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Article

4-Alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline Derivatives as New Heterocyclic Analogues of Indolo[2,3-b]quinoxalines: Synthesis and Antitubercular Activity

by
Gusein A. Sadykhov
1,2,
Danila V. Belyaev
1,3,
Ekaterina E. Khramtsova
4,
Diana V. Vakhrusheva
3,
Svetlana Yu. Krasnoborova
3,
Dmitry V. Dianov
3,
Marina G. Pervova
1,
Gennady L. Rusinov
1,3,
Egor V. Verbitskiy
1,2,* and
Valery N. Charushin
1,2
1
Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, S. Kovalevskoy Street, 22, Ekaterinburg 620137, Russia
2
Department of Organic and Biomolecular Chemistry, Ural Federal University, Mira Street, 19, Ekaterinburg 620002, Russia
3
Ural Research Institute for Phthisiopulmonology—The Branch of National Medical Research Center for Phthisiopulmonology and Infection Diseases, 22 Parts’ezda Street, 50, Ekaterinburg 620039, Russia
4
Department of Chemistry, Perm State University, Bukireva Street, 15, Perm 614990, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(1), 369; https://doi.org/10.3390/ijms26010369
Submission received: 10 December 2024 / Revised: 24 December 2024 / Accepted: 1 January 2025 / Published: 3 January 2025
(This article belongs to the Section Physical Chemistry and Chemical Physics)
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Versions Notes

Abstract

:
The synthetic approach based on a sequence of Buchwald–Hartwig cross-coupling and annulation through intramolecular oxidative cyclodehydrogenation has been used for the construction of novel 4-alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline derivatives. For the first time, these polycyclic compounds were evaluated for antimycobacterial activity, including extensively drug-resistant strains. A reasonable bacteriostatic effect against Mycobacterium tuberculosis H37Rv was demonstrated. A plausible mechanism for antimycobacterial activity of heterocyclic analogues of indolo[2,3-b]quinoxalines has been advanced on the basis of their molecular docking data.

1. Introduction

Indolo[2,3-b]quinoxaline derivatives are crucial in medicinal chemistry and material science (Figure 1). Compounds of this series have been proven to exhibit antiviral [1,2] (for example, agent B-220), antitumor [3,4,5,6,7,8,9], and antidiabetic [10] properties and can be used for the treatment of neurodegenerative diseases [11]. Additionally, indoloquinoxaline-bearing compounds are used as semiconductors and emitting layers in organic electronics devices [12,13,14,15,16,17,18,19,20,21,22], as well as promising multifunctional chemosensors [23,24]. Several main approaches are based on the annulation of the indole moiety to the quinoxaline core [25,26,27,28]. We have recently [29] proposed a new route for the synthesis of indolo[2,3-b]quinoxaline derivatives (I) based on the sequential application of the Buchwald–Hartwig cross-coupling and intramolecular nucleophilic aromatic substitution of hydrogen (the so-called SNH reaction [30,31]) (Scheme 1). Moderate anticoagulant and tuberculostatic activities have been revealed for the obtained compounds (I) [29,32].
To the best of our knowledge, the literature describes only one example of the synthesis of compounds bearing the thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline scaffold (II) (Scheme 2) [33].
In this communication, we wish to report a new synthetic procedure for the preparation of a series of 4-alkyl-4H-thieno[2′,3′: 4,5]pyrrolo[2,3-b]quinoxalines as new heterocyclic analogues of indolo[2,3-b]quinoxalines, and to present the results of their evaluation for antitubercular activity against Mycobacterium tuberculosis H37Rv.

2. Results and Discussion

2.1. Synthesis

We have decided to explore an opportunity to use the previously developed two-step approach (see Scheme 1) for the synthesis of the desired 4-alkyl-4H-thieno[2′,3′: 4,5]pyrrolo[2,3-b]quinoxalines. At the first stage, we have optimized the conditions for the preparation of N1,N1-dimethyl-N2-(2-(quinoxalin-2-yl)thiophen-3-yl)ethane-1,2-diamine (2a) by reacting 2-(3-bromo-thiophen-2-yl)quinoxaline (1a) with 1,2-dimethylethylenediamine (DMEDA) under Buchwald–Hartwig cross-coupling conditions (Scheme 3, Table 1). Using the previously discovered conditions [29] for the synthesis of N1,N1-dimethyl-N2-(2-(quinoxalin-2-yl)phenyl)ethane-1,2-diamine, Pd(OAc)2 was used as a catalyst in the presence of tricyclohexyl-phosphine, acting as the ligand, and t-BuONa, acting as the base, under microwave synthesis conditions for 15 min (entry 1, Table 1).
The variation of the phosphine ligand has shown that the highest yield of product 2a is observed in the reaction mixture using 1,1′-ferrocenediyl-bis(diphenylphosphine) (Table 1, entries 2–12). By further varying the base, solvent, and temperature, the optimal reaction conditions have been selected for the synthesis of quinoxaline 2a (Table 1, entries 13–21). It should be noted that, as with the reaction involving 2-(2-bromophenyl)quinoxaline [20], the main issue was related to the side debromination of the starting material 1a, resulting in the formation of 2-(thiophen-2-yl)quinoxaline (2-ThioQx).
Thus, the optimal conditions for the preparation of N1,N1-dimethyl-N2-(2-(quinoxalin-2-yl)thiophen-3-yl)ethane-1,2-diamine (2a) in 75% yield proved to be the following: the reaction is carried out in the presence of 0.1 equiv. Pd(OAc)2 and 0.2 equiv. dppf in toluene under microwave activation for 15 min (Table 1, entry 20). This procedure has been applied to obtain products with a series of amines, such as 1-propylamine (nPrNH2), 1-butylamine (nBuNH2), N,N-dimethylethylenediamine, N,N-dimethyl-1,3-propanediamine (DMPDA), and 4-(2-aminoethyl)-morpholine (AEM). The corresponding N-alkyl-2-(quinoxaline-2-yl)anilines (2a–6a) and N-alkyl-2-(6,7-dimethylquinoxaline-2-yl)anilines (2b–6b) were obtained in high yields (Scheme 4).
The resulting N-alkyl-2-(quinoxalin-2-yl)thiophen-3-amines (2a–6a) and N-alkyl-2-(6,7-dimethylquinoxalin-2-yl)thiophen-3-amines (2b–6b) were formed in situ and subsequently underwent an intramolecular reaction of nucleophilic aromatic substitution of hydrogen (SNH). This reaction was carried out by treating the reaction mixture with a solution of concentrated hydrochloric acid in ethanol, using a volume ratio of 1:10, in the presence of air as an oxidizing agent, as previously suggested [29].
This one-pot synthesis allowed us to obtain the target polycyclic indolo[2,3-b]quinoxaline analogues, namely 4-alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxalines 7–11, in good yields (Scheme 5).

