mL and 6 mg/mL, incubation at 37 °C for 48 h.

4. Conclusions

Novel-substituted-[(pyridinyl-and-[(pyrimidin-2-ylimino)-ethyl]-4-hydroxy-chromen-2-ones 4(a-e) and respective 3-substituted pyridin-2-yl and pyrimidin-2-yl-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one 5(a-e) are synthesized in the moderate and high yield. The synthesis was done stepwise with different reactants in different condition. Synthesis is carried off by refluxing the reaction mixture for a given period. Synthesized compounds were characterized on the basis of their spectrometric data. The impact of polar substituents in antibacterial activity was significant, so compounds with chlorine and hydroxyl substituents showed expressed activity against S. aureus, E. coli, and Klebsiella bacteria. Antibacterial activity is shown to be proportional to the concentration of these compounds. The compounds 4e and 5e have shown significant activity at E. coli. The compounds 5b and 5e showed very good antibacterial activity at Klebsiella, whereas compound 4b has shown good activity at S. aureus.

Supplementary Materials

The following are available online, all synthesized compounds are characterization by spectral methods, IR and NMR. Graphical presentation of inhibition zone diameter (mm) against S. aureus. Graphical presentation of inhibition zone diameter (mm) against E. coli. Graphical presentation of inhibition zone diameter (mm) against Klebsiella. Melting points are shown melting points for synthesized compounds 4(a-e) and 5(a-e). Figure S1. 2. 3-Acetyl-4-hydroxy-chromen-2-one. Figure S2. 5a. 3-[1-(5-Chloro-pyridin-2-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one. Figure S3. 5b. 3-[1-(3,5-Dichloro-pyridin-2-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one. Figure S4. 5d. 3-[1-(3-Benzyloxy-pyridin-2-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one. Figure S5. 5e. 3-[1-(2,6-Dihydroxy-pyrimidin-4-yl)-5-methyl-2,5-dihydro-1H-tetrazol-5-yl]-4-hydroxy-chromen-2-one.

Author Contributions

Conceptualization, R.H., H.I. and V.T.; Methodology, R.H., H.I. and G.M.-O.; Investigation, R.H., H.I., V.T., M.P.-Z., A.B. and G.M.-O.; Writing–Original Draft, R.H., H.I. and V.T.; Writing—Review & Editing, R.H., H.I., V.T. and M.P.-Z.; Resources, R.H., H.I. and A.B.; Supervision, R.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 2, 4(a-d), 4e, 5(a-d) and 5e are available from the authors.

