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Synthesis, characterization, and biological target prediction of novel 1,3-dithiolo[4,5-b]quinoxaline and thiazolo[4,5-b]quinoxaline derivatives

  • Mohamed S. A. El-Gaby EMAIL logo , Yousry A. Ammar , Mostafa A. Ismail , Ahmed Ragab EMAIL logo and Moustafa S. Abusaif
Published/Copyright: December 25, 2023
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 29 Issue 1

Abstract

Quinoxalines are a family of nitrogen-based heterocyclic compounds that have garnered much interest because of their wide range of applications. 2,3-Dichloroquinoxaline is an aromatic molecule that frequently serves as a synthetic intermediate in materials science, pharmaceuticals, and organic chemistry. 1,3-Dithiolo[4,5-b]quinoxaline derivatives 8a–c and thiazolo[4,5-b]quinoxaline derivatives 11a,b were synthesized by the reaction of 2,3-dichloro-6-sulfonyl quinoxaline derivative 5 with 1,3-binucleophiles. Moreover, 1,3-dithiolo[4,5-b]quinoxalin2-ylidene derivatives 8a–c were obtained by treating 2,3-dichloro-6-sulfonyl quinoxaline derivative 5 with potassium salts of hydrazonodithioates 7a–c at room temperature. Additionally, 2,3-dichloroquinoxaline derivative 5 was reacted with thioureas 9a,b in 1,4-dioxane to yield 6-(pyrrolidin-1-yl sulfonyl)thiazolo[4,5-b]quinoxalin-2(3H)-imines 11a,b rather than thiazolo[5,4-b]quinoxaline 10. Elemental analysis, infrared spectroscopy, 1H NMR, 13C NMR, and mass spectroscopy were used to confirm the structures of the newly synthesized compounds. Finally, we used artificial intelligence to perform biological evaluation via predicting the possible molecular targets and antimicrobial activity of the designed derivative. The results showed good bacterial activity, weak fungal potency, and potential biological targets.

Keywords: 2,3-dichloroquinoxaline; 1,3-dithiolo[4,5-b]quinoxaline; thiazolo[4,5-b]quinoxaline; 1,3-binucleophile; biological target prediction

1 Introduction

A basic organic chemistry approach extensively used in laboratories for academic research and industrial chemical synthesis is nucleophilic aromatic substitution in electron-deficient arenes [1]. Based on a literature review, 2,3-dichloroquinoxaline can be used to synthesize a variety of quinoxaline derivatives because it contains two chlorine atoms at C2 and C3, making it a good electrophilic partner for nucleophilic substitution reactions [2]. By functionalizing 2,3-dichloroquinoxalines with various nucleophiles, many unique 2,3-disubstituted quinoxalines and condensed quinoxalines have been created [3]. Heterocyclic scaffolds are among the most active research areas in organic chemistry due to their wide spectrum of biological functions. Quinoxaline derivatives have many biological and pharmacological properties, including anticancer [4], antidiabetic [4], anti-mycobacterium tuberculosis [5], antimicrobial [6,7,8], antidepressant [9], anthelmintic [10], analgesic [11], anti-inflammatory [12], antifungal [13], antiviral, antimalarial [14], antibacterial [15,16], antioxidant [17], antithrombotic [18], and antiprotozoal properties [19]. Furthermore, quinoxaline-based drugs, namely, quinacillin as anti-bacterial, brimonidine as antiglaucoma, XK469 NSC as selective topoisomerase II poison, and varenicline used for smoking cessation, have been useful in treating many diseases [20,21,22].

Furthermore, the sulfonamide moiety (SO2–N–) is an essential part of most recent drugs, namely, chlortalidone as an antidiuretic agent, sulfamethazine as an antibacterial agent, chlorpropamide as anti-diabetic, ethoxzolamide as a carbonic anhydrase inhibitor, and mafenide as an antimicrobial agent (Figure 1) [23,24]. Similarly, new and versatile hybrid structures combining quinoxaline and sulfonamide moieties have a high therapeutic promise against various diseases. The chemical structures of sulfaquinoxaline as an antimicrobial, and quinoxaline sulfonamide and chloro-quinoxaline sulfonamide as topoisomerase-IIα are shown in Figure 1 [25,26]. Additionally, polythia-organic substances are unique and interesting heterocyclic classes with diverse biological properties, particularly 1,2-dithiole and 1,3-dithiole [27,28]. Moreover, the biological activity of 1,3-dithiolane derivatives containing the 2-ylidine group has been found to possess antibacterial [29], insecticidal [30], antioxidant, and anticancer properties [31]. The important functions of 1,2-dithiol and 1,3-dithiol-2-ylidenes are their electron-donating capability [32] and their utilization in creating electronic materials [33]. Furthermore, pyrrolidine has a variety of pharmacological effects, such as cholinesterase inhibition [34], and anti-HIV [35], anti-microbial [36], anti-inflammatory [37], antioxidant [38], and anticancer properties [39]. Numerous bioactive compounds, such as scalusamide-A, have anti-microbial activity; (R)-bgugaine has anti-cancer activity; and nicotine has anti-inflammatory, antioxidant, and anti-hyperglycemic activity, including the pyrrolidine moiety [40]. These compounds are found in plants and in microbially generated alkaloids.

