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Design and microwave-assisted synthesis of a novel Mannich base and conazole derivatives and their biological assessment

  • Yıldız Uygun Cebeci EMAIL logo and Şengül Alpay Karaoğlu
Published/Copyright: November 9, 2021
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 27 Issue 1

Abstract

4-Amino-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (1) was converted to the corresponding Schiff base (2) by treatment with salicylaldehyde. 1,2,4-Triazoles were then converted to the corresponding Mannich bases containing fluroquinolone core using a one-pot three-component procedure. Moreover, the synthesis of six compounds, which can be considered as conazole analogues, was performed starting from 1,2,4-triazole-3-one compounds via three steps by either conventional or microwave-mediated conditions. All the newly synthesized compounds were screened for their antimicrobial activities. Most exhibited good to moderate antibacterial and/or antifungal activity. The structural assignments of the new compounds were based on elemental analysis and spectral (IR, 1H NMR, 13C NMR, and LC-MS) data.

Keywords: 1,2,4-triazole; fluoroquinolone; conazole; antimicrobial activity

1 Introduction

Heterocyclic compounds are common structural units in marketed drugs and also in medicinal chemistry targets in the drug discovery process. The main reason behind this is the high prevalence of oxygen, sulfur, and especially nitrogen-containing rings in drug molecules [1]. In the last few decades, the chemistry of N-heterocycles derived from 1,2,4-triazole and their fused heterocyclic derivatives have received much attention owing to their synthetic and effective medical applications. These N-bridged heterocyclic compounds are known to possess significant activity, such as antibacterial [2], anti-inflammatory [3], anticancer [4], anti-allergic [5], antimicrobial [6], antitubercular [7], antiviral [8], antitumor [9], antioxidant [10], anthelmintic [11], anticonvulsant [12,13], antifungal [14], analgesic [15], and antiparasitic [16] properties.

Triazole Schiff base derivatives have many important applications in industry, agriculture, and medicine [16,17]. They can be used as fungicides, anticancer drugs, pharmaceutical intermediates, antioxidants of polymers, and ultraviolet absorbers [18,19]. Triazole Schiff base derivatives, as five-membered heterocyclic compounds, contain the basic structural skeleton of a Schiff base in their molecular structure; therefore, they can also be used as ligands to chelate some trace metal ions in organisms and thus have a wide range of biological activities and play an important role in pharmacodynamics [20,21]. These compounds have good bioactivities and are widely used in medicine, materials, and other fields. They can also be used as antibacterial agents, insecticides, and plant growth regulators in medicine and agriculture [22,23].

Of the classes of antimycotics, the most useful in the treatment of fungal infections are compounds with an azole moiety within the structure (conazoles) [24,25].

Investigations of the first generation of conazoles, e.g., fluconazole and itraconazole, that involved broadening of the activity spectrum and improvement of the therapeutic index, resulted in the development of new drugs with posaconazole being one of the most promising antifungals [26,27,28] (Figure 1).

Figure 1 Some known azole class antifungals.
Figure 1

Some known azole class antifungals.

Posaconazole, a structural analogue of itraconazole, was approved in the E. U. (2005) as well as in the USA (2006) for treatment of aspergillosis, candidiasis, and other invasive fungal infections in immunocompromised patients older than 13 years. At present, there are three approved formulations of posaconazole that include oral suspension, intravenous injections, and delayed-release tablets [27–29].

Compared to the previous conazoles, posaconazole has an extended spectrum of antimycotic activity including most yeasts, filamentous fungi, and Candida spp., as well as these resistant to fluconazole like C. glabata, C. krusei, C. guilliermondii, C. dubliniensis, C. parapsilosis, and C. tropicalis [30,31].

This study focused on the design, eco-friendly synthesis, and antimicrobial assessment of new azole class antifungals (Figure 2).

Figure 2 Schematic representation of the relationship between the structures of miconazole and the synthesized conazole analogues.
Figure 2

Schematic representation of the relationship between the structures of miconazole and the synthesized conazole analogues.

2 Results and discussion

2.1 Chemistry

In this study, we aim to synthesize new triazole-fluoroquinolone hybrids as possible drug candidates with antibacterial activity. On the basis of 1H, 13C NMR, FT IR, and EI-MS data, the structure of the target products was established. The MICs against clinically important Gram-negative and Gram-positive pathogens were determined as well. The synthetic methodologies adopted to obtain the target compounds are depicted in Scheme 1.

Scheme 1 (i) 2-Bromo-1-(4-chlorophenyl)ethanone or 2-chloro-1-(2,4-dichlorophenyl)ethanone, NaOEt, reflux, or 175 W MW; (ii) NaBH4, EtOH, reflux; (iii) 2,6-dichlorobenzylchloride, 2,4-dichlorobenzylchloride, or 4-chlorobenzylchloride, THF, NaH, reflux, or 200 W MW, (iv) Ciprofloxacine or norfloxacine, DMF, and HCHO.
Scheme 1

(i) 2-Bromo-1-(4-chlorophenyl)ethanone or 2-chloro-1-(2,4-dichlorophenyl)ethanone, NaOEt, reflux, or 175 W MW; (ii) NaBH4, EtOH, reflux; (iii) 2,6-dichlorobenzylchloride, 2,4-dichlorobenzylchloride, or 4-chlorobenzylchloride, THF, NaH, reflux, or 200 W MW, (iv) Ciprofloxacine or norfloxacine, DMF, and HCHO.

The synthesis of 4-{[(1E)-(2-hydroxyphenyl)methylidene]amino}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (2) was performed by the treatment of aromatic aldehyde. The process via MW irradiation ensured the more helpful road with developed synthesis yields and shorter synthesis times (Table 1) [32]. Green Chemistry has the advantages of the high yield of synthesis processes, the use of less toxic solvents, and the decrease in phases of synthetic schemes [33].