References

  1. Stefanachi, A.; Leonetti, F.; Pisani, L.; Catto, M.; Carotti, A. Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds. Molecules 2018, 23, 250. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Jameel, E.; Umar, T.; Kumar, J.; Hoda, N. Coumarin: A Privileged Scaffold for the Design and Development of Antineurodegenerative Agents. Chem. Biol. Drug Des. 2016, 87, 21–38. [Google Scholar] [CrossRef] [PubMed]
  3. Musa, M.; Cooperwood, J.; Khan, M.O. A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer. Curr. Med. Chem. 2008, 15, 2664–2679. [Google Scholar] [CrossRef] [Green Version]
  4. Marcu, M.G.; Schulte, T.W.; Neckers, L. Novobiocin and Related Coumarins and Depletion of Heat Shock Protein 90-Dependent Signaling Proteins. JNCI J. Natl. Cancer Inst. 2000, 92, 242–248. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Khan, M.S.; Agrawal, R.; Ubaidullah, M.; Hassan, M.I.; Tarannum, N. Design, Synthesis and Validation of Anti-Microbial Coumarin Derivatives: An Efficient Green Approach. Heliyon 2019, 5, e02615. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Kushwaha, K.; Kaushik, N.; Lata; Jain, S.C. Design and Synthesis of Novel 2H-Chromen-2-One Derivatives Bearing 1,2,3-Triazole Moiety as Lead Antimicrobials. Bioorg. Med. Chem. Lett. 2014, 24, 1795–1801. [Google Scholar] [CrossRef]
  7. Prusty, J.S.; Kumar, A. Coumarins: Antifungal Effectiveness and Future Therapeutic Scope. Mol. Divers. 2020, 24, 1367–1383. [Google Scholar] [CrossRef]
  8. Guerra, F.Q.S.; Araújo, R.S.A.; Sousa, J.P.; Silva, V.A.; Pereira, F.O.; Mendonça-Junior, F.J.B.; Barbosa-Filho, J.M.; Pereira, J.A.; Lima, E.O. A New Coumarin Derivative, 4-Acetatecoumarin, with Antifungal Activity and Association Study against Aspergillus spp. Braz. J. Microbiol. 2018, 49, 407–413. [Google Scholar] [CrossRef]
  9. Patel, K.; Karthikeyan, C.; Hari Narayana Moorthy, N.S.; Deora, G.S.; Solomon, V.R.; Lee, H.; Trivedi, P. Design, Synthesis and Biological Evaluation of Some Novel 3-Cinnamoyl-4-Hydroxy-2H-Chromen-2-Ones as Antimalarial Agents. Med. Chem. Res. 2012, 21, 1780–1784. [Google Scholar] [CrossRef]
  10. Salem, M.; Marzouk, M.; El-Kazak, A. Synthesis and Characterization of Some New Coumarins with in Vitro Antitumor and Antioxidant Activity and High Protective Effects against DNA Damage. Molecules 2016, 21, 249. [Google Scholar] [CrossRef]
  11. Kenchappa, R.; Bodke, Y.D.; Chandrashekar, A.; Aruna Sindhe, M.; Peethambar, S.K. Synthesis of Coumarin Derivatives Containing Pyrazole and Indenone Rings as Potent Antioxidant and Antihyperglycemic Agents. Arab. J. Chem. 2017, 10, S3895–S3906. [Google Scholar] [CrossRef] [Green Version]
  12. Mohareb, R.; MegallyAbdo, N. Uses of 3-(2-Bromoacetyl)-2H-Chromen-2-One in the Synthesis of Heterocyclic Compounds Incorporating Coumarin: Synthesis, Characterization and Cytotoxicity. Molecules 2015, 20, 11535–11553. [Google Scholar] [CrossRef] [Green Version]
  13. Liu, C.-F.; Shen, Q.-K.; Li, J.-J.; Tian, Y.-S.; Quan, Z. Synthesis and Biological Evaluation of Novel 7-Hydroxy-4-Phenylchromen-2-One–Linked to Triazole Moieties as Potent Cytotoxic Agents. J. Enzym. Inhib. Med. Chem. 2017, 32, 1111–1119. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Patel, P.; Patel, T.; Baxi, S.; Acharya, H.; Tripathi, C. Antitubercular Effect of 8-[(4-Chloro Phenyl) Sulfonyl]-7-Hydroxy-4-Methyl-2H-Chromen-2-One in Guinea Pigs. J. Pharmacol. Pharmacother. 2011, 2, 253–260. [Google Scholar] [CrossRef]
  15. O’Reilly, R.A.; Aggeler, P.M.; Leong, L.S. STUDIES ON THE COUMARIN ANTICOAGULANT DRUGS: THE PHARMACODYNAMICS OF WARFARIN IN MAN*. J. Clin. Invest. 1963, 42, 1542–1551. [Google Scholar] [CrossRef] [Green Version]