Figure 1 Chemical structures of the quinoxaline and quinoxaline sulfonamide drugs.
Figure 1

Chemical structures of the quinoxaline and quinoxaline sulfonamide drugs.

To extend our research interest to the design of a new poly-substituted heterocyclic compound with a quinoxaline moiety [15,41,42], we investigated whether it is feasible to substitute the active chlorine atom in 2,3-dichloro-6-sulfonyl quinoxaline derivative 5 with 1,3-binucleophiles when the quinoxaline moiety contains an electron-withdrawing substituent at position-6. The authors reported the facile synthesis of unreported 1,3-dithiolo[4,5-b]quinoxaline and thiazolo[4,5-b]quinoxaline derivatives.

2 Results and discussion

Schemes 1–3 show the synthetic routes used to produce the desired quinoxaline derivatives. Quinoxaline sulfonyl chloride derivative 2, the key intermediate, was achieved via the cyclization of benzene-1,2-diamine as a bi-nucleophile with ethanedioic acid as a bi-electrophile in the presence of an acidic medium (HCl 4N) to give the corresponding quinoxaline-2,3-dione 1, which was then refluxed with chlorosulfonic acid for 4 h, as mentioned in the literature survey [26,34]. Also, the organic compound pyrrolidine sulfonamide derivative 4 was obtained in good yield (88%) by dissolving sulfonyl chloride 2 in 1,4-dioxane and then allowing it to react with the secondary amine, namely, pyrrolidine 3 at room temperature for 3 h [27]. Then, the reaction of sulfonamide derivative 4 with phosphoryl chloride (2 equivalent) in the presence of DMF as the solvent and catalyst was conducted to obtain the required starting material 2,3-dichloro-6-sulfonyl quinoxaline derivative 5 (Scheme 1) [27].

Scheme 1 Synthetic routes for 2,3-dichloro-6-sulfonyl quinoxaline derivative 5.
Scheme 1

Synthetic routes for 2,3-dichloro-6-sulfonyl quinoxaline derivative 5.

Scheme 2 Reaction of hydrazonodithioate anions 7a–c with dichloro derivatives 5 to produce the desired 1,3-dithiolo[4,5-b]quinoxaline containing substituted hydrazide 8a–c.
Scheme 2

Reaction of hydrazonodithioate anions 7a–c with dichloro derivatives 5 to produce the desired 1,3-dithiolo[4,5-b]quinoxaline containing substituted hydrazide 8a–c.

Scheme 3 Possible mechanism for the formation of N′-(6-(pyrrolidin-1-ylsulfonyl)-[1,3]dithiolo[4,5-b]quinoxaline derivatives 8a–c.
Scheme 3

Possible mechanism for the formation of N′-(6-(pyrrolidin-1-ylsulfonyl)-[1,3]dithiolo[4,5-b]quinoxaline derivatives 8a–c.

Our strategy for annulating the 1,3-dithiol-2-ylidene group linked to the quinoxaline moiety depended on potassium hydrazonodithioates anions 7a–c, which have strong nucleophilicity, and the mechanism of the reaction, classified as nucleophilic aromatic substitution reaction, is known to take place on the 2,3-dichloroquinoxaline core [13,27]. An initial reaction step occurred between acid hydrazide derivatives 6a–c and carbon disulfide at room temperature with two equivalents of potassium hydroxide to generate potassium hydrazonodithioate anions 7a–c. Furthermore, as shown in Scheme 2, the target novel N′-(6-(pyrrolidin-1-ylsulfonyl)-[1,3]dithiolo[4,5-b]quinoxaline derivatives 8a–c were obtained in good yields via the reaction of potassium hydrazonodithioate anions 7a–c as 1,3-binucleophile at room temperature with dichloro derivative 5 (Scheme 2). The molecular structures of the resulting products 8a–c were identified using spectral data and elemental analysis (CHN). The IR spectra of 1,3-dithiolo[4,5-b]quinoxaline derivatives 8a–c show distinct bands for the 2-ylidene group. For example, the IR spectrum of quinoxaline derivative 8a revealed absorption bands at υ 3,419, 1,681, and 1,607 cm−1 attributed to NH, carbonyl (C═O), and imino (C═N) groups, respectively, as well as the bands of sulfonyl group (SO2) at υ 1,339 and 1,142 cm−1. The typical 1H NMR spectra exhibited two signals at δ 1.91 and 3.72 ppm, which were ascribed to the four methylene groups of the pyrrolidine moiety. In addition, the aromatic signals appeared at δ 7.71, 7.92, and 8.04 ppm as two doublets with coupling constant J = 8.0 and 10.0 Hz and one singlet signal attributed to H7, H8, and H5 of the quinoxaline ring, respectively. Besides, a D2O exchangeable signal appeared downfield at δ 9.66 ppm due to the NH group. The 13C NMR spectrum of 8b indicated signals at δ 25.22 (2CH2; pyrrolidine), 50.01 (2CH2–N; pyrrolidine), and signals at δ 122.19, 124.67, 125.02, 127.18, 128.02, 130.32, 131.65, 136.04, 139.00, 140.29, 143.28, and 148.21 ppm, related to the aromatic carbon. Also, the imine (C═N) and carbonyl (C═O) groups were displayed in the downfield region at δ 159.45 and 162.97 ppm, respectively.