2.2. Antimycobacterial Activity

The series of compounds 7a–11a and 7b–11b were explored for their activities in vitro against M. tuberculosis H37Rv (Table 2) with the employment of the aerobic resazurin microplate assay (REMA) [34,35]. The experimental data indicate that most of the tested compounds exhibited relatively low activity, with minimal inhibitory concentrations (MICs) greater than 25 μg/mL. The only 4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline derivative 7b that bears the N,N-dimethylethan-1-amine moiety demonstrated an average value of antitubercular activity of 12.5 μg/mL (Table 2, entry 6). It should be noted that all 4H-thieno[2′,3′: 4,5]pyrrolo[2,3-b]-quinoxalines 7–11 proved to have 2-fold lower values of activities than those reported earlier for similar indolo[2,3-b]quinoxaline derivatives [29].
The antitubercular activity of the most active compound 7b was assessed against the strain Mycobacterium tuberculosis 5521, which has extensive drug resistance (XDR) to drugs such as bedaquiline, isoniazid, rifampicin, fluoroquinolones, and others [36]. The minimum inhibitory concentration for compound 7b against the XDR strain of Mycobacterium tuberculosis was found to be 12.5 μg/mL. This indicates the potential for discovering new active agents targeting Mycobacterium tuberculosis, particularly those with extensive drug resistance, using such polycyclic derivatives.
An in vitro cytotoxicity test (IC50) for the most active agent 7b was fulfilled on the VERO epithelial cells (ATCC CCL81) using the colorimetric MTT assay (Table 2, Entry 6) [37].
Polycyclic compound 7b demonstrated a cytotoxicity level that proved to be nearly two times lower than that of the corresponding indolo[2,3-b]quinoxaline derivative (IC50 = 5.08 ± 1.57 μg/mL) [29] and had a good correlation with the known antitumor activity of similar compounds [3,4,5].

2.3. Molecular Docking of Antitubercular Activity

The reverse docking strategy has been used to suggest the mechanism of antimycobacterial activity [29,38]. The complete library of potential targets for Mycobacterium tuberculosis H37Rv found in the literature has been utilized to realize this idea (Table 3) [39].
Ligands 7a,b, 8a,b, and 11a,b bearing the N,N-alkylamino moiety were subjected to docking experiments both in non-protonated and protonated forms. Protonated forms are indicated by adding «H» to the number of the corresponding compound (for example, ligand 7aH means the protonated ligand 7a). Calculated docking scores are shown in Figure 1 (for each target, docking experiments were performed in triplicate, and each cell corresponds to a mean value).
Docking of compounds 7–11 to isocitrate lyase (icl1) (Table 1, entry 11) demonstrates negative scores (Figure 2), which imply that ligands have a much larger size than the cavity of the binding site. Thus, this protein has been excluded from further consideration.
While executing the reverse docking procedure, we aimed to identify a target that would yield optimal docking scores for the ligands. The docking scores we obtained were normalized and divided into two categories to illustrate the ranking of ligands in relation to each protein (see Figure 3).
According to Figure 3, compounds possessing the best minimal inhibitory concentration values demonstrate the highest normalized docking scores (top 25%) relative to adenosine kinase (Rv2202c) (Table 3, Entry 32). Based on this observation, we have supposed that the estimated target of these substances in Mycobacterium tuberculosis appears to be Rv2202c. This enzyme generally promotes the transformation of adenosine into adenosine monophosphate in the purine salvage pathway within mycobacteria [40]. The substrate for Rv2202c is adenosine, and some adenosine-like substances [41] (Figure 4) can inhibit this enzyme. The considered derivatives 7–11 contain an adenosine-like segment (Figure 4), which likely determines good docking scores to Rv2202c.
Docking data of derivatives 7–11 to the cavity of the enzyme are given in Table 4 (only non-protonated forms are given since the protonated compounds proved to have lower scores, see Figure 2). For comparison, values for 5-iodotubercidin (cognate ligand of 6c67, see Figure 2) are calculated.
π-stacking interactions display a significant contribution to the binding ability of inhibitors of Rv2202c for the enzyme with Phe102 and Phe116 residues [38]. Several hydrogen bonds also contribute to the binding, with residues Gln172, Gln173, Ser8, Ser36′, Asp12, Gly48, Asn52, and Asp257 [38]. In the best-docked poses of compounds 7–11, some of these significant interactions were observed along with some other types of interactions (Figure 5). The best-docked pose of substances 8b and 11b shows unfavorable bumps of methyl substituents with Asn52 and Thr253. We have supposed that these unfavorable interactions can be corrected by the flexibility of these amino acid residues. Notably, compounds 7–10 demonstrate a hydrogen bond with the binding site (Ser8). Moreover, derivatives 8a–10a, 7b, 9b, and 10b proved to form a sulfur–X bond with the binding site (Met121) due to the presence of a thiophene fragment. Compound 11b has two sulfur–X bonds with the binding site (Met121, Ser8). This observation aligns well with the results obtained for antimycobacterial activity.

3. Materials and Methods

3.1. Synthesis

Since we have already described the general data on the analytical equipment and methods used [29], they are presented in the “General Information” Section (see Supporting Information). Starting compound 1a was prepared according to the earlier reported procedure [42]. Details on the antimycobacterial assay, experiments for molecular docking, and the binding sites of the investigated proteins are provided in Supporting Information.

3.1.1. Synthesis of 2-(3-Bromothiophen-2-yl)-6,7-dimethylquinoxaline (1b)

A 10 mL microwave reactor vial equipped with a magnetic stirrer bar was charged with selenium dioxide (0.89 g, 8 mmol), 1,4-dioxane/H2O 15:1 (16 mL), and 2′-bromoacetophenone (1.64 g, 8 mmol). The vial was capped and placed in the microwave reactor for 1.5 h at 150 °C. After the full conversion of the starting material (checked by TLC) (if needed, an extra 0.1 equiv. of SeO2 can be added and heated again for 30 min), the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give corresponding aryl glyoxal as a dark orange oil. The residue was transferred with EtOH (10 mL) in a round-bottom flask charged with a magnetic stirrer and 4,5-dimethyl-1,2-phenylenediamin (0.76 g, 5.6 mmol) was added. The mixture was refluxed for 1 h. After that, the mixture was cooled down, and the precipitate was filtered off, washed with ethanol, and then air-dried. Yield: 67% (1205 g). Physical State: beige solid. 1H NMR (500 MHz, CDCl3): δ 9.67 (s, 1H), 7.85 (d, J = 7.1 Hz, 2H), 7.46 (d, J = 5.3 Hz, 1H), 7.14 (d, J = 5.3 Hz, 1H), 2.51 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 149.9, 142.2, 141.1, 141.1, 140.7, 140.4, 137.1, 132.8, 128.8, 128.3, 128.2, 109.2, 20.4, 20.3. MP: 135–136 °C. HRMS (ESI): calc’d for C14H12BrN2S [M+H]+ m/z 318.9899, found 318.9899. Rf = 0.44 (10% EtOAc/hexanes). Purification: recrystallization from ethanol.