  16. Olmedo, D.; Sancho, R.; Bedoya, L.M.; López-Pérez, J.L.; del Olmo, E.; Muñoz, E.; Alcamí, J.; Gupta, M.P.; San Feliciano, A. 3-Phenylcoumarins as Inhibitors of HIV-1 Replication. Molecules 2012, 17, 9245–9257. [Google Scholar] [CrossRef]
  17. Bhavsar, D.; Trivedi, J.; Parekh, S.; Savant, M.; Thakrar, S.; Bavishi, A.; Radadiya, A.; Vala, H.; Lunagariya, J.; Parmar, M.; et al. Synthesis and in Vitro Anti-HIV Activity of N-1,3-Benzo[d]Thiazol-2-Yl-2-(2-Oxo-2H-Chromen-4-Yl)Acetamide Derivatives Using MTT Method. Bioorg. Med. Chem. Lett. 2011, 21, 3443–3446. [Google Scholar] [CrossRef]
  18. Domitrović, R.; Potočnjak, I. A Comprehensive Overview of Hepatoprotective Natural Compounds: Mechanism of Action and Clinical Perspectives. Arch. Toxicol. 2016, 90, 39–79. [Google Scholar] [CrossRef]
  19. Soni, R.; Durgapal, S.D.; Soman, S.S.; Georrge, J.J. Design, Synthesis and Anti-Diabetic Activity of Chromen-2-One Derivatives. Arab. J. Chem. 2019, 12, 701–708. [Google Scholar] [CrossRef]
  20. Servet Altay, A.; Leonetti, F.; Pisani, L.; Catto, M.; Carotti, A. Prolonged Coagulopathy Related to Coumarin Rodenticide in a Young Patient: Superwarfarin Poisoning. Cardiovasc. J. Afr. 2012, 23, 9–11. [Google Scholar] [CrossRef]
  21. Amin, K.M.; Abou-Seri, S.M.; Awadallah, F.M.; Eissa, A.A.M.; Hassan, G.S.; Abdulla, M.M. Synthesis and Anticancer Activity of Some 8-Substituted-7-Methoxy-2H-Chromen-2-One Derivatives toward Hepatocellular Carcinoma HepG2 Cells. Eur. J. Med. Chem. 2015, 90, 221–231. [Google Scholar] [CrossRef] [PubMed]
  22. Liu, X.-H.; Li, J.; Wu, F.-R.; Song, B.-A.; Pinaki, S.B.; Shi, L. Novel 3-(2-(3-Methyl-5-Substituted-Phenyl-4,5-Dihydropyrazol-1-Yl)-2-Oxoethoxy)-2-Substituted-Phenyl-4H-Chromen-4-One: Synthesis and Anticancer Activity. Med. Chem. 2011, 7, 605–610. [Google Scholar] [CrossRef] [PubMed]
  23. Cai, W.; Liu, W.; Xie, Y.; Wu, J.; Liu, Y.; Liu, C.; Xu, W.; Tang, L.; Wang, J.; Zhao, G. Design, Synthesis and Biological Activity of Tetrazole-Bearing Uric Acid Transporter 1 Inhibitors. Chem. Res. Chin. Univ. 2017, 33, 49–60. [Google Scholar] [CrossRef]
  24. Vellalacheruvu, R.; Leela R, S.; Lk, R. Novel Route for Synthesis of Antihypertensive Activity of Tetrazole Analogues as a Carbamate and Urea Derivatives. Med. Chem. 2017, 7, 239–246. [Google Scholar] [CrossRef]
  25. Rajasekaran, A.; Thampi, P.P. Synthesis and Analgesic Evaluation of Some 5-[β-(10-Phenothiazinyl)Ethyl]-1-(Acyl)-1,2,3,4-Tetrazoles. Eur. J. Med. Chem. 2004, 39, 273–279. [Google Scholar] [CrossRef]
  26. Lamie, P.F.; Philoppes, J.N.; Azouz, A.A.; Safwat, N.M. Novel Tetrazole and Cyanamide Derivatives as Inhibitors of Cyclooxygenase-2 Enzyme: Design, Synthesis, Anti-Inflammatory Evaluation, Ulcerogenic Liability and Docking Study. J. Enzym. Inhib. Med. Chem. 2017, 32, 805–820. [Google Scholar] [CrossRef] [Green Version]
  27. Hoti, R.; Nura-Lama, A.; Mulliqi-Osmani, G.; Troni, N.; Gashi, F.; Ismaili, H.; Thaçi, V. Synthesis of 4-Triazolylamino- and 4-Benzothiazolylamino-3- Nitro-2H-[1]-Benzopyran-2-Ones and Their Antimicrobial Activity. Orbital Electron. J. Chem. 2014, 6, 184–190. [Google Scholar]
  28. Hoti, R.; Ismaili, H.; Vehapi, I.; Troni, N.; Mulliqi-Osmani, G.; Thaçi, V. Synthesis of new [(3-nitro-2-oxo-2H-chromen-4-ylamino)-phenyl]-phenyl-triazolidin-4-ones and their antibacterial activity. Chem. Bulg. J. Sci. Educ. 2017, 26, 262–274. [Google Scholar]
  29. Hoti, R.; Troni, N.; Ismaili, H.; Pllana, M.; Pacarizi, M.; Thaçi, V.; Mulliqi-Osmani, G. Synthesis of new 3-[(chromen-3-YL)-ethylideneamino]-phenyl]-thiazolidin-4-ones and their antibacterial activity. Chem. Bulg. J. Sci. Educ. 2018, 27, 109–119. [Google Scholar]