Table 1

Yield difference between the conventional method and the MW irradiation method

MW irradiation method Conventional method
3a 95 80
3b 98 81
4a 95 72
4b 99 71
5a 83 65
5b 85 63
5c 81 62
5d 79 59
5e 80 60
5f 84 64

Alkylation of product 3 via 2-bromo-1-(4-chlorophenyl)-ethanone and 2-bromo-1-(2,4-dichlorophenyl)ethanone in ethanol yielded compound 3. The NH protons attached to the triazole group disappeared for compound 3 in the 1H NMR data. New aromatic protons were resonated in the region 6.92–7.94 ppm. In the 13C NMR data of molecules, the carbon atom (C═O) was observed at 192.62 and 194.51 ppm for the newly added carbonyl group. Considering the EI MS spectra of the product, the existence of [M + Na] ion signals confirmed its molecular mass. Compound 4 was obtained with a reduction of the carbonyl structure of product 3 with sodium borohydride using MW irradiation. Considering compound 4, the carbonyl group peak evanesced at the 1H NMR and 13C NMR data, and the OH peak resonated at 3.99 and 4.51 ppm in the 1H NMR spectra. The spreading band for the OH group appeared at 3,236 and 3,286 cm−1, in the FT-IR data of molecules. In the 1H NMR and 13C NMR data of molecules, extra signals from the substituted benzyl group were observed at the concerned chemical ranges. Compounds 5a–f were synthesized using the MW synthesis method at 100°C and 150 W for 17 minutes using molecule 4a–b and benzyl chlorides such as 4-chloro-, 2,4-dichloro-, and 2,6-dichlorobenzyl chlorides with NaH. In the 13C NMR spectra, triazole C-3 and C-5 of compounds 5a–f resonated at 155.21–158.17 (triazole C-3) and 157.39–158.48 (triazole C-5), respectively, consistent with the literature findings [34–36]. Moreover, [M + K] and [M + Na] ion signals appeared at the concerned m/z ranges in addition to the obtained structures of molecules 5a–f.

Furthermore, several Mannich bases of triazole derivatives, including piperazine, thiomorpholine, or morpholine moiety, were synthesized as antimicrobial agents in our laboratory [37,38]. Moreover, it is well known that the presence of fluorinated units in organic compounds may dramatically modify the physicochemical profile of organic molecules. Thus, the heterocyclic compounds containing fluorine atom have been attracting much interest due to their potent biological activities and their role in the development of new drug candidates [39]. Considering these facts in this research, the aminoalkylation of structure 2 with different amines, such as norfloxacin (for 6a), ciprofloxacin (for 6b), morpholine (for 6c), thiomorpholine (6d), 4-phenylpiperazine (for 6e) and 4-fluorphenylpiperazine (for 6f) in an ambiance with formaldehyde was performed using the MW-assisted Mannich synthesis reactions.

In the 1H NMR and 13C NMR spectra of molecules, additional signals arising from amine moieties were seen at the attended chemical ranges. These molecules exhibition spectral datum and elemental analysis records fair with their structures. MW-mediated methods were used in the literature to introduce 1,2,4-triazole nuclei into the piperazine skeleton and biologically active compounds were obtained [40]. Mannich reactions were made without solvent in an occasion with Lewis and Bronsted acid catalysts such as HCl. Solvent-free handles are particularly dependent on organic reactions for Green Chemistry situations. The use of the microwave (MW) irradiation method consequences in very influential and clean results with notable developments compared to classical processes.

For MW-mediated reactions leading to the formation of compounds 5a–f, the production of compound 5b was selected as a model and the effects of various reaction parameters, including solvent, temperature, time, and MW power were examined on the model reaction, and the results are summarized in Table 2.

Table 2

Optimization of the model reaction conditions for compounds 3b–5b

Entry Time (min) Power (W) Yield (%) Temperature (oC) Solvent
Comp 3b
  1 15 200 97 175 EtOH
  2 10 100 98 125 EtOH
  3 20 150 96 125 EtOH
  4 16 125 97 100 EtOH
  5 10 100 90 100 EtOH
  6 10 100 92 125 EtOH
Comp 4b
  1 6 200 97 150 EtOH
  2 8 150 99 125 EtOH
  3 10 200 96 150 THF
  4 4 150 93 100 THF
  5 10 200 74 150 MeCN
  6 10 200 81 200 MeCN
Comp 5b
  1 25 100 65 100 EtOH
  2 25 75 85 75 THF
  3 25 100 60 100 MeCN
  4 27 100 50 100 DCM
  5 15 150 71 100 EtOH
  6 17 150 77 100 THF
  7 16 150 69 100 MeCN
  8 18 150 68 100 DCM
  9 10 200 65 100 EtOH
  10 10 200 70 100 THF
  11 10 200 73 100 MeCN
  12 8 200 40 100 DCM

In order to improve the MW conditions, the reaction leading to the formation of 5b was selected as a model reaction and the effects of several parameters including time, power, and solvent were examined. The best conditions were obtained in 25 min of MW irradiation at 75 W in THF. After optimization of the conditions for the preparation of 5b, the synthesis of the remaining compounds 5 was carried out. By comparison of the two methods, conventional and MW-irradiated procedures showed that the use of MW irradiation provided a more efficient and green way for the synthesis of compounds 5a–f with better reaction yields and much shorter reaction times. In the NMR spectra of compounds 5a–f, the number of signals and their chemical shifts are in accordance with the assigned structures.

2.2 Antimicrobial activity

Most of the compounds synthesized in the present study exhibited activity on the test compounds (Table 3). Among them, 6a–d, which contain a fluoroquinolone nucleus in their structures, demonstrated excellent activities on Gram-positive and Gram-negative bacteria of the test microorganisms with the mic values <0.24 μg mL−1. The carboamides, 2a, 2b, and triazoles, 3a, 3b, which were obtained from intramolecular cyclization of 2a, 2b, displayed selective activity on a Gram-positive coccal bacterium, Staphylococcus aureus (Sa), and Mycobacterium smegmatis (Ms), atypical tuberculosis factor leading to morbidity and mortality. A remarkable antifungal activity was observed for 5a–f and 6a–f with the MIC values.