The mechanism for the synthesis of target compounds 8a–c is shown in Scheme 3. The reaction proceeds through the nucleophilic addition of potassium hydrazonodithioate anions 7a–c at the C═N position-3 in 2,3-dichloroquinoxaline derivative 5, which produces the non-isolable intermediate A that subsequently undergoes intramolecular cyclization via the nucleophilic attack of thiolate anions at position-2 to obtain the desired final products 8a–c. Figure 2 illustrates the three possible tautomeric forms of the synthesized 1,3-dithiolo[4,5-b]quinoxalines 8a–c.

Figure 2 Tautomeric forms of 1,3-dithiolo[4,5-b]quinoxalines 8a–c.
Figure 2

Tautomeric forms of 1,3-dithiolo[4,5-b]quinoxalines 8a–c.

The scope of our investigation was extended to examine the reactivity of compound 5 towards thiourea derivatives 9a,b as non-identical 1,3-binucleophiles. Compound 5 was reacted with thiourea 9a to obtain the corresponding thiazolo[4,5-b]quinoxalin-2(3H)-imine 11a rather than thiazolo[5,4-b]quinoxaline 10; see Scheme 4.

Scheme 4 Reaction of thiourea derivatives 9a,b with dichloroquinoxaline derivative 5 to obtain the desired-6-(pyrrolidin-1-yl sulfonyl)thiazolo[4,5-b]quinoxalin-2(3H)-imine derivatives 11a and b.
Scheme 4

Reaction of thiourea derivatives 9a,b with dichloroquinoxaline derivative 5 to obtain the desired-6-(pyrrolidin-1-yl sulfonyl)thiazolo[4,5-b]quinoxalin-2(3H)-imine derivatives 11a and b.

The chemical structure of thiazolo-quinoxaline derivative 11a was identified using elemental analysis and spectral data. Additionally, the IR spectrum of compound 11a displayed characteristic bands that were assigned to two imino groups (2NH) at υ 3,429 and 3,380 cm−1. According to the 1H NMR spectrum of the same molecule, the pyrrolidine protons represented two singlet signals at δ 1.65 and 3.70 ppm for (CH2)2 and –N(CH2)2, respectively. The three signals of the quinoxaline protons (H7, H8, and H5) shown at δ 7.80, 8.03, and 8.32 ppm appeared as two doublet signals with the same coupling constant value (J = 8.0 Hz) and one singlet signal, respectively. Additionally, two downfield signals at δ 9.71 and 9.97 ppm were attributed to the 2NH groups. The 13C NMR spectrum of thiazolo-quinoxaline derivative 11a displayed signals at δ 25.30 (2CH2 pyrrolidine), 48.38 (2CH2pyrolidine), 124.18, 127.65, 129.37, 131.21, 133.91, 134.88, 137.40 (Ar.Cs), 162.16 (C═NH), and 164.75 (C═N).

The mechanism illustrates the formation of thiazolo[4,5-b]quinoxaline 11 via nucleophilic addition of the mercapto group of thiourea 9a into the C═C at position-3 in compound 5, resulting in the non-isolated intermediates C and D, followed by intramolecular cyclization via hydrogen chloride elimination to yield the final product 11 (Scheme 5). Under the same experimental conditions, compound 5 reacted with N-phenylthiourea 9b to yield thiazolo[4,5-b]quinoxalin-2(3H)-imine 11b. The IR spectrum demonstrates the position of two imino groups (2NH) at υ 3,419 and 3,135 cm−1, as well as 1,562 cm−1 related to the C═N group. Also, the 1H NMR spectrum showed signals for pyrrolidine protons at δ 1.64 and 3.67 ppm. In addition, a singlet signal at δ 9.79 ppm confirmed the presence of the NH proton. The rest of the signals correspond to the aromatic protons.