3.1.2. General Procedure for the Synthesis of N-Alkyl-2-(quinoxaline-2-yl)thiophen-3-amines (2a–6a) and N-Alkyl-2-(6,7-dimethylquinoxalin-2-yl)thiophen-3-amines (2b–6b)

A 10 mL microwave reactor vial equipped with a magnetic stirrer bar was charged with 50 mg of quinoxaline (1.72 mmol), the corresponding amine (2.0 equiv), Pd(OAc)2 (0.1 equiv.), dppf (0.2 equiv.), t-BuONa (2.5 equiv.), and 6 mL of toluene sparged with argon for 10 min. The empty volume of the vial was also spared with argon, the cap was quickly sealed, and then the vial was placed in a microwave reactor for 15 min. After that, the reaction mixture was filtered through a pad of Celite, washed with CH2Cl2, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel) provided the products 2a–6a and 2b–6b.

3.1.3. N1,N1-Dimethyl-N2-(2-(quinoxalin-2-yl)thiophen-3-yl)ethane-1,2-diamine (2a)

Yield: 75% (38 mg). Physical State: orange solid. 1H NMR (500 MHz, CDCl3): δ 8.97–8.92 (m, 1H), 8.87 (s, 1H), 7.95 (dd, J = 8.3, 1.1 Hz, 1H), 7.87 (dd, J = 8.4, 1.1 Hz, 1H), 7.66 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.54 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 7.36 (d, J = 5.5 Hz, 1H), 6.81 (d, J = 5.4 Hz, 1H), 3.49 (q, J = 6.1 Hz, 2H), 2.68 (t, J = 6.3 Hz, 2H), 2.34 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 153.0, 150.2, 144.0, 141.2, 139.1, 130.0, 129.0, 128.3, 127.6, 127.0, 117.5, 105.7, 58.7, 45.5, 43.3. MP: 103–104 °C. HRMS (ESI): calc’d for C16H19N4S [M+H]+ m/z 299.1325, found 299.1323. Rf = 0.26 (50% EtOAc/hexanes + 1% TEA). Purification: (SiO2, 50% EtOAc/hexanes + 1% TEA).

3.1.4. N1,N1-Dimethyl-N3-(2-(quinoxalin-2-yl)thiophen-3-yl)propane-1,3-diamine (3a)

Yield: 86% (46 mg). Physical State: orange semisolid. 1H NMR (500 MHz, CDCl3): δ 8.9 (s, 1H), 8.73–8.67 (m, 1H), 7.96 (dd, J = 8.2, 1.0 Hz, 1H), 7.87 (dd, J = 8.3, 0.8 Hz, 1H), 7.66 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.54 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 7.36 (d, J = 5.4 Hz, 1H), 6.84 (d, J = 5.5 Hz, 1H), 3.50 (q, J = 6.4 Hz, 2H), 2.57 (t, J = 7.3 Hz, 2H), 2.35 (s, 6H), 1.97 (quint, J = 7.1 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 153.0, 150.2, 144.1, 141.0, 139.1, 130.0, 129.1, 128.5, 127.4, 127.1, 117.4, 105.7, 57.0, 45.2, 43.3, 27.8. MP: -. HRMS (ESI): calc’d for C17H21N4S [M+H]+ m/z 313.1481, found 313.1481. Rf = 0.10 (50% EtOAc/hexanes + 1% TEA). Purification: (SiO2, 50% EtOAc/hexanes + 1% TEA).

3.1.5. N-Propyl-2-(quinoxalin-2-yl)thiophen-3-amine (4a)

Yield: 85% (39 mg). Physical State: orange solid. 1H NMR (500 MHz, CDCl3): δ 8.87 (s, 1H), 8.76–8.69 (m, 1H), 7.95 (dd, J = 8.2, 1.3 Hz, 1H), 7.83 (dd, J = 8.3, 1.0 Hz, 1H), 7.65 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.53 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.35 (d, J = 5.5 Hz, 1H), 6.81 (d, J = 5.6 Hz, 1H), 3.38 (dt, J = 5.7, 6.8 Hz, 2H), 1.79 (sext, J = 7.2 Hz, 2H), 1.1 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 153.3, 150.3, 144.2, 141.1, 139.1, 130.0, 129.1, 128.4, 127.4, 127.0, 117.4, 105.3, 47.2, 23.3, 11.7. MP: 79–80 °C. HRMS (ESI): calc’d for C15H16N3S [M+H]+ m/z 270.1059, found 270.1058. Rf = 0.24 (5% EtOAc/hexanes). Purification: (SiO2, 5% EtOAc/hexanes).

3.1.6. N-Butyl-2-(quinoxalin-2-yl)thiophen-3-amine (5a)

Yield: 81% (39 mg). Physical State: orange solid. 1H NMR (500 MHz, CDCl3): δ 8.87 (s, 1H), 8.73–8.67 (m, 1H), 7.95 (dd, J = 8.2, 1.1 Hz, 1H), 7.82 (dd, J = 8.3, 1.1 Hz, 1H), 7.65 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.74 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 7.35 (d, J = 5.5 Hz, 1H), 6.81 (d, J = 5.6 Hz, 1H), 3.41 (dt, J = 5.7, 6.8 Hz, 2H), 1.75 (quint, J = 7.2 Hz, 2H), 1.55 (sext, J = 7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 153.4, 150.3, 144.2, 141.1, 139.1, 130.0, 129.1, 128.4, 127.4, 127.0, 117.4, 105.3, 45.0, 32.1, 20.2, 13.9. MP: 83–84 °C. HRMS (ESI): calc’d for C16H18N3S [M+H]+ m/z 284.1216, found 284.1215. Rf = 0.27 (5% EtOAc/hexanes). Purification: (SiO2, 5% EtOAc/hexanes).