Table 3

Screening for the activity of newly synthesized compounds

Comp no. Microorganisms and minimal inhibitory concentrations (µg mL−1)
Ec Yp Pa Sa Ef Bc Ms Ca Sc
2 — — — 250 — — 31.25 — —
3a — — — — — — — — —
3b — — — — — — — — —
4a 0.24 — — — — — — 125 125
4b — — — — — — — — —
5a 0.24 — — — — — — 125 125
5b — — — — — — — — —
5c 0.24 — — — — — — 125 125
5d 0.24 — — — — — — 125 500
5e 0.24 — — — — — — — —
5f 0.24 — — — — — — 125 125
6a <0.24 <0.24 <0.24 <0.24 <0.24 <0.24 — 500 125
6b <0.24 <0.24 <0.24 <0.24 <0.24 <0.24 — 500 —
6c <0.24 <0.24 <0.24 <0.24 <0.24 <0.24 — 500 125
6d <0.24 <0.24 <0.24 <0.24 <0.24 <0.24 — 500 —
6e <0.24 <0.24 <0.24 <0.24 <0.24 <0.24 — 500 500
6f <0.24 <0.24 <0.24 <0.24 <0.24 <0.24 — 125 500
Amp. 10 18 >128 10 35 15
Strep. 4
Flu. <8 <8

Ec: Escherichia coli ATCC 25922, Yp: Yersinia pseudotuberculosis ATCC 911, Pa: Pseudomonas aeruginosa ATCC 43288, Sa: Staphylococcus aureus ATCC 25923, Ef: Enterococcus faecalis ATCC 29212, Bc: Bacillus cereus 702 Roma, Ms: Mycobacterium smegmatis ATCC607, Ca: Candida albicans ATCC 60193, Sc: Saccharomyces cerevisiae RSKK 251, Amp.: ampicillin, Str.: streptomycin (—): Flu.: fluconazole, (—): no activity.

3 Experimental

3.1 General

All the chemicals were purchased from Fluka Chemie AG Buchs (Switzerland) and used without further purification. The melting points of the synthesized compounds were determined in open capillaries on a Büchi B-540 melting point apparatus and are uncorrected. Reactions were monitored by thin-layer chromatography (TLC) on silica gel 60 F254 aluminum sheets. The mobile phase was ethyl acetate/ethyl ether (1:1), and detection was made using UV light. MW-irradiated syntheses were carried out using monomode CEM-Discover MW apparatus. FT-IR spectra were recorded using a Perkin Elmer 1600 series FTIR spectrometer. 1H NMR and 13C NMR spectra were registered in DMSO-d 6 on a BRUKER AVENE II 400 MHz NMR Spectrometer (400.13 MHz for 1H and 100.62 MHz for 13C). The chemical shifts are given in ppm relative to Me4Si as an internal reference, and J values are given in Hz. The mass spectra were obtained on a Quattro EI-MS (70 eV) Instrument.

3.1.1 4-Amino-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (1)

Hydrazine hydrate (0.025 mol) in 3% water solution was added to the ester ethoxycarbonylhydrazone compound (0.01 mol) contained in a round bottom flask and the reaction was boiled under a reflux system for 8 h. The white solid formed after the flask was left in the freezer overnight was filtered off and purified by crystallization from ethanol.

Yield: 70%, m.p.: 210–212°C. FT-IR (υ max, cm−1): 3,295 and 3,207 (NH2), 3,218 (NH), 1,683 (C═O), 1,588 (C═N). 1H NMR (DMSO-d 6, δ ppm): 2.07 (3H, s, CH3), 5.13 (2H, s, NH2), 11.22 (1H, s NH). 13C NMR (DMSO-d 6, δ ppm): 11.23 (CH3), 146.21 (triazole C-3), 154.97 (triazole C-5). EI MS m/z (%): 113.15 (100), 113.40 (90), 154.06 ([M + K + 1]+, 13), 135.18 (12).

3.1.2 4-{[(1E)-(2-Hydroxyphenyl)methylidene]amino}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (2)

A solution of the corresponding compound 1 (10 mmol) in absolute ethanol was refluxed with salicylaldehyde (10 mmol) for 3 h. On cooling the mixture to room temperature, a white solid appeared. This crude product was recrystallized from ethanol to afford the desired product.

Yield: 75%, m.p.: 245–247°C. FT-IR (υ max, cm−1): 3,170 (OH), 3,047 (aromatic CH), 1,697 (C═O), 1,595 (C═N). 1H NMR (DMSO-d 6, δ ppm): 2.26 (3H, s, CH3), 6.89–6.97 (2H, m, arH), 7.33 (1H, d, J = 8.0 Hz, arH), 7.79 (1H, t, J = 8.0 Hz, arH), 9.96 (1H, s, CH), 10.33 (1H, s, NH), 11.80 (1H, d, J = 8.0 Hz, OH). 13C NMR (DMSO-d 6, δ ppm): 11.58 (CH3), 116.88 (CH), arC: [119.93 (CH), 119.9 (C), 127.00 (CH), 133.26 (CH), 144.67 (C), 151.70 (CH)], 151.75 (triazole C-3), 157.99 (triazole C-5). EI MS m/z (%): 241.05 ([M + Na]+, 100), 242.18 ([M + Na + 1]+, 21), 219.09 ([M + 1]+, 16), 257.20 ( [M + K]+, 12).

3.1.3 General method for the synthesis of compounds 3a–b

The solution of compounds 2 (10 mmol) and sodium ethoxide (10 mmol) in ethanol (10 mL) was irradiated in closed vessels at 100°C, 125 W, for 10 min (the progress of the reaction was monitored by TLC). Then, 2-bromo-1-(4-chlorophenyl)ethanone (for 3a) or 2-chloro-1-(2,4-dichlorophenyl)ethanone (10 mmol) (for 3b) was added into it and irradiated for additional 15 min. The mixture was poured into ice-water and a solid was obtained. This crude product was collected by filtration and recrystallized from an appropriate solvent to afford the desired product.