Scheme 5 The mechanism of formation of 6-(pyrrolidin-1-yl sulfonyl)thiazolo[4,5-b]quinoxalin-2(3H)-imine derivatives 11a and b.
Scheme 5

The mechanism of formation of 6-(pyrrolidin-1-yl sulfonyl)thiazolo[4,5-b]quinoxalin-2(3H)-imine derivatives 11a and b.

3 Biological target prediction

We extended our work to study the predicted biological evaluation for the newly designed 1,3-dithiolo[4,5-b]quinoxaline 8a–c and thiazolo[4,5-b]quinoxaline 11a,b using swiss-target prediction (http://www.swisstargetprediction.ch/) and PASS Targets web tools (https://www.way2drug.com/PassOnline/index.php) as described previously [43,44]. The tested derivatives were constructed using Chembiodraw2014 and exported to web tools as a smile code as described previously [45].

First, the Swiss Target Prediction web tool was used to predict the top 15 homo sapiens protein targets for the newly designed derivatives 8a–c and 11a,b. As described in Figure 3, 2-(2-acetylhydrazinyl)-[1,3]-thiazolo[4,5-b]quinoxaline derivative 8a was predicted to have activity against kinase, lyase, phosphodiesterase with probability values of 53.3, 20.0, and 13.3%, respectively. In addition, 2-(2-benzoylhydrazinyl)-[1,3]-thiazolo[4,5-b]quinoxaline derivative 8b was predicted to have potency on enzyme, kinase, and phosphatase with probability of 26.7, 13.3, and 13.3%, while quinoxaline derivative 8c was predicted to have activity via the family AG protein-coupling receptor with probability 46.7% followed by kinase (P ∼ 26.7%), and enzyme (P ∼ 13.3%). 2-Amino-thiazolo[4,5-b]quinoxaline 11a was predicted to have activity over enzyme inhibitor (33.3%), ligand-gated ion channel (P ∼ 13.3%), and protease (P ∼ 13.3%), while 2(N-phenyl)-amino-thiazolo[4,5-b]quinoxaline 11b expected to display its activity via the family AG protein-coupling receptor with probability 33.3%.

Figure 3 Top 15 target prediction for the newly designed 1,3-dithiolo[4,5-b]quinoxaline 8a–c and thiazolo[4,5-b]quinoxaline 11a and b using Swiss target prediction.
Figure 3

Top 15 target prediction for the newly designed 1,3-dithiolo[4,5-b]quinoxaline 8a–c and thiazolo[4,5-b]quinoxaline 11a and b using Swiss target prediction.

For the PASS Targets web tools, we studied the following two activities: the predicted biological activity including the predicted molecular target (proteins as the possible target on homo sapiens) for the most active three predictions with confidence values. First, for biological evaluation prediction, it was found that 2-(2-acetylhydrazinyl)-[1,3]-thiazolo[4,5-b]quinoxaline derivative 8a showed activity for the insulysin inhibitor (insulinase), anaphylatoxin receptor antagonist, and thioredoxin inhibitor with probability activity values of 0.717, 0.619, and 0.607, respectively In contrast, 2-(2-benzoylhydrazinyl)-[1,3]-thiazolo[4,5-b]quinoxaline derivative 8b exhibited biological activity prediction on the insulysin inhibitor, transcription factor STAT3 inhibitor, and anaphylatoxin receptor antagonist with active probability of 0.714, 0.636, and 0.607, respectively. In addition, N-phenyl-2-(thiazolo[4,5-b]quinoxalin-2-yl)hydrazine-1-carbothioamide derivative 8c demonstrated activity for the insulysin inhibitor, transcription factor STAT3 inhibitor, and transcription factor STAT inhibitor (i.e. suppress the transcription of various target genes) with probabilities of 0.764, 0.600, and 0.559, respectively.

Furthermore, 2-amino-thiazolo[4,5-b]quinoxaline 11a revealed many target predictions, and the most probable targets are neurodegenerative disease treatment (P ∼ 0.622), thioredoxin inhibitor (P ∼ 0.624), and muramoyltetrapeptide carboxypeptidase inhibitor (P ∼ 0.603). In contrast, N-phenyl-thiazolo[4,5-b]quinoxalin-2-amine 11b showed that the most active prediction inhibitors are insulysin, thioredoxin, and kinase with probabilities of 0.691, 0.607, and 0.538, respectively.

Moreover, the predicted antimicrobial activity for the designed derivatives 8a–c and 11a,b was calculated and the results showed that these derivatives exhibited good to moderate antibacterial activity with confidence values ranging between 0.0042 and 0.5523. Moreover, the designed quinoxaline derivatives displayed weak antifungal activity with confidence values ranging from 0.349 to 0.1177. In addition, 1,3-thiazolo[4,5-b]quinoxaline derivatives 8a–c and thiazolo[4,5-b]quinoxaline derivatives 11a,b showed antibacterial activity, mainly against Staphylococcus lugdunensis with higher confidence values compared to other bacterial strains (Table 1).