3.1.7. N-(2-Morpholinoethyl)-2-(quinoxalin-2-yl)thiophen-3-amine (6a)

Yield: 88% (51 mg). Physical State: orange solid. 1H NMR (500 MHz, CDCl3): δ 8.89 (s, 1H), 8.85–8.80 (m, 1H), 7.97 (dd, J = 8.5, 1.1 Hz, 1H), 7.95 (dd, J = 8.4, 1.1 Hz, 1H) 7.67 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.56 (ddd, J = 8.3, 6,9, 1.3 Hz, 1H), 7.37 (d, J = 5.4 Hz, 1H), 6.82 (d, J = 5.3 Hz, 1H), 3.79 (t, J = 4.6 Hz, 4H), 3.52 (q, J = 5.85 Hz, 2H), 2.75 (t, J = 6.1 Hz, 2H), 2.59 (br s, 4H). 13C NMR (125 MHz, CDCl3): δ 152.7, 150.2, 144.1, 141.2, 139.1, 130.0, 129.1, 128.4, 127.5, 127.1, 117.6, 106.0, 67.1, 57.8, 53.6, 42.2. MP: 130–131 °C. HRMS (ESI): calc’d for C18H21N4OS [M+H]+ m/z 341.1431, found 341.1430. Rf = 0.37 (% EtOAc/hexanes). Purification: (SiO2, 50% EtOAc/hexanes).

3.1.8. N1-(2-(6,7-Dimethylquinoxalin-2-yl)thiophen-3-yl)-N2,N2-dimethylethane-1,2-diamine (2b)

Yield: 73% (36 mg). Physical State: orange-brown solid. 1H NMR (500 MHz, CDCl3): δ 8.90–8.83 (m, 1H), 8.78 (s, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.31 (d, J = 5.4 Hz, 1H), 6.80 (d, J = 5.4 Hz, 1H), 3.49 (q, J = 6.0 Hz, 2H), 2.69 (t, J = 6.4 Hz, 2H), 2.46 (s, 3H), 2.44 (s, 3H), 2.40 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 152.3, 149.5, 142.9, 140.1, 139.9, 138.0, 137.2, 128.3, 127.5, 127.1, 117.5, 106.0, 58.7, 45.5, 43.3, 20.4, 20.1. MP: 82–83 °C. HRMS (ESI): calc’d for C18H23N4S [M+H]+ m/z 327.1638, found 327.1638. Rf = 0.21 (50% EtOAc/hexanes + 1% TEA). Purification: (SiO2, 50% EtOAc/hexanes).

3.1.9. N1-(2-(6,7-Dimethylquinoxalin-2-yl)thiophen-3-yl)-N3,N3-dimethylpropane-1,3-diamine (3b)

Yield: 80% (41 mg). Physical State: orange solid. 1H NMR (500 MHz, CDCl3): δ 8.79 (s, 1H), 8.66–8.58 (m, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.31 (d, J = 5.4 Hz, 1H), 6.82 (d, J = 5.4 Hz, 1H), 3.46 (q, J = 6.3 Hz, 2H), 2.48 (t, J = 7.0 Hz, 2H), 2.46 (s, 3H), 2.44 (s, 3H), 2.29 (s, 6H), 1.92 (quint, J = 7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 152.6, 149.6, 143.1, 140.2, 139.8, 138.0, 137.2, 128.4, 127.6, 126.9, 117.5, 105.9, 57.3, 45.6, 43.5, 28.3, 20.2, 20.0. MP: 76–77 °C. HRMS (ESI): calc’d for C19H25N4S [M+H]+ m/z 341.1794, found 341.1794. Rf = 0.12 (50% EtOAc/hexanes + 1% TEA). Purification: (SiO2, 50% EtOAc/hexanes).

3.1.10. 2-(6,7-Dimethylquinoxalin-2-yl)-N-propylthiophen-3-amine (4b)

Yield: 78% (35 mg). Physical State: yellow-orange solid. 1H NMR (500 MHz, CDCl3): δ 8.78 (s, 1H), 8.72–8.54 (m, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.31 (d, J = 5.4 Hz, 1H), 6.80 (d, J = 5.4 Hz, 1H), 3.37 (t, J = 7.0 Hz, 2H), 2.45 (s, 3H), 2.44 (s, 3H), 1.78 (sext, J = 7.2 Hz, 2H), 1.10 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 152.7, 149.6, 143.1, 140.2, 139.8, 138.0, 137.2, 128.4, 127.6, 126.8, 117.5, 105.6, 47.2, 23.4, 20.3, 20.0, 11.7. MP: 118–119 °C. HRMS (ESI): calc’d for C17H20N3S [M+H]+ m/z 298.1372, found 298.1373. Rf = 0.20 (% EtOAc/hexanes). Purification: (SiO2, 40% → 50% EtOAc/hexanes).

3.1.11. N-Butyl-2-(6,7-dimethylquinoxalin-2-yl)thiophen-3-amine (5b)

Yield: 77% (36 mg). Physical State: orange solid. 1H NMR (500 MHz, CDCl3): δ 8.78 (s, 1H), 8.71–8.49 (m, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.31 (d, J = 5.5 Hz, 1H), 6.80 (d, J = 5.6 Hz, 1H), 3.40 (t, J = 7.0 Hz, 2H), 2.46 (s, 3H), 2.44 (s, 3H), 1.75 (quint, J = 7.2 Hz, 2H), 1.54 (sext, J = 7.4 Hz, 2H), 1.02 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 152.7, 149.6, 143.1, 140.2, 139.8, 138.0, 137.2, 128.4, 127.6, 126.8, 117.4, 105.6, 45.1, 32.2, 20.3, 20.3, 20.0, 13.7. MP: 80–81 °C. HRMS (ESI): calc’d for C18H22N3S [M+H]+ m/z 312.1529, found 312.1527. Rf = 0.21 (% EtOAc/hexanes). Purification: (SiO2, 40% → 50% EtOAc/hexanes).

3.1.12. 2-(6,7-Dimethylquinoxalin-2-yl)-N-(2-morpholinoethyl)thiophen-3-amine (6b)

Yield: 87% (48 mg). Physical State: orange solid. 1H NMR (500 MHz, CDCl3): δ 8.80 (s, 1H), 8.78–8.74 (m, 1H), 7.72 (d, J = 7.7 Hz, 2H), 7.32 (d, J = 5.4 Hz, 1H), 6.80 (d, J = 5.4 Hz, 1H), 3.81 (t, J = 4.6 Hz, 4H), 3.50 (q, J = 5.9 Hz, 2H), 2.75 (t, J = 6.1 Hz, 2H), 2.62–2.56 (m, 4H), 2.47 (s, 3H), 2.45 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 152.1, 149.5, 143.0, 140.2, 139.9, 138.1, 137.3, 128.4, 127.5, 127.0, 117.6, 106.3, 67.1, 57.9, 53.6, 42.2, 20.3, 20.0. MP: 149–150 °C. HRMS (ESI): calc’d for C20H25N4OS [M+H]+ m/z 369.1744, found 369.1742. Rf = 0.26 (50% EtOAc/hexanes). Purification: (SiO2, 50% EtOAc/hexanes).