3.1.3.1 2-[2-(4-Chlorophenyl)-2-oxoethyl]-4-{[(1E)-(2-hydroxyphenyl)methylidene]amino}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (3a)

Yield: 95% m.p.: 160–162°C. FT-IR (υ max, cm−1): 3,372 (OH), 3,063 (aromatic CH), 1,704 (C═O), 1,693 (C═O), 1,589 (C═N). 1H NMR (DMSO-d 6, δ ppm): 2.33 (3H, s, CH3), 5.39 (2H, s, CH2), 6.93–6.97 (2H, m, arH), 7.67 (3H, d, J = 8.0 Hz, arH), 8.06 (3H, d, J = 8.0 Hz, arH), 9.93 (1H, s, CH), 11.79 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 11.48 (CH3), 52.14 (CH2), arC: [112.77 (CH), 116.93 (CH), 119.87 (C), 120.00 (CH), 124.38 (CH), 124.69 (CH), 126.86 (CH), 129.35 (CH), 130.56 (CH), 133.56 (C), 139.52 (C), 144.20 (C)], 152.07 (CH), 150.70 (triazole C-3), 158.11 (triazole C-5), 192.62 (C═O). EI MS m/z (%): 393.26 ([M + Na]+, 100), 146.05 (84), 320.30 (78), 233.08 (62), 371.30 ([M + 1]+, 46), 395.20 (31), 425.29 (28), 276.13 (26).

3.1.3.2 2-[2-(2,4-Dichlorophenyl)-2-oxoethyl]-4-{[(1E)-(2-hydroxyphenyl)methylidene]amino}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (3b)

Yield: 98%. e.n.: 167–169°C. FT-IR (υ max, cm−1): 3,174 (OH), 3,066 (aromatic CH), 1,704 (C═O), 1,666 (C═O), 1,597 (C═N). 1H NMR (DMSO-d 6, δ ppm): 2.33 (3H, s, CH3), 5.25 (2H, s, CH2), 6.92–6.98 (2H, m, arH), 7.36–7.63 (1H, m, arH), 7.80–7.84 (1H, m, arH), 7.92–7.94 (2H, m, arH), 10.32 (1H, s, CH), 11.78 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 11.60 (CH3), 54.10 (CH2), arC: [126.83 (CH), 126.96 (CH), 128.15 (CH), 130.94 (CH), 131.86 (CH), 132.46 (CH), 133.56 (C), 134.21 (C), 137.79 (C), 144.35 (C), 151.75 (C)], 150.52 (CH), 152.06 (triazole C-3), 158.13 (triazole C-5), 194.51 (C═O). EI MS m/z (%): 273.13 (100), 360.60 (62), 447.57 (42), 428.42 ([M + Na]+, 10).

3.1.4 General method for the synthesis of compounds 4a–b

The solution of the corresponding compound 3 (10 mmol) in ethanol was irradiated with MW energy at 150°C, 125 W in the presence of NaBH4 (30 mmol) with pressure control (the progress of the reaction was monitored by TLC). Then, the solvent was removed under reduced pressure and the solid appeared. This crude product was washed with water and recrystallized from acetone/water (1:3).

3.1.4.1 2-[2-(4-Chlorophenyl)-2-hydroxyethyl]-4-{[(1Z)-(2-hydroxyphenyl) methyl ene]amino}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (4a)

Yield: 95%. FT-IR (υ max, cm−1): 3,236 (OH), 1,673 (C═O), 1,596 (C═N). 1H NMR (DMSO-d 6, δ ppm): 1.70 (3H, s, CH3), 3.79 (2H, d, J = 8.0 Hz, CH), 3.99 (1H, d, J = 4.0 Hz, OH), 4.88–4.91 (2H, m, CH2), 6.67–6.70 (2H, m, arH), 6.69 (2H, d, J = 8.0 Hz, arH), 6.80 (2H, d, J = 8.0 Hz, arH), 6.91 (2H, d, J = 8.0 Hz, arH), 9.81 (1H, s, CH), 10.20 (1H, s, NH), 11.80 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 10.55 (CH3), 52.27 (CH2), 70.08 (CH), arC: [103.55 (CH), 115.64 (CH), 118.95 (CH), 123.72 (C), 128.52 (CH), 128.53 (CH), 128.96 (CH), 129.13 (CH), 131.30 (2CH), 141.51 (C), 142.23 (C), 144.88 (C)], 152.86 (triazole C-3), 156.57 (triazole C-5). EI MS m/z (%): 397.20 ([M + Na + 2]+, 100), 399.14 (30), 323.18 (29), 291.02 (25), 327.31 (18).

3.1.4.2 2-[2-(2,4-Dichlorophenyl)-2-hydroxyethyl]-4-{[(1E)-(2hydroxyphenyl) methylene]amino} -5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (4b)

Yield: 99%. FT-IR (υ max, cm−1): 3,286 (OH), 1,686 (C═O), 1,589 (C═N). 1H NMR (DMSO-d 6, δ ppm): 1.08–1.15 (3H, m, CH3), 3.78 (2H, s, CH2), 4.40 (1H, s, CH), 4.51 (1H, s, OH), 7.28–7.50 (7H, m, arH), 9.53 (1H, d, J = 8.0 Hz, CH), 11.81 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 10.52 (CH3), 48.23 (CH2), 78.19 (CH), arC: [111.57 (CH), 115.61 (CH), 121.72 (CH), 123.35 (CH), 123.75 (CH), 124.81 (CH), 128.03 (CH), 128.11 (C), 128.79 (C), 129.07 (C), 129.15 (C), 129.47 (C)], 144.92 (CH), 152.98 (triazole C-3), 157.99 (triazole C-5). EI MS m/z (%): 431.25 ([M + Na + 1]+, 100), 134.98 (68), 433.25 (60), 325.19 (34).

3.1.5 General method for the synthesis of compounds 5a–f

3.1.5.1 Method 1

NaH (10 mmol) was added to the solution of the corresponding compound 4 (10 mmol) in THF and the mixture was refluxed for 6 h. Then, the corresponding benzyl chloride was added to it and the mixture was refluxed for an additional 14 h. After evaporating the solvent under reduced pressure, an oily mass formed. This was extracted with 15 mL of ethyl acetate three times in the presence of K2CO3 and the organic layer was dried on Na2SO4. After the removal of solvents at reduced pressure, a solid was obtained, which was recrystallized from acetone.