  30. Abdou, M.M. 3-Acetyl-4-Hydroxycoumarin: Synthesis, Reactions and Applications. Arab. J. Chem. 2017, 10, 3664–3675. [Google Scholar] [CrossRef] [Green Version]
  31. Bauer, A.W.; Kirby, W.M.M.; Sherris, J.C.; Turck, M. Antibiotic Susceptibility Testing by a Standardized Single Disk Method. Am. J. Clin. Pathol. 1966, 45, 493–496. [Google Scholar] [CrossRef] [PubMed]
  32. Hudzicki, J. Kirby-Bauer Disk Diffusion Susceptibility Test Protocol; ASM MicrobeLibrary; American Society for Microbiology: New York, NY, USA, 2009. [Google Scholar]
  33. Abdelmajeid, A.; Ali, a.A.; Ashour, M. Synthesis and Evaluation of in Vitro Biological Activity of New Series of Quinazolinone and Benzoxazinone Derivatives. Egypt. J. Chem. 2021, 64, 2653–2661. [Google Scholar] [CrossRef]
  34. Saleh, M.; Ayoub, A.; Hammady, A. Synthesis Biological Studies of Some New Heterocyclic Compound Derived from 2-Chloro-3-Formyl Quinoline and 4-(Benzyl Sulfonyl) Acetophenone. Egypt. J. Chem. 2020, 63, 4769–4776. [Google Scholar] [CrossRef]
Molbank 2021 m1303 sch001 550
Scheme 1. Synthetic procedure to obtain the analogs of tetrazole derivatives.
Scheme 1. Synthetic procedure to obtain the analogs of tetrazole derivatives.
Molbank 2021 m1303 sch001
Molbank 2021 m1303 g001 550
Figure 1. Graphical presentation of inhibition zone diameter (mm) against S. aureus.
Figure 1. Graphical presentation of inhibition zone diameter (mm) against S. aureus.
Molbank 2021 m1303 g001
Molbank 2021 m1303 g002 550
Figure 2. Graphical presentation of inhibition zone diameter (mm) against E. coli.
Figure 2. Graphical presentation of inhibition zone diameter (mm) against E. coli.
Molbank 2021 m1303 g002
Molbank 2021 m1303 g003 550
Figure 3. Graphical presentation of inhibition zone diameter (mm) against Klebsiella.
Figure 3. Graphical presentation of inhibition zone diameter (mm) against Klebsiella.
Molbank 2021 m1303 g003
Table
Table 1. Physical properties of compounds 4(a-e) and 5(a-e) and their elemental analysis.
Table 1. Physical properties of compounds 4(a-e) and 5(a-e) and their elemental analysis.
NrMolecular FormulasMolecular MassElemental Analysis %
Calc/Found		mp/°CYield %
4aC16H11N2O3Cl314.71(C-61.06; H-3.52; N-8.90; O-15.25; Cl-11.26)
(C-61.02; H-3.51; N-8.85; Cl: 11.28)		204–20666
4bC16H10N2O3Cl2349.15(C-55.03; H-2.89; N-8.02; O-13.75; Cl-20.31)
(C-49.99; H-2.86; N-8.04; Cl-20.27)		212–21472
4cC16H11N2O3Br359.16(C-53.50; H-3.09; N-7.80; O-13.36; Br-22.25)
(C-53.48; H-3.12; N-7.76; Br-22.21)		225–22775
4dC23H18N2O4385.38(C-71.68; H-4.70; N-7.27; O-16.60)
(C-71.72; H-4.67; N-7.24)		305–30738
4eC15H11N3O5313.26(C-57.51; H-3.54; N-13.41; O-25.54)
(C-57.47; H-3.56; N-13.38)		302–30462
5aC16H12N5O3Cl357.74(C-53.71; H-3.38; N-19.57; O-13.42; Cl-9.91)
(C-53.66; H-3.42; N-19.60; Cl-9.87)		211–21365
5bC16H11N5O3Cl2392.18(C-48.99; H-2.83; N-17.86; O-12.24; Cl-18.08)
(C-49.03; H-2.79; N-17.84; Cl-18.03)		208–21173
5cC16H12N5O3Br402.19(C-47.78; H-3.01; N-17.41; O-11.93; Br-19.87)
(C-47.82; H-2.98; N-17.38; Br-19.90)		120–12270
5dC23H19N5O4429.41(C-64.33; H-4.46; N-16.31; O-14.19)
(C-64.29; H-4.44; N-16.28)		224–22667
5eC15H12N6O5356.29(C-50.56; H-3.39; N-23.59; O-22.45)
(C-50.58; H-3.43; N-23.62)		223–22545
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Hoti, R.; Ismaili, H.; Thaçi, V.; Mulliqi-Osmani, G.; Pllana-Zeqiri, M.; Bytyqi, A. An Efficient Synthesis of Novel 3-[(Heteroaryl-2-ylimino)-methyl]-4-hydroxy-chromen-2-ones and Analogue of Tetrazole Derivatives and Their Antibacterial Activity. Molbank 2021, 2021, M1303. https://doi.org/10.3390/M1303