3.1.13. General Procedure for Syntheses of 4-Alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline Derivatives (7–11)

A 10 mL microwave reactor vial equipped with a magnetic stirrer bar was charged with 50 mg of quinoxaline (3.34 mmol), the corresponding amine (2.0 equiv), Pd(OAc)2 (10 mol.%), dppf (20 mol.%), t-BuONa (2.5 equiv.), and 6 mL of toluene sparged with argon for 40 min. The empty volume of the vials was also spared with argon, the cap was quickly sealed, and then the vial was placed in a microwave reactor for 15 min. The reaction was carried out twice and the reaction mixtures were combined. After, the reaction mixture was filtered through a pad of Celite, washed with CH2Cl2, and concentrated under reduced pressure. The crude product was dissolved in 10 mL of ethanol with 1 mL of concentrated hydrochloric acid and stirred at 80 °C for a few days. After reaction completion (monitored by TLC), NaHCO3 was added to the reaction mixture until the end of the gas evolution. The mixture was filtered through a cotton plug, washed with CH2Cl2, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel) provided the products 7a–11a and 7b–11b.

3.1.14. N,N-Dimethyl-2-(4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxalin-4-yl)ethan-1-amine (7a)

Yield: 48% (49 mg). Physical State: pale orange solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (dd, J = 8.2, 1.7 Hz, 1H), 8.11 (dd, J = 8.0, 1.6 Hz, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.72–7.64 (m, 2H), 7.25 (d, J = 5.2 Hz, 1H), 4.60 (t, J = 6.73 Hz, 2H), 2.86 (t, J = 7.0 Hz, 2H), 2.36 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 152.3, 146.7, 139.2, 138.7, 137.4, 134.2, 128.8, 128.0, 127.6, 126.3, 112.6, 111.4 58.0, 45.7, 41.8. MP: 95–96 °C. HRMS (ESI): calc’d for C16H17N4S [M+H]+ m/z 297.1168, found 297.1167. Rf = 0.13 (50% EtOAc/hexanes + 1% TEA). Purification: (SiO2, 40% → 50% EtOAc/hexanes).

3.1.15. N,N-Dimethyl-3-(4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxalin-4-yl)propan-1-amine (8a)

Yield: 50% (53 mg). Physical State: green-orange solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (dd, J = 8.1, 1.7 Hz, 1H), 8.12 (dd, J = 8.0, 1.7 Hz, 1H), 7.80 (d, J = 5.2 Hz, 1H), 7.71–7.65 (m, 2H), 7.28 (d, J = 5.2 Hz, 1H), 4.56 (t, J = 6.9 Hz, 2H), 2.34 (t, J = 6.7 Hz, 2H), 2.23 (s, 6H), 2.14 (quint, J = 6.9 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 152.6, 146.7, 139.1, 138.7, 137.4, 134.1, 128.8, 127.9, 127.5, 126.3, 112.2, 111.5, 56.5, 45.4, 41.5, 27.3. MP: 78–79 °C. HRMS (ESI): calc’d for C17H19N4S [M+H]+ m/z 311.1325, found 311.1324. Rf = 0.07 (50% EtOAc/hexanes + 1% TEA). Purification: (SiO2, 50% EtOAc/hexanes).

3.1.16. 4-Propyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline (9a)

Yield: 57% (52 mg). Physical State: orange-yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J = 8.2, 1.7 Hz, 1H), 8.12 (dd, J = 7.9, 1.7 Hz, 1H), 7.80 (d, J = 5.1 Hz, 1H), 7.72–7.64 (m, 2H), 7.22 (d, J = 5.2 Hz, 1H), 4.46 (t, J = 7.2 Hz, 2H), 2.00 (sext, J = 7.3 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 152.4, 146.7, 139.1, 138.7, 137.3, 134.2, 128.8, 127.9, 127.5, 126.2, 112.3, 111.3, 45.1, 22.7, 11.5. MP: 140–141 °C. HRMS (ESI): calc’d for C15H14N3S [M+H]+ m/z 268.0903, found 268.0906. Rf = 0.10 (5% EtOAc/hexanes). Purification: (SiO2, 5% EtOAc/hexanes).

3.1.17. 4-Butyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline (10a)

Yield: 55% (53 mg). Physical State: yellow-orange solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (dd, J = 7.9, 1.7 Hz, 1H), 8.12 (dd, J = 8.0, 1.7 Hz, 1H), 7.80 (d, J = 5.2 Hz, 1H), 7.72–7.64 (m, 2H), 7.22 (d, J = 5.1 Hz, 1H), 4.50 (t, J = 7.0 Hz, 2H), 1.95 (quint, J = 7.4 Hz, 2H), 1.41 (sext, J = 7.5 Hz, 2H), 0.97 (t, J = 7.3, 3H). 13C NMR (125 MHz, CDCl3): δ 152.3, 146.7, 139.1, 138.7, 137.3, 134.2, 128.8, 128.0, 127.5, 126.2, 112.3, 111.3, 43.3, 31.5, 20.2, 13.7. MP: 77–78 °C. HRMS (ESI): calc’d for C16H16N3S [M+H]+ m/z 282.1059, found 282.1061. Rf = 0.13 (5% EtOAc/hexanes). Purification: (SiO2, 5% EtOAc/hexanes).

3.1.18. 4-(2-(4H-Thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxalin-4-yl)ethyl)morpholine (11a)

Yield: 56% (65 mg). Physical State: pale orange solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (dd, J = 7.8, 1.9 Hz, 1H), 8.09 (dd, J = 8.0, 1.7 Hz, 1H), 7.80 (d, J = 5.2 Hz, 1H), 7.73–7.65 (m, 2H), 7.24 (d, J = 5.2 Hz, 1H), 4.61 (t, J = 6.5 Hz, 2H), 3.61 (t, J = 4.5 Hz, 4H), 2.88 (t, J = 6.6 Hz, 2H), 2.67 (t, J = 4.1 Hz, 4H). 13C NMR (125 MHz, CDCl3): δ 152.3, 146.8, 139.2, 138.6, 137.4, 134.1, 128.8, 127.9, 127.6, 126.3, 112.5, 111.4, 66.9, 57.3, 53.8, 41.0. MP: 148–149 °C. HRMS (ESI): calc’d for C18H19N4OS [M+H]+ m/z 339.1274, found 339.1276. Rf = 0.15 (% EtOAc/hexanes). Purification: (SiO2, 40% → 50% EtOAc/hexanes).