3.1.5.2 Method 2

NaH (1 mmol) was added to the solution of the corresponding compound 4 (1 mmol) in THF (10 mL) and the mixture was irradiated at 75°C, 75 W for 10 min. Then, the corresponding substituted benzylchloride (3 mmol) was added to it and irradiation was continued for 45 min (for 5a–f) at 125°C, 150 W. The solvent was evaporated under reduced pressure, and the obtained oily product was extracted with 15 mL of ethyl acetate three times in the presence of K2CO3. The organic layer was dried on Na2SO4. After the removal of solvents at reduced pressure, an oily product was formed, which was purified by column chromatography (n-hexane/ethyl acetate) on silica gel.

3.1.5.1 2-{2-(4-Chlorophenyl)-2-[(2,4-dichlorobenzyl)oxy]ethyl}-4-{[(1Z)-(2hydroxyphenyl)methylene]amino}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (5a)

Yield: 83%. FT-IR (υ max, cm−1): 3,275 (OH), 1,587 (C═N). 1H NMR (DMSO-d 6, δ ppm): 1.10–1.13 (3H, m, CH3), 3.87 (2H, s, CH2), 3.95 (2H, s, CH2), 4.38 (1H, s, CH), 7.10–7.35 (7H, m, arH), 7.40–7.55 (4H, m, arH), 9.10 (1H, d, J = 8.0 Hz, CH), 11.10 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 11.78 (CH3), 47.85 (CH2), 50.12 (CH2), 76.12 (CH), arC: [110.17 (CH), 110.98 (CH), 111.85 (CH), 112.85 (CH), 113.20 (CH), 114.78 (CH), 115.69 (CH), 117.33 (CH), 118.87 (CH), 121.91 (CH), 122.53 (CH), 123.98 (C), 130.58 (C), 132.10 (C), 133.83 (C), 139.17 (C), 140.23 (C), 141.37 (C)], 145.21 (CH), 156.89 (triazole C-3), 158.41 (triazole C-5). EI MS m/z (%): 570.83 ([M + K]+, 100), 312.85 (85), 187.12 (51).

3.1.5.2 2-{2-(4-Chlorophenyl)-2-[(2,6-dichlorobenzyl)oxy]ethyl}-4-{[(1Z)-(2-hydroxyphenyl) methylene]amino}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (5b)

Yield: 85%. FT-IR (υ max, cm−1): 3,288 (OH), 3,083 (aromatic CH), 1,685 (C═O), 1,582 (C═N). 1H NMR (DMSO-d 6, δ ppm): 2.31 (3H, s, CH3), 3.36 (1H, s, CH), 5.17 (2H, s, CH2), 5.50 (2H, s, CH2), 7.17–7.48 (5H, m, arH), 7.91–8.30 (6H, m, arH), 9.74 (1H, s, CH), 11.69 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 19.30 (CH3), 55.87 (CH2), 663.28 (CH2), 75.23 (CH), arC: [111.94 (CH), 112.87 (CH), 114.61 (CH), 115.52 (CH), 118.78 (CH), 119.65 (CH), 120.21 (CH), 121.84 (CH), 123.59 (CH), 126.74 (CH), 128.95 (CH), 131.10 (C), 132.41 (C), 133.73 (C), 135.74 (C), 136.74 (C), 137.20 (C), 138.36 (C)], 147.10 (CH), 155.21 (triazole C-3), 158.20 (triazole C-5). EI MS m/z (%): 555.14 ([M + K]+, 100), 557.16 ([M + K + 2]+, 98), 559.11 (38), 397.20 (28).

3.1.5.3 2-[2-[(4-Chlorobenzyl)oxy]-2-(4-chlorophenyl)ethyl]-4-{[(1Z)-(2-hydroxyphenyl)methyl ene]amino}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (5c)

Yield: 81%. FT-IR (υ max, cm−1): 3,312 (OH), 3,075 (aromatic CH), 1,695 (C═O), 1,573 (C═N). 1H NMR (DMSO-d 6, δ ppm): 2.08 (3H, s, CH3), 3.09 (1H, s, CH), 3.22 (2H, s, CH2), 3.37 (2H, s, CH2), 6.97–7.09 (5H, m, arH), 7.26–7.46 (7H, m, arH), 8.69 (1H, s, CH), 8.72 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 18.74 (CH3), 50.78 (CH2), 58.37 (CH2), 77.21 (CH), arC: [118.10 (2CH), 119.10 (2CH), 120.64 (2CH), 123.54 (2CH), 124.21 (CH), 125.71 (CH), 126.30 (CH), 127.41 (CH), 128.63 (CH), 130.61 (C), 131.31 (C), 133.10 (C), 134.87 (C), 136.44 (C), 140.69 (C)], 148.21 (CH), 157.60 (triazole C-3), 158.37 (triazole C-5). EI MS m/z (%): 536.38 ([M + K]+, 100), 387.64 (77), 134.21 (41).

3.1.5.4 2-[2-[(2,4-Dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-4-{[(1E)-(2-hydroxyphenyl) methylene]amino}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (5d)

Yield: 79%. FT-IR (υ max, cm−1): 3,289 (OH), 3,095 (aromatic CH), 1,692 (C═O), 1,588 (C═N). 1H NMR (DMSO-d 6, δ ppm): 2.07 (3H, s, CH3), 4.55 (2H, s, CH2), 4.78 (2H, s, CH2), 4.86 (1H, s, CH), 7.39–7.41 (5H, m, arH), 7.57–7.61 (5H, m, arH), 10.45 (1H, s, CH), 11.64 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 14.20 (CH3), 50.28 (CH2), 57.71 (CH2), 77.21 (CH), arC: [114.45 (CH), 115.21 (CH), 116.20 (CH), 117.80 (CH), 118.34 (CH), 119.49 (CH), 120.21 (CH), 121.61 (CH), 123.66 (CH), 125.52 (CH), 130.57 (C), 131.10 (C), 132.47 (C), 135.45 (C), 136.27 (C), 137.88 (C)], 146.21 (CH), 158.17 (triazole C-3), 159. 37 (triazole C-5). EI MS m/z (%): 605.27 ([M + K]+, 100), 398.27 (58), 117.21 (33).

