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Synthesis and PASS-assisted evaluation of new heterocyclic compounds containing hydroquinoline scaffolds

BMC Chemistry volume 18, Article number: 162 (2024) Cite this article

Abstract

Currently, there is a growing interest in the synthesis of heterocyclic compounds containing hydroquinoline fragments. This surge can be attributed to the broad range of pharmaceutical and industrial applications that these compounds possess. In this study, the synthesis of both linear and fused heterocyclic systems that incorporate hydroquinoline fragments was described. Furthermore, the pharmacological activity spectra of the synthesized compounds were predicted using the in silico method, employing the Prediction of Activity Spectra of Substances (PASS) program. Hydroquinolines containing the nitrile functionality 7 and 8 were synthesized through the reaction of the corresponding hydroquinolinecarbaldehyde 5a, 6b with hydroxylamine hydrochloride and iodine in aqueous ammonia under ambient conditions, respectively. 2-Phenyl-1,3-oxazol-5(4 H)-ones 9a, b and 10a, b were synthesized via the condensation of compounds 5a, b and 6a, b with hippuric acid in acetic acid in 30–60% yield. When the methyl activated 7-methylazolopyrimidines 11a, b were reacted with N-alkyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline-6-carbaldehydes 6a, b, 60–70% yield of triazolo/pyrazolo[1,5-a]pyrimidin-6-yl carboxylic acids 12a, b were obtained. The condensation of 7-hydroxy-1,2,3,4-tetramethyl-1,2-dihydroquinoline 3 h with dimethylacetylenedicarboxylate (DMAD) and ethyl acetoacetate afforded cyclic products 16 and 17, respectively. The condensation reaction of 6-formyl-7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline 5e with methylene-active compounds such as ethyl cyanoacetate/dimethyl-3-oxopentanedioate/ethyl acetoacetate/diethylmalonate/Meldrum’s acid afforded 3-substituted coumarins 19 and 21 containing dihydroquinoline moiety. The pentacyclic coumarin 22 was obtained via the tandom condensation reaction of malononitrile with 5e in the presence of a catalytic amount of piperidine in ethanol. The biological activities of the synthesized compounds were predicted using the PASS program. Based on the prognosis, compounds 13a, b, and 14 exhibited a high likelihood of being active as inhibitors of gluconate 2-dehydrogenase, as well as possessing antiallergic, antiasthmatic, and antiarthritic properties, with a probability value (Pa) ranging from 0.849 to 0.870. Furthermore, it was discovered that compounds 7 and 8 tended to act as effective progesterone antagonists and displayed antiallergic, antiasthmatic, and antiarthritic effects (Pa = 0.276–0.827). Among the hydroquinolines containing coumarin moieties, compounds 17, 19a, and 19c were predicted to be potent progesterone antagonists, with Pa values of 0.710, 0.630, and 0.615, respectively.

Graphical Abstract

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Introduction

Currently, heterocyclic compounds have attracted a great deal of research interest because of their numerous significant medical