Table 1

Expected bacterial and fungal strains for the newly designed quinoxaline derivatives 8a–c and 11a and b

Cpd. No. Predicted antimicrobial activity
Predicted bacterial strains Predicted fungal strains
Strain name Confidence Strain name Confidence
8a Staphylococcus lugdunensis 0.4946 Galactomyces geotrichum 0.0839
Staphylococcus hominis 0.1129 Microsporum canis 0.0500
8b Staphylococcus lugdunensis 0.4804 M. canis 0.1177
S. hominis 0.0601 Galactomyces geotrichum 0.0523
8c Staphylococcus lugdunensis 0.4043 M. canis 0.0699
Resistant Mycobacterium phlei 0.0547 Candida 0.0574
Mycobacterium vaccae 0.0191 G. geotrichum 0.0375
11a S. lugdunensis 0.5523 — —
Clostridium ramosum 0.1983 G. geotrichum 0.0622
Salmonella typhimurium 0.1690 — —
11b S. lugdunensis 0.4655 G. geotrichum 0.0349
S. typhimurium 0.0042 — —

Finally, it can be concluded that the designed quinoxaline derivatives are expected to have good antibacterial activity with low antifungal activity. In addition, these derivatives showed multiprotein targets, but mainly, they can be used as insulysin inhibitor (insulinase) based on prediction studies.

4 Conclusion

The reaction of 2,3-dichloro-6-(pyrrolidin-1-ylsulfonyl)quinoxaline derivative 5 with 1,3-binucleophiles when the quinoxaline moiety has an electron-withdrawing moiety at position-6 was explored. A simple and effective approach to synthesize the hitherto unknown 2-ylidene-1,3-dithiolo[4,5-b]quinoxaline derivatives 8a–c and thiazolo[4,5-b]quinoxalin-2(3H)-imines 11a,b are presented. The elucidation and characterization of the novel synthesized compounds by spectral data are also reported. Finally, the biological target prediction including the antimicrobial activity and enzymes molecular targets were calculated using two web tools.

5 Experimental and methods

The fine chemicals and reagents used in the experiments were bought from Aldrich Chemicals without undergoing further purification, and the solvents employed were acquired from Fisher Scientific. An automated Gallen Kamp MFB-595 instrument with an open capillary tube was used to detect compounds with inaccurate melting points. The KBr disc technique was employed to record IR spectra on a Shimadzu 440 spectrophotometer within the 400–4,000 cm−1 spectral range. NMR spectroscopy (1H/13C) was used to determine chemical shifts (in δ ppm) relative to TMS (= 0 ppm) using DMSO-d 6 as solvents on a JOEL spectrometer with frequencies of 400 and 101 MHz. The mass spectra of some novel organic compounds were calculated at 70 eV at the Regional Center for Biotechnology of Al-Azhar University on a DI-50 unit of a Shimadzu GC/MSQP5050A spectrometer. Compound 1 was synthesized and identified as light grey needles with melting points in the range 310–312°C according to the previously reported survey [27]. Also, compound 2 was synthesized and identified as a white powder with melting points in the range of 290–292°C according to the previously reported survey [27].

5.1 Synthesis of 6-(pyrrolidin-1-ylsulfonyl)-1,4-dihydroquinoxaline-2,3-dione (4)

A suspension solution of compound 2 (0.1 mol) in acetonitrile (15 mL) and pyrrolidine (0.15 mol) was added dropwise for 10 min at 25°C, and the suspension solution was stirred for 3 h (monitored by TLC). The precipitated new product was collected by filtration and crystallized using a suitable solvent to obtain a pale-white powder with melting points in the range of 275–277°C [27].

5.2 Synthesis of 6-sulfonyl-2,3-dichloroquinoxaline derivative 5

Compound 4 (0.04 mol) in DMF (5 mL) as a solvent, and the phosphoryl chloride (POCl3, 0.10 mol) was added for 15 min, and the solution was stirred at 80°C for 8 h (monitored by TLC). The viscous solution was poured into ice-water and neutralized with 31% NH3 solution, collected by filtration, and crystallized using a suitable solvent to obtain compound (5).

M. p.: 190–192°C: grey powder; yield: 85%; IR (KBr, cm−1): ν max = 3,051(arom.CH), 2,970, 2,875 (aliph.CH), 1,615 (C═N, imine), 1,336, 1,151 (SO2, sulfonamide); 1H NMR (δ, ppm) 1.63 (Pentet, 4H, 2CH2.cyclic), 3.26 (t, 4H, 2CH2–N.cyclic), 8.22 (d, J = 8.0 Hz, 1H, arom.H7), 8.28 (d, J = 8.0 Hz, 1H, arom.H8), 8.42 (s, 1H, arom.H5); 13C NMR (δ, ppm) = 25.10 (2CH2.cyclic), 48.31 (2CH2–N.cyclic), 125.99, 127.68, 130.03, 138.99, 139.53, 141.78, 147.09 (N═C), 147.77 (N═C); Anal. Calcd: C12H11ClN3O2S (332.20): C, 43.39; H, 3.34; N, 12.65; found: C, 43.46; H, 3.68; N, 12.21.