3.1.5.5 2-[2-[(2,6-Dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-4-{[(1E)-(2-hydroxyphenyl) methylene]amino}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (5e)

Yield: 80%. FT-IR (υ max, cm−1): 3,067 (aromatic CH), 1,576 (C═N). 1H NMR (DMSO-d 6, δ ppm): 2,11 (3H, s, CH3), 3,86 (2H, s, CH2), 4,28 (2H, s, CH2), 4,97 (1H, s, CH), 7,12–7,20 (6H, m, arH), 7.33–7.47 (4H, m, arH), 10.36 (1H, s, CH). 13C NMR (DMSO-d 6, δ ppm): 15.23 (CH3), 52.21 (CH2), 53.85 (CH2), 78.10 (CH), arC: [110.52 (CH), 111.74 (CH), 112.30 (CH), 113.10 (CH), 114.74 (CH), 115.30 (CH), 116.17 (CH), 120.19 (CH), 121.38 (CH), 122.41 (CH), 125.33 (C), 129.76 (C), 130,30 (C), 131.11 (C), 132.88 (C), 133.28 (C), 134.74 (C), 138.29 (C)], 147.20 (CH), 156.71 (triazole C-3), 157.39 (triazole C-5). EI MS m/z (%): 589.27 ([M + Na]+, 100), 371.30 (60), 122.21 (37).

3.1.5.6 2-[2-[(4-Chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-4-{[(1E)-(2-hydroxyphenyl) methylene]amino}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (5f)

Yield: 84%. FT-IR (υ max, cm−1): 3,291 (OH), 3,095 (aromatic CH), 1,692 (C═O), 1,589 (C═N). 1H NMR (DMSO-d 6, δ ppm): 1.71 (3H, s, CH3), 3.37 (2H, s, CH2), 4.77 (2H, s, CH2), 5.11 (1H, s, CH), 7.43–7.48 (11H, m, arH), 9.46 (1H, s, CH), 11.78 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 10.56 (CH3), 45.63 (CH2), 62.55 (CH2), arC: [104.41 (CH), 111.55 (CH), 115.56 (CH), 119.14 (CH), 121.70 (CH), 123.33 (CH), 123.73 (CH), 124.73 (CH), 124.78 (CH), 130.11(CH), 130.41 (CH), 131.17 (CH), 131. 31 (CH), 132.57 (CH), 133.04 (C), 133.42 (C), 137.18 (C), 139.75 (C), 142.03 (C), 144.91 (C), 152.86 (C)], 156.89 (triazole C-3), 158.48 (triazole C-5). EI MS m/z (%): 310.25 (100), 532.85 ([M + 1]+, 75), 432.52 (61).

3.1.6 General method for the synthesis of compounds 6a–f

To the solution of corresponding compound 2 (10 mmol) in dimethylformamide, suitable primary or secondary amine (10 mmol) was added and the mixture was stirred at room temperature in the presence of formaldehyde (37 %, 3.72 mL, 5 mmol) for 24 h (the progress of the reaction was monitored by TLC). The solid that precipitated was collected by filtration and recrystallized from dimethylsulfoxide/water (1:1) to give the desired compound.

3.1.6.1 1-Ethyl-6-fluoro-7-{4-[(4-{[(1Z)-(2-hydroxyphenyl)methylene]amino}-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (6a)

Yield: 85%. FT-IR (υ max, cm−1): 3,057 (aromatic CH), 1,727 (C═O), 1,705 (C═O), 1,518 (C═N). 1H NMR (DMSO-d 6, δ ppm): 1.41 (3H, s, CH3), 2.28 (3H, d, J = 16.0 Hz, CH3), 2.74 (2H, s, CH2), 2.83 (2H, s, CH2), 2.89 (2H, s, CH2), 4.56 (4H, d, J = 8.0 Hz, 2CH2), 4.64 (2H, s, CH2), 6.91–6.97 (2H, m, arH), 7.15 (1H, d, J = 8.0 Hz, arH), 7.35 (1H, s, arH), 7.78–7.88 (2H, m, arH), 8.90 (1H, s, CH), 9.93 (1H, s, CH), 10.21 (1H, s, OH), 15.26 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 11.50 (CH3), 14.75 (CH3), 49.49 (CH2), 49.73 (CH2), 49.86 (CH2), 49.90 (CH2), 55.39 (CH2), 66.07 (CH2), 106.38 (CH), 107.51 (C), arC: [111.47 (CH), 111.70 (CH), 116.89 (CH), 119.62 and 119.69 (C, d, J = 7.0 Hz), 119.93 (CH), 126.79 (CH), 133.26 and 133.44 (CH, d, J = 18.0 Hz), 137.59 (CH), 143.58 (C), 145.78 and 145.88 (C, d, J = 10.0 Hz), 152.03 (C)], 148.86 (CH), 154.51 (triazole C-3), 158.09 (triazole C-5), 166.55 (C═O), 176.58 (C═O). EI MS m/z (%): 542.31 (100), 550.74 ([M + 1]+, 75), 572.07 ([M + Na]+, 70), 619.39 (69), 516.70 (61), 512.23 (58), 607.31 (52), 589.38 ([M + K + 1]+, 28).

3.1.6.2 1-Cyclopropyl-6-fluoro-7-{4-[(4-{[(1Z)-(2-hydroxyphenyl)methylene]amino}-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (6b)