3.1.19. 2-(7,8-Dimethyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxalin-4-yl)-N,N-dimethylethan-1-amine (7b)

Yield: 54% (60 mg). Physical State: green-orange solid. 1H NMR (500 MHz, CDCl3): δ 7.97 (s, 1H), 7.88 (s, 1H), 7.76 (d, J = 5.2 Hz, 1H). 7.25 (d, J = 5.2 Hz, 1H), 4.60 (t, J = 6.9 Hz, 2H), 2.87 (t, J = 7.0 Hz, 2H), 2.53 (s, 3H), 2.53 (s, 3H), 2.37 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 151.5, 146.4, 138.1, 137.9, 137.4, 136.6, 136.3, 133.3, 127.9, 127.1, 112.6, 111.3, 58.0, 45.7, 41.7, 20.3, 20.2. MP: 141–142 °C. HRMS (ESI): calc’d for C18H21N4S [M+H]+ m/z 325.1481, found 325.1483. Rf = 0.13 (50% EtOAc/hexanes + 1% TEA). Purification: (SiO2, 50% EtOAc/hexanes).

3.1.20. 3-(7,8-Dimethyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxalin-4-yl)-N,N-dimethylpropan-1-amine (8b)

Yield: 53% (62 mg). Physical State: pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.96 (s, 1H), 7.87 (s, 1H), 7.74 (d, J = 5.1 Hz, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.53 (t, J = 6.9 Hz, 2H), 2.52 (s, 6H), 2.33 (t, J = 7.0 Hz, 2H), 2.22 (s, 6H), 2.12 (quint, J = 6.9, 2H). 13C NMR (125 MHz, CDCl3): δ 151.8, 146.4, 138.0, 137.9, 137.4, 136.6, 136.3, 133.2, 127.9, 127.1, 112.2, 111.4, 56.5, 45.4, 41.4, 27.4, 20.3, 20.2. MP: 126–127 °C. HRMS (ESI): calc’d for C19H23N4S [M+H]+ m/z 339.1638, found 339.1639. Rf = 0.07 (50% EtOAc/hexanes + 1% TEA). Purification: (SiO2, 50% EtOAc/hexanes).

3.1.21. 7,8-Dimethyl-4-propyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline (9b)

Yield: 50% (51 mg). Physical State: yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.96 (s, 1H), 7.87 (s, 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.19 (d, J = 5.2 Hz, 1H), 4.43 (t, J = 7.1 Hz, 2H), 2.51 (s, 6H), 1.99 (sext, J = 7.3 Hz, 2H), 0.99 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 151.1, 146.0, 137.5, 137.4, 137.0, 136.1, 135.8, 132.8, 127.4, 126.6, 111.8, 110.7, 44.6, 22.3, 19.8, 19.7, 11.0. MP: 119–120 °C. HRMS (ESI): calc’d for C17H18N3S [M+H]+ m/z 296.1216, found 296.1215. Rf = 0.13 (5% EtOAc/hexanes). Purification: (SiO2, 40% → 50% EtOAc/hexanes).

3.1.22. 4-Butyl-7,8-dimethyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline (10b)

Yield: 50% (53 mg). Physical State: pale orange solid. 1H NMR (500 MHz, CDCl3): δ 7.96 (s, 1H), 7.87 (s, 1H), 7.75 (d, J = 5.1 Hz, 1H), 7.19 (d, J = 5.2 Hz, 1H), 4.47 (t, J = 7.2 Hz, 2H), 2.51 (s, 6H), 1.97–1.89 (m, 2H), 1.40 (sext, J = 7.5 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 151.1, 146.0, 137.5, 137.4, 137.0, 136.1, 135.8, 132.8, 127.4, 126.6, 111.8, 110.7, 42.7, 31.0, 29.2, 19.8, 19.7, 13.3. MP: 142–143 °C. HRMS (ESI): calc’d for C18H20N3S [M+H]+ m/z 310.1372, found 310.1373. Rf = 0.19 (% EtOAc/hexanes). Purification: (SiO2, CH2Cl2).

3.1.23. 4-(2-(7,8-Dimethyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxalin-4-yl)ethyl)morpholine (11b)

Yield: 53% (67 mg). Physical State: pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.96 (s, 1H), 7.84 (s, 1H), 7.75 (d, J = 5.2 Hz, 1H). 7.21 (d, J = 5.2 Hz, 1H), 4.58 (t, J = 6.6 Hz, 2H), 3.61 (t, J = 4.4 Hz, 4H), 2.87 (t, J = 6.5 Hz, 2H), 2.59–2.54 (m, 4H), 2.52 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 151.5, 146.5, 138.1, 138.0, 137.4, 136.6, 136.4, 133.2, 127.9, 127.0, 112.6, 111.3, 66.9, 57.3, 53.8, 40.9, 20.3, 20.2. MP: 166–167 °C. HRMS (ESI): calc’d for C20H23N4OS [M+H]+ m/z 367.1587, found 367.1587. Rf = 0.17 (50% EtOAc/hexanes). Purification: (SiO2, 50% EtOAc/hexanes).

3.2. Evaluation of Antimycobacterial Activity and Molecular Docking

The study of the antimycobacterial activity of the compounds was carried out based on the previously described procedure [29]. For details, see Supporting Information.

4. Conclusions

In summary, we have suggested an original procedure for the synthesis of novel 4-alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline derivatives, which are similar to antivirals and antibacterials of the indolo[2,3-b]quinoxaline family, through intramolecular oxidative cyclodehydrogenation of the corresponding N-alkyl-2-(quinoxaline-2-yl)thiophen-3-amines. The antimycobacterial activity of these derivatives has been estimated for the first time. Molecular docking data demonstrate that 4-alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxalines appear to be inhibitors of adenosine kinase (Rv2202c). The authors believe that the obtained results can be useful for the development of novel antibacterials against various mycobacterial strains.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms26010369/s1.

Author Contributions

Methodology, G.A.S., D.V.V., D.V.D. and M.G.P.; Software, E.E.K.; Formal analysis, D.V.B. and E.E.K.; Investigation, G.A.S., D.V.B., E.E.K., D.V.V., S.Y.K., D.V.D. and M.G.P.; Resources, D.V.V. and G.L.R.; Data curation, S.Y.K., G.L.R. and E.V.V.; Writing—original draft, G.A.S. and E.V.V.; Writing—review & editing, V.N.C.; Supervision, E.V.V. and V.N.C.; Project administration, E.V.V. All authors have read and agreed to the published version of the manuscript.

Funding

The synthetic part of the work was carried out with financial support from the Russian Science Foundation (project No. 24-23-00084).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original research data is available upon request.

Acknowledgments

Analytical studies were performed using equipment from the Center for Joint Use «Spectroscopy and Analysis of Organic Compounds» at the Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Sciences.

Conflicts of Interest

The authors declare no conflict of interest.