5.3 Synthesis of dianion potassium salt linked to hydrazide moiety (7a–c)

Hydrazine derivatives (0.01 mmol) and carbon disulfide (0.01 mmol) were dissolved in absolute ethanol (20 mL) and then stirred for 30 min at 25°C. Then, potassium hydroxide (0.02 mmol) was added to form the potassium salt. The solid product was filtered off and washed with diethyl ether.

5.4 Reaction of dichloro-quinoxaline derivative 5 with dianion potassium salt to obtain the target molecules 8a–c

A mixture of 2,3-dichloroquinoxaline derivative 5 (0.01 mol) was dissolved in DMF (7 mL); then, the bis-thiolate derivative 7 (0.01 mol) was added. The solution was stirred for 4–7 h at 25°C (monitored by TLC). The suspension solution was dissolved in ethanol to precipitate the new products as colored solid, collected by filtration, and crystallized with acetonitrile.

5.4.1 N′-(6-(Pyrrolidin-1-ylsulfonyl)-[1,3]dithiolo[4,5-b]quinoxalin-2-ylidene)acetylhydrazine (8a)

M. p.: 166–168°C; yellow powder; yield: 74%; IR (KBr, cm−1): ν max = 3,419 (N–H), 3,040 (arom.CH), 2,966, 2,922, 2,873 (aliph.CH), 1,681 (CO, acetyl), 1,607 (C═N, imine), 1,339, 1,142 (SO2, sulfonamide); 1H NMR (δ, ppm) = 1.91 (s, 4H, 2CH2.cyclic), 2.21 (s, 3H, CH3.acetyl), 3.72 (s, 4H, 2CH2–N.cyclic), 7.71 (d, J = 8.0 Hz, 1H, arom.H7), 7.92 (d, J = 10.0 Hz, 1H, arom.H8), 8.04 (s, 1H, arom.H5), 9.66 (s, 1H, NH); 13C NMR (δ, ppm) = 20.98 (CH3.acetyl), 27.73 (2CH2.cyclic), 50.61 (2CH2–N.cyclic), 127.61, 128.35, 130.71, 132.20, 140.46, 140.53, 145.02, 149.30, 153.74 (N═C), 168.43 (CO- acetyl); Anal. Calcd: C15H15N5O3S3 (409.50), C = 44.00, H = 3.69, N = 17.10; found: C = 43.97, H = 3.62, N = 17.03.

5.4.2 N′-(6-(Pyrrolidin-1-ylsulfonyl)-[1,3]dithiolo[4,5-b]quinoxalin-2-ylidene)benzohydrazide (8b)

M. p.: 179–181°C; deep-yellow powder; yield: 81%; IR (KBr, cm−1): ν max = 3,416 (N–H), 3,135, 3,040 (arom.CH), 2,924 (aliph.CH), 1,658 (CO, benzoyl), 1,629 (C═N, imine), 1,348, 1,154 (SO2, sulfonamide); 1H NMR (δ, ppm) = 1.95 (s, 4H, 2CH2.cyclic), 3.76 (s, 4H, 2CH2–N.cyclic), 7.40 (t, J = 6.4 Hz, 1H, arom.H), 7.49 (t, J = 7.2 Hz, 2H, arom.H), 7.54 (d, J = 8.4 Hz, 2H, arom.H), 7.75 (d, J = 7.6 Hz, 1H, arom.H7), 7.88 (d, 1H, J = 7.2 Hz, arom.H8), 8.35 (s, 1H, arom.H5), 11.62 (s, 1H, NH); 13C NMR (δ, ppm) = 25.22 (2CH2.cyclic), 50.01 (2CH2–N.cyclic), 122.19, 124.67, 125.02, 127.18, 128.02, 130.32, 131.65, 136.04, 139.00, 140.29, 143.28, 148.21, 159.45 (NVC), 162.97 (C═O); Anal. Calcd: C20H17N5O3S3 (471.57), C = 50.94, H = 3.63, N = 14.85; Found: C = 50.87, H = 3.60, N = 14.81.