Yield: 88%. FT-IR (υ max, cm−1): 3,516 (OH), 3,351 (OH), 3,052 (aromatic CH), 1,729 (C═O), 1,706 (C═O), 1,538 (C═N). 1H NMR (DMSO-d 6, δ ppm): 1.15 (2H, s, CH2), 1.30 (2H, d, J = 4.0 Hz, CH2), 2.30 (3H, s, CH3), 2.83 (2H, s, CH2), 3.32 (2H, s, CH2), 3.78 (2H, s, CH2), 4.64 (4H, s, 2CH2), 6.89–6.95 (2H, m, arH), 7.33 (1H, d, J = 8.0 Hz, arH), 7.51 (1H, d, J = 4.0 Hz, arH), 7.78–7.82 (2H, m, arH), 8.60 (2H, s, 2CH), 9.94 (1H, s, CH), 10.29 (1H, s, OH), 15.16 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 8.01 (CH2), 11.52 (CH3), 36.25 (CH2), 49.09 (CH2), 49.77 (CH2), 49.81 (CH2), 66.06 (2CH2), 106.85 (CH), 107.16 (C), arC: [111.20 and 111.43 (CH, d, J = 23.0 Hz), 116.88 (CH), 118.95 and 119.02 (C, d, J = 7.0 Hz), 119.87 (C), 119.92 (CH), 126.75 (CH), 131.30 (CH), 133.44 (CH), 139.53 (C), 143.60 (C), 145.46 and 145.56 (C, d, J = 10.0 Hz), 150.75 (C), 152.15 (C), 154.63 (C)], 148.30 (CH), 151.81 (CH), 158.08 (triazole C-3), 159.10 (triazole C-5), 166.34 (C═O), 176.71 (C═O). EI MS m/z (%): 584.22 ([M + Na]+, 100), 585.10 ([M + Na + 1]+, 49), 150.97 (21), 134.92 (18).

3.1.6.3 4-[(Z)-2-(2-Hydroxyphenyl)vinyl]-5-methyl-2-(morpholin-4-ylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (6c)

Yield: 86%. FT-IR (υ max, cm−1): 3,059 (aromatic CH), 1,698 (C═O), 1,595 (C═N). 1H NMR (DMSO-d 6, δ ppm): 2.30 (3H, s, CH3), 2.57 (4H, t, J = 4.0 Hz, 2CH2), 3.54–3.57 (4H, m, 2CH2), 4.52 (2H, s, CH2), 6.89–6.96 (2H, m, arH), 7.33–7.37 (1H, m, arH), 7.80 -7.83 (1H, m, arH), 9.94 (1H, s, CH), 10.31 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 11.49 (CH3), 50.42 (CH2), 66.32 (2CH2), 66.49 (2CH2), arC: [116.91 (CH), 118.66 (CH), 119.90 (C), 126.81 (CH), 131.30 (CH), 143.53 (C)], 151.91 (CH), 150.76 (triazole C-3), 158.09 (triazole C-5). EI MS m/z (%): 217.17 (100), 113.02 (56), 155.03 (49), 318.36 ([M + 1]+, 47), 175.41 (35), 340.19 ([M + Na]+, 26).

3.1.6.4 4-[(Z)-2-(2-Hydroxyphenyl)vinyl]-5-methyl-2-(thiomorpholin-4-ylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (6d)

Yield: 89%. FT-IR (υ max, cm−1): 3,062 (aromatic CH), 1,708 (C═O), 1,594 (C═N). 1H NMR (DMSO-d 6, δ ppm): 2.30 (3H, s, CH3), 2.58–2.61 (4H, m, 2CH2), 2.84 (4H, t, J = 4.0 Hz, 2CH2), 4.54 (2H, s, CH2), 6.90–7.00 (2H, m, arH), 7.33–7.37 (1H, m, arH), 7.81 (1H, d, J = 4.0 Hz, arH), 9.94 (1H, s, CH), 10.30 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 11.50 (CH3), 27.61 (2CH2), 52.44 (2CH2), 67.68 (CH2), arC: [116.91 (CH), 119.90 (C), 119.96 (CH), 126.83 (CH), 133.48 (CH), 143.50 (C)], 151.93 (CH), 150.71 (triazole C-3), 158.10 (triazole C-5). EI MS m/z (%): 334.40 ([M + 1]+, 100), 340.41 (78), 178.96 (62), 134.74 (55).

3.1.6.5 4-[(Z)-2-(2-Hydroxyphenyl)vinyl]-5-methyl-2-[(4-phenylpiperazin-1-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (6e)

Yield: 90%. FT-IR (υ max, cm−1): 3,305 (OH), 3,059 (aromatic CH), 1,700 (C═O), 1,601 (C═O). 1H NMR (DMSO-d 6, δ ppm): 2.09 (3H, s, CH3), 2.30 (2H, s, CH2), 2.73 (2H, m, CH2), 3.31 (2H, s, CH2), 4.61 (2H, s, CH2), 5.01 (2H, d, J = 8.0 Hz, CH2), 6.76 (1H, s, arH), 6.90 (1H, d, J = 8.0 Hz, arH), 6.96 (3H, d, J = 8.0 Hz, arH), 7.18 (2H, d, J = 8.0 Hz, arH), 7.34 (1H, d, J = 8.0 Hz, arH), 7.80 (1H, d, J = 4.0 Hz, arH), 9.94 (1H, d, J = 12.0 Hz, CH), 10.30 (1H, d, J = 12.0 Hz, OH). 13C NMR (DMSO-d 6, δ ppm): 11.50 (CH3), 48.73 (CH2), 50.04 (CH2), 66.13 (CH2), 67.54 (2CH2), arC: [116.07 (2CH), 116.91 (2CH), 119.37 (CH), 119.91 (C), 119.95 (CH), 126.82 (CH), 129.34 (CH), 133.46 (CH), 143.50 (C), 143.88 (C)], 151.90 (CH), 151.53 (triazole C-3), 158.10 (triazole C-5). EI MS m/z (%): 120.08 (100), 175.14 (18), 393.26 ([M + 1]+, 10).

3.1.6.6 2-{[4-(2-Fluorophenyl)piperazin-1-yl]methyl}-4-[(Z)-2-(2-hydroxyphenyl) vinyl]-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (6f)

Yield: 91%. FT-IR (υ max, cm−1): 3,239 (OH), 3,059 (aromatic CH), 1,708 (C═O), 1,686 (C═O), 1,595 (C═N). 1H NMR (DMSO-d 6, δ ppm): 2.30 (3H, s, CH3), 2.73 (2H, s, CH2), 3.06 (2H, m, CH2), 3.35 (2H, s, CH2), 4.60 (2H, s, CH2), 5.01 (2H, d, J = 8.0 Hz, CH2), 6.89–7.05 (6H, m, arH), 7.35 (1H, s, arH), 7.82 (2H, d, J = 4.0 Hz, arH), 10.31 (1H, s, CH), 11.13 (1H, s, OH). 13C NMR (DMSO-d 6, δ ppm): 11.50 (CH3), 49.52 (CH2), 50.03 (CH2), 66.09 (CH2), 67.54 (2CH2), arC: [115.57 (CH), 115.79 (CH), 116.91 (CH), 117.80 (CH), 117.88 (CH), 126.81 (CH), 133.47 (CH), 148.43 (C), 149.74 (C), 150.76 (C), 151.89 (CH), 155.34 (C)], 157.69 (triazole C-3), 158.10 (triazole C-5). EI MS m/z (%): 411.48 ([M + 1]+, 100), 412.23 (50), 433.44 ([M + K]+, 49), 459.28 (46).