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Ijms 26 00369 g001
Figure 1. Representative compounds bearing the indoloquinoxaline scaffold.
Figure 1. Representative compounds bearing the indoloquinoxaline scaffold.
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Scheme 1. Synthesis of indolo[2,3-b]quinoxaline derivatives through the Buchwald–Hartwig cross-coupling and intramolecular SNH reactions.
Scheme 1. Synthesis of indolo[2,3-b]quinoxaline derivatives through the Buchwald–Hartwig cross-coupling and intramolecular SNH reactions.
Ijms 26 00369 sch001
Ijms 26 00369 sch002
Scheme 2. Synthesis of a thieno[2′,3′: 4,5]pyrrolo[2,3-b]quinoxaline derivative (II) (on the top); the structures of 6H-indolo[2,3-b]quinoxaline and 4H-thieno[2′,3′: 4,5]pyrrolo[2,3-b]quinoxaline (on the bottom).
Scheme 2. Synthesis of a thieno[2′,3′: 4,5]pyrrolo[2,3-b]quinoxaline derivative (II) (on the top); the structures of 6H-indolo[2,3-b]quinoxaline and 4H-thieno[2′,3′: 4,5]pyrrolo[2,3-b]quinoxaline (on the bottom).
Ijms 26 00369 sch002
Ijms 26 00369 sch003
Scheme 3. Optimization of conditions for the reaction of 1a with DMEDA.
Scheme 3. Optimization of conditions for the reaction of 1a with DMEDA.
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Scheme 4. Syntheses of N-alkyl-2-(quinoxalin-2-yl)thiophen-3-amines (2a–6a) and N-alkyl-2-(6,7-dimethylquinoxalin-2-yl)thiophen-3-amines (2b–6b).
Scheme 4. Syntheses of N-alkyl-2-(quinoxalin-2-yl)thiophen-3-amines (2a–6a) and N-alkyl-2-(6,7-dimethylquinoxalin-2-yl)thiophen-3-amines (2b–6b).
Ijms 26 00369 sch004
Ijms 26 00369 sch005
Scheme 5. Syntheses of 4-alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxalines 7–11.
Scheme 5. Syntheses of 4-alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxalines 7–11.
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Figure 2. Data of docking scores.
Figure 2. Data of docking scores.
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Figure 3. Categorized normalized docking scores.
Figure 3. Categorized normalized docking scores.
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Figure 4. Adenosine and similar structures.
Figure 4. Adenosine and similar structures.
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Figure 5. Protein–ligand interactions of compounds 7–11 with Rv2202c (6c67) (red—unfavorable bumps or unfavorable donor–donor interactions, green—conventional hydrogen bonds, pale green—carbon hydrogen bonds or π–donor hydrogen bonds, pale pink—alkyl and π–alkyl interactions, pink—π–π stacks, orange—π–anion interactions, yellow—sulfur–X interactions).
Figure 5. Protein–ligand interactions of compounds 7–11 with Rv2202c (6c67) (red—unfavorable bumps or unfavorable donor–donor interactions, green—conventional hydrogen bonds, pale green—carbon hydrogen bonds or π–donor hydrogen bonds, pale pink—alkyl and π–alkyl interactions, pink—π–π stacks, orange—π–anion interactions, yellow—sulfur–X interactions).
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Table 1. Optimization of conditions for the synthesis of N1,N1-dimethyl-N2-(2-(quinoxalin-2-yl)thiophen-3-yl)ethane-1,2-diamine (2a).
Table 1. Optimization of conditions for the synthesis of N1,N1-dimethyl-N2-(2-(quinoxalin-2-yl)thiophen-3-yl)ethane-1,2-diamine (2a).
№Pd Catalyst
(0.1 Equiv.)		Ligand
(0.2 Equiv.)		Base
(2.5 Equiv.)		SolventReaction Time, TemperatureReaction Mixtures a
GC–MS (%)
1Pd(OAc)2Xantphost-BuONatoluene15 min, 150 °C2a—91
1a—0
2-ThioQx—9
2Pd(OAc)2PCy3t-BuONatoluene15 min, 150 °C2a—0
1a—0
2-ThioQx—100
3Pd(PPh3)4-t-BuONatoluene15 min, 150 °C2a—0
1a—0
2-ThioQx—100
4Pd(OAc)2PPh3t-BuONatoluene15 min, 150 °C2a—0
1a—0
2-ThioQx—100
5Pd(OAc)2DPEPhost-BuONatoluene15 min, 150 °C2a—4
1a—90
2-ThioQx—2
6Pd(OAc)BrettPhost-BuONatoluene15 min, 150 °C2a—2.4
1a—94.4
2-ThioQx—3.2
7Pd(OAc)2P(o-Tol)3t-BuONatoluene15 min, 150 °C2a—2.7
1a—86.5
2-ThioQx—10.8
8Pd(OAc)2XPhost-BuONatoluene15 min, 150 °C2a—3.4
1a—82.5
2-ThioQx—14.1
9Pd(dba)2-t-BuONatoluene15 min, 150 °C2a—7.7
1a—72.0
2-ThioQx—20.3
10Pd2(dba)3-t-BuONatoluene15 min, 150 °C2a—9.8
1a—52.3
2-ThioQx—37.9
11Pd(OAc)2rac-BINAPt-BuONatoluene15 min, 150 °C2a—90.3
1a—0
2-ThioQx—9.3
12Pd(OAc)2dppft-BuONatoluene15 min, 150 °C2a—94,4
1a—0
2-ThioQx—5.6
13Pd(OAc)2dppfKFtoluene15 min, 150 °C2a—0
1a—98,3
2-ThioQx—1.7
14Pd(OAc)2dppfK2CO3toluene15 min, 150 °C2a—0
1a—100
2-ThioQx—0
15Pd(OAc)2dppfDABCOtoluene15 min, 150 °C2a—0
1a—89.3
2-ThioQx—10.7
16Pd(OAc)2dppfK3PO4toluene15 min, 150 °C2a—8.7
1a—91.3
2-ThioQx—0
17Pd(OAc)2dppft-BuOKtoluene15 min, 150 °C2a—40.9
1a—0
2-ThioQx—59.1
18Pd(OAc)2dppft-BuONadioxane15 min, 150 °C2a—80.3
1a—0
2-ThioQx—19.7
19Pd(OAc)2dppft-BuONaTHF15 min, 150 °C2a—81.7
1a—0
2-ThioQx—18.3
20Pd(OAc)2dppft-BuONatoluene15 min, 120 °C2a—94.9
1a—0
2-ThioQx—5.1
21Pd(OAc)2dppft-BuONatoluene15 min, 100 °C2a—90.6
1a—6.2
2-ThioQx—3.2
a The amount of 1a, 2a, and 2-ThioQx in the reaction mixture by GC–MS; MW—reactions performed under microwave irradiation; PCy3—Tricyclohexylphosphine; Pd(PPh3)4—Tetrakis(triphenylphosphine)palladium(0); PPh3—Triphenylphosphine; DPEPhos—Bis[(2-diphenylphosphino)phenyl]ether; BrettPhos—2-(Dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl; P(o-tol)3—Tri(o-tolyl)phosphine; XPhos—2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; Pd(dba)2—Bis(dibenzylideneacetone)palladium(0); Pd2(dba)3—Tris(dibenzylideneacetone)dipalladium(0); rac-BINAP—(±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene; Xantphos—4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; dppf—1,1′-Ferrocenediyl-bis(diphenylphosphine).
Table 2. In vitro antimycobacterial activity and cytotoxicity against Vero cells—data for indolo[2,3-b]pyrazine derivatives (7–11).
Table 2. In vitro antimycobacterial activity and cytotoxicity against Vero cells—data for indolo[2,3-b]pyrazine derivatives (7–11).
EntryCompoundAntimycobacterial Activity Against Mycobacterium tuberculosis H37Rv (MIC) aIC50 (μg/mL)
μg/mLμM
17a2584.35n.d
28a>25>80.54n.d.
39a2593.51n.d.
410a>25>88.85n.d.
511a>2573.87n.d.
67b12.538.5311.8 ± 1.4
78b2573.86n.d
89b>25>84.63n.d.
910b>2580.79n.d.
1011b>2568.22n.d.
13INH0.064.38n.d.
a These results were obtained in three independent experiments. The MIC values were the same in all three experiments, so the standard deviation is not given (equal to 0). n.d.—not determined; INH—Isoniazid.
Table 3. Targets of Mycobacterium tuberculosis H37Rv selected for reverse docking.
Table 3. Targets of Mycobacterium tuberculosis H37Rv selected for reverse docking.
EntryPDB IDProtein (Gene)
11z6kCitrate lyase (citE)
21kpg, 1kphCyclopropane synthase (cmaA1)
31kpiCyclopropane synthase (cmaA2)
46ddp, 6nnh, 6nniDihydrofolate reductase (dfrA)
51zljDosR regulator protein (DosR)
62qo1β-Ketoacyl-ACP synthase (fabH)
75hm3Acyl-AMP ligase (fadD32)
85zueFilamentation temperature-sensitive protein (ftsZ)
95ecv, 5h8u, 5t8gMalate synthase (glcB)
104tvmCitrate synthase (gltA2)
115dqlIsocitrate lyase (icl1)
126ee1Isocitrate lyase (icl2)
132isyIron-dependent regulator (IdeR)
144ohu, 4tzk, 5g0tEnoyl-ACP reductase (inhA)
155ld8, 6p9l, 6p9mβ-Ketoacyl-ACP synthase (kasA)
162gp6β-Ketoacyl-ACP synthase (kasB)
172a8x, 4m52Dihydrolipoyl dehydrogenase (lpdC)
181uznβ-Ketoacyl-ACP reductase (mabA)
194qij1,4-Dihydroxy-2-naphthoate-coenzyme A synthase (menB)
206o0j2-Succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate synthase (menD)
211tpyCyclopropane synthase (mmaA2)
223ha5S-Adenosylmethionine-dependent methyltransferase (mmaA4)
234ewlN-Acetyl-1-D-myo-inosityl-2-deoxy-α-D-glucopyranoside deacetylase (mshB)
241ozp, 1p0hMycothiol synthase (mshD)
251mop, 1n2h, 4fzjPantothenate synthetase (panC)
266p02, 6oyy, 6oz8Aspartate decarboxylase (panD)
271q9jPhthiocerol dimycocerosyl transferase (papA5)
281l1eCyclopropane synthase (pcaA)
294n9w, 4nc9Phosphatidyl mannosyltransferase (pimA)
306c4qPolyketide synthase (pks13)
315xnxRelA protein (relA)
326c67Adenosine kinase (Rv2202c)
332byoLipoprotein LppX (Rv2945c)
345uhbTranscription initiation complex (Rv3457c)
354unrThymidylate kinase (tmk)
Table 4. Docking scores and binding energies of compounds 7–11 relative to the cavity of Rv2202c.
Table 4. Docking scores and binding energies of compounds 7–11 relative to the cavity of Rv2202c.
LigandScoresΔGbind, kJ/mol
7a33.44−34.49
8a33.53−34.81
9a34.14−34.01
10a34.62−34.90
11a33.48−37.41
7b34.09−36.81
8b34.53−37.53
9b29.5−36.01
10b32,23−36.71
11b30.14−30.47
Cognate ligand (6c67)21.46−26.76
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Sadykhov, G.A.; Belyaev, D.V.; Khramtsova, E.E.; Vakhrusheva, D.V.; Krasnoborova, S.Y.; Dianov, D.V.; Pervova, M.G.; Rusinov, G.L.; Verbitskiy, E.V.; Charushin, V.N. 4-Alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline Derivatives as New Heterocyclic Analogues of Indolo[2,3-b]quinoxalines: Synthesis and Antitubercular Activity. Int. J. Mol. Sci. 2025, 26, 369. https://doi.org/10.3390/ijms26010369