5.4.3 N-Phenyl-2-(6-(yrrolidin-1-ylsulfonyl)-[1,3]dithiolo[4,5-b]quinoxalin-2-ylidene)hydrazine-1-carbothioamide (8c)

M. p.: 192–194°C; orange powder; yield: 71%; IR (KBr, cm−1): ν max = 3,429, 3,380 (2N–H), 3,082, 3,034 (arom.CH), 2,946 (aliph.CH), 1,642 (C═N, imine), 1,425 (CS), 1,337, 1,126 (SO2, sulfonamide); 1H NMR (δ, ppm) = 1.92 (s, 4H, 2CH2.cyclic), 3.75 (s, 4H, 2CH2–N.cyclic), 7.20 (t, J = 7.2 Hz, 1H, arom.H), 7.37 (t, J = 8.8 Hz, 2H, arom.H), 7.60 (d, J = 6.4 Hz, 2H, arom.H), 7.73 (d, J = 10.0 Hz, 1H, arom.H8), 7.93 (d, J = 10.0 Hz, 1H, arom.H7), 8.07 (s, 1H, arom.H5), 9.64, 10.39 (2 s, 2H, NH); 13C NMR (δ, ppm) = 25.28 (2CH2.cyclic), 48.74 (2CH2–N.cyclic), 116.19, 123.56, 125.16, 126.04, 128.86, 133.30, 135.05, 135.48, 137.93, 137.98, 143.61, 155.66 (N═C), 182.07 (C═S); Anal. Calcd: C20H18N6O2S4 (502.64), C = 47.79, H = 3.61, N = 16.72; Found: C = 47.70, H = 3.58, N = 16.70.

5.5 Synthesis of substituted thiazolo-quinoxaline sulfonamide (11a and b)

To a solution of 2,3-dichloro-quinoxaline derivative 5 (0.02 mol), thiourea derivative (0.02 mol) in 1,4-dioxane as a solvent was added. The solution was heated under reflux for 4 h (monitored by TLC). The solution was cooled to room temperature and the precipitate of the new products was obtained as a colored solid, which was collected by filtration and crystallized with acetonitrile.

5.5.1 6-(Pyrrolidin-1-ylsulfonyl)thiazolo[4,5-b]quinoxalin-2(3H)-imine (11a)

M. p.: 230–232°C; orange powder; yield: 86%; IR (KBr, cm−1): ν max = 3,429, 3,380 (2N–H), 3,073, 3,038 (arom.CH), 2,972 (aliph.CH), 1,327, 1,140 (SO2, sulfonamide); 1H NMR (δ, ppm) = 1.65 (s, 4H, 2CH2.cyclic), 3.70 (s, 4H, 2CH2–N.cyclic), 7.80 (d, J = 8.8 Hz, 1H, arom.H8), 8.03 (d, J = 9.2 Hz, 1H, arom.H7), 8.32 (s, 1H, arom.H5), 9.71, 9.97 (2 s, 2H, 2NH); 13C NMR (δ, ppm) = 25.30 (2CH2.cyclic), 48.38 (2CH2–N.cyclic), 124.18, 127.65, 129.37, 131.21, 133.91, 134.88, 137.40, 162.16 (C═NH), 164.75 (C═NH); Anal. Calcd: C13H13N5O2S2 (335.40), C = 46.55, H = 3.91, N = 20.88; Found: C = 46.52, H = 3.87, N = 20.83.

5.5.2 N-Phenyl-6-(pyrrolidin-1-ylsulfonyl)thiazolo[4,5-b]quinoxalin-2(3H)-imine (11b)

M. p.: 250–252°C; red powder; yield: 85%; IR (KBr, cm−1): ν max = 3,419 (N–H), 3,135, 3,054 (arom.CH), 2,924 (aliph.CH), 1,562 (C═N, imine), 1,341, 1,156 (SO2, sulfonamide); 1H NMR (δ, ppm) = 1.64 (s, 4H, 2CH2.cyclic), 3.67 (s, 4H, 2CH2–N.cyclic), 7.16 (d, J = 11.6 Hz, 2H, arom.H), 7.84 (t, J = 9.2 Hz, 1H, arom.H), 8.14 (t, J = 8.2 Hz, 2H, arom.H), 8.14 (d, J = 8.8 Hz, 2H, arom.H), 8.19 (d, J = 8.8 Hz, 1H, arom.H7), 8.31 (d, J = 7.2 Hz, 1H, arom.H8), 8.43 (s, 1H, arom.H5), 9.79 (s, 1H, NH); 13C NMR (δ, ppm) 25.31 (2CH2.cyclic), 48.51 (2CH2–N.cyclic), 124.72, 127.87, 128.30, 130.12, 131.34, 132.25, 136.99, 139.11, 140.63, 144.99, 146.69, 164.02 (C═N); Anal. Calcd: C19H17N5O2S2 (411.50), C = 55.46, H = 4.16, N = 17.02; Found: C = 55.41, H = 4.02, N = 16.97.