3.2 Antimicrobial activity assessment

The test microorganisms were obtained from the Hifzissihha Institute of RefikSaydam (Ankara, Turkey) and were as follows: Escherichia coli (E. coli) ATCC35218, Yersinia pseudotuberculosis (Y. pseudotuberculosis) ATCC911, Pseudomonas aeruginosa (P. aeruginosa) ATCC43288, Enterococcus faecalis (E. faecalis) ATCC29212, Staphylococcus aureus (S. aureus) ATCC25923, Bacillus cereus (B. cereus) 709 Roma, Mycobacterium smegmatis (M. smegmatis) ATCC607, Candida albicans (C. albicans)ATCC60193, and Saccharomyces cerevisiae (S. cerevisia) RSKK 251. All the newly synthesized compounds were weighed and dissolved in hexane to prepare the extract stock solution of 20.000 μg mL−1.

The antimicrobial effects of the substances were tested quantitatively in respective broth media by using double microdilution and the minimal inhibition concentration (MIC) values (µg mL−1) were determined. The antibacterial and antifungal assays were performed in Mueller–Hinton broth (MH) (Difco, Detroit, MI) at pH.7.3 and buffered Yeast Nitrogen Base (Difco, Detroit, MI) at pH 7.0, respectively. The micro dilution test plates were incubated for 18–24 h at 35°C. Brain heart infusion broth (BHI) (Difco, Detriot, MI) was used for M. smegmatis and incubated for 48–72 h at 35°C [41]. Ampicillin (10 μg) and fluconazole (5 μg) were used as standard antibacterial and antifungal drugs, respectively. Dimethyl sulfoxide with a dilution of 1:10 was used as solvent control. The results obtained are presented in Table 2.

4 Conclusion

In this research, the successful synthesis of some new 4-{[(1E)-(2-hydroxyphenyl)methylidene]amino}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one and conversion of some of them into the corresponding Mannich bases and conazole derivatives as well as the antimicrobial screening studieswere carried out . 1,2,4-Triazole nucleus is one of the effective unit currents in many standard drugs and it is known to enhance the pharmacological activity of the molecules. The presence of N-methylpiperazine, morpholine, norfloxacin, and ciprofloxacin moiety is also instrumental in contributing to the net biological activity of a system. Also, we already reported antimicrobial activities of some biheterocyclic compounds incorporating 1,2,4-triazole ring, in addition to some alkylated derivatives of 1,2,4-triazole compounds. Hence, herein, we combined all these two potential units, namely 1,2,4-triazole methyl piperazine, morpholine, norfloxacin, and ciprofloxacin rings. The antimicrobial screening suggests that among the newly synthesized compounds, 2, 3a–b, 4a–b, 5a–f and 6a–f exhibited moderate activity against all the tested microorganisms except M. smegmatis and C. albicans. On the contrary to what was expected, the structure of compounds 5a–f by Conazole derivatives did not exhibit antimicrobial activity.

  1. Funding information: The authors state no funding involved.

  2. Conflict of interest: The authors state no conflict of interest.

  3. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2021-05-17
Revised: 2021-07-26
Accepted: 2021-07-29
Published Online: 2021-11-09

© 2021 Yıldız Uygun Cebeci and Şengül Alpay Karaoğlu, published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/hc-2020-0126
Keywords for this article
1,2,4-triazole; fluoroquinolone; conazole; antimicrobial activity
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Molecular, Electronic, Nonlinear Optical and Spectroscopic Analysis of Heterocyclic 3-Substituted-4-(3-methyl-2-thienylmethyleneamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones: Experiment and DFT Calculations
  3. Lewis acid / Base-free Strategy for the Synthesis of 2-Arylthio and Selenyl Benzothiazole / Thiazole and Imidazole
  4. Synergistic promoting effect of ball milling and Fe(ii) catalysis for cross-dehydrogenative-coupling of 1,4-benzoxazinones with indoles
  5. Magnetic nanoparticle-supported sulfonic acid as a green catalyst for the one-pot synthesis of 2,4,5-trisubstituted imidazoles and 1,2,4,5-tetrasubstituted imidazoles under solvent-free conditions
  6. Synthesis, characteristic fragmentation patterns, and antibacterial activity of new azo compounds from the coupling reaction of diazobenzothiazole ions and acetaminophen
  7. Para toluenesulfonic acid-catalyzed one-pot, three-component synthesis of benzo[5,6]chromeno[3,2-c]quinoline compounds in aqueous medium
  8. Design and microwave-assisted synthesis of a novel Mannich base and conazole derivatives and their biological assessment
  9. Quantum chemical studies on structural, spectroscopic, nonlinear optical, and thermodynamic properties of the 1,2,4-triazole compound
  10. Design, synthesis, and biological evaluation of phenyl-isoxazole-carboxamide derivatives as anticancer agents
  11. Quantum chemistry study on the promoted reactivity of substituted cyclooctynes in bioorthogonal cycloaddition reactions
  12. Quantum chemical calculations of phenazine-based organic dyes in dye-sensitized solar cells
  13. Rapid Communications
  14. One-pot synthesis of benzofurans via heteroannulation of benzoquinones
  15. Design and development of novel thiazole-sulfonamide derivatives as a protective agent against diabetic cataract in Wistar rats via inhibition of aldose reductase
  16. Review Articles
  17. Organic electrochemistry: Synthesis and functionalization of β-lactams in the twenty-first century
  18. Some applications of deep eutectic solvents in alkylation of heterocyclic compounds: A review of the past 10 years
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