AMA Style

Sadykhov GA, Belyaev DV, Khramtsova EE, Vakhrusheva DV, Krasnoborova SY, Dianov DV, Pervova MG, Rusinov GL, Verbitskiy EV, Charushin VN. 4-Alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline Derivatives as New Heterocyclic Analogues of Indolo[2,3-b]quinoxalines: Synthesis and Antitubercular Activity. International Journal of Molecular Sciences. 2025; 26(1):369. https://doi.org/10.3390/ijms26010369

Chicago/Turabian Style

Sadykhov, Gusein A., Danila V. Belyaev, Ekaterina E. Khramtsova, Diana V. Vakhrusheva, Svetlana Yu. Krasnoborova, Dmitry V. Dianov, Marina G. Pervova, Gennady L. Rusinov, Egor V. Verbitskiy, and Valery N. Charushin. 2025. "4-Alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline Derivatives as New Heterocyclic Analogues of Indolo[2,3-b]quinoxalines: Synthesis and Antitubercular Activity" International Journal of Molecular Sciences 26, no. 1: 369. https://doi.org/10.3390/ijms26010369

APA Style

Sadykhov, G. A., Belyaev, D. V., Khramtsova, E. E., Vakhrusheva, D. V., Krasnoborova, S. Y., Dianov, D. V., Pervova, M. G., Rusinov, G. L., Verbitskiy, E. V., & Charushin, V. N. (2025). 4-Alkyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline Derivatives as New Heterocyclic Analogues of Indolo[2,3-b]quinoxalines: Synthesis and Antitubercular Activity. International Journal of Molecular Sciences, 26(1), 369. https://doi.org/10.3390/ijms26010369

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