  1. Funding information: Authors state no funding involved.

  2. Conflict of interest: 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: 2023-08-31
Revised: 2023-10-06
Accepted: 2023-11-08
Published Online: 2023-12-25

© 2023 the author(s), published by De Gruyter

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

Articles in the same Issue

  1. Research Articles
  2. Synthesis, characterization, and antibacterial activity of a new poly azo compound containing N-arylsuccinimid and dibenzobarrelene moieties
  3. Design, synthesis, and antiviral activities evaluation of novel quinazoline derivatives containing sulfonamide moiety
  4. Design, synthesis, and anticancer activity of novel 4,6-dimorpholinyl-1,3,5-triazine compounds
  5. Design, synthesis, biological evaluation, and bio-computational modeling of imidazo, thieno, pyrimidopyrimidine, pyrimidodiazepene, and motifs as antimicrobial agents
  6. Synthesis of a novel phosphate-containing ligand rhodium catalyst and exploration of its optimal reaction conditions and mechanism for the polymerization of phenylacetylene
  7. Design, synthesis, and antiproliferative activity of novel 1,2,4-triazole-chalcone compounds
  8. Synthesis of metal–organic nanofiber/rGO nanocomposite as the sensing element for electrochemical determination of hypoxanthine
  9. Design and synthesis of various 1,3,4-oxadiazoles as AChE and LOX enzyme inhibitors
  10. Bis(2-cyanoacetohydrazide) as precursors for synthesis of novel azoles/azines and their biological evaluation
  11. Synthesis, characterization, and biological target prediction of novel 1,3-dithiolo[4,5-b]quinoxaline and thiazolo[4,5-b]quinoxaline derivatives
  12. Sustainable conversion of carbon dioxide into novel 5-aryldiazenyl-1,2,4-triazol-3-ones using Fe3O4@SP-vanillin-TGA nanocomposite
  13. Erratum
  14. Erratum to “Design, synthesis and study of antibacterial and antitubercular activity of quinoline hydrazone hybrids”
  15. SI: Undergraduate Research in the Synthesis of Biologically Active Small Molecules and Their Applications
  16. Preparation of novel acyl pyrazoles and triazoles by means of oxidative functionalization reactions
  17. Synthesis and conformational analysis of N-BOC-protected-3,5-bis(arylidene)-4-piperidone EF-24 analogs as anti-cancer agents
  18. SI: Development of Heterocycles for Biomedical and Bioanalytical Applications
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https://doi.org/10.1515/hc-2022-0170
Keywords for this article
2,3-dichloroquinoxaline; 1,3-dithiolo[4,5-b]quinoxaline; thiazolo[4,5-b]quinoxaline; 1,3-binucleophile; biological target prediction
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Articles in the same Issue

  1. Research Articles
  2. Synthesis, characterization, and antibacterial activity of a new poly azo compound containing N-arylsuccinimid and dibenzobarrelene moieties
  3. Design, synthesis, and antiviral activities evaluation of novel quinazoline derivatives containing sulfonamide moiety
  4. Design, synthesis, and anticancer activity of novel 4,6-dimorpholinyl-1,3,5-triazine compounds
  5. Design, synthesis, biological evaluation, and bio-computational modeling of imidazo, thieno, pyrimidopyrimidine, pyrimidodiazepene, and motifs as antimicrobial agents
  6. Synthesis of a novel phosphate-containing ligand rhodium catalyst and exploration of its optimal reaction conditions and mechanism for the polymerization of phenylacetylene
  7. Design, synthesis, and antiproliferative activity of novel 1,2,4-triazole-chalcone compounds
  8. Synthesis of metal–organic nanofiber/rGO nanocomposite as the sensing element for electrochemical determination of hypoxanthine
  9. Design and synthesis of various 1,3,4-oxadiazoles as AChE and LOX enzyme inhibitors
  10. Bis(2-cyanoacetohydrazide) as precursors for synthesis of novel azoles/azines and their biological evaluation
  11. Synthesis, characterization, and biological target prediction of novel 1,3-dithiolo[4,5-b]quinoxaline and thiazolo[4,5-b]quinoxaline derivatives
  12. Sustainable conversion of carbon dioxide into novel 5-aryldiazenyl-1,2,4-triazol-3-ones using Fe3O4@SP-vanillin-TGA nanocomposite
  13. Erratum
  14. Erratum to “Design, synthesis and study of antibacterial and antitubercular activity of quinoline hydrazone hybrids”
  15. SI: Undergraduate Research in the Synthesis of Biologically Active Small Molecules and Their Applications
  16. Preparation of novel acyl pyrazoles and triazoles by means of oxidative functionalization reactions
  17. Synthesis and conformational analysis of N-BOC-protected-3,5-bis(arylidene)-4-piperidone EF-24 analogs as anti-cancer agents
  18. SI: Development of Heterocycles for Biomedical and Bioanalytical Applications
  19. Influence of octreotide on apoptosis and metabolome expression in lipopolysaccharide-induced A549 cells
  20. Crude extract of J1 fermentation promotes apoptosis of cervical cancer cells
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