AMA Style

Hoti R, Ismaili H, Thaçi V, Mulliqi-Osmani G, Pllana-Zeqiri M, Bytyqi A. An Efficient Synthesis of Novel 3-[(Heteroaryl-2-ylimino)-methyl]-4-hydroxy-chromen-2-ones and Analogue of Tetrazole Derivatives and Their Antibacterial Activity. Molbank. 2021; 2021(4):M1303. https://doi.org/10.3390/M1303

Chicago/Turabian Style

Hoti, Ramiz, Hamit Ismaili, Veprim Thaçi, Gjyle Mulliqi-Osmani, Malësore Pllana-Zeqiri, and Agon Bytyqi. 2021. "An Efficient Synthesis of Novel 3-[(Heteroaryl-2-ylimino)-methyl]-4-hydroxy-chromen-2-ones and Analogue of Tetrazole Derivatives and Their Antibacterial Activity" Molbank 2021, no. 4: M1303. https://doi.org/10.3390/M1303

APA Style

Hoti, R., Ismaili, H., Thaçi, V., Mulliqi-Osmani, G., Pllana-Zeqiri, M., & Bytyqi, A. (2021). An Efficient Synthesis of Novel 3-[(Heteroaryl-2-ylimino)-methyl]-4-hydroxy-chromen-2-ones and Analogue of Tetrazole Derivatives and Their Antibacterial Activity. Molbank, 2021(4), M1303. https://doi.org/10.3390/M1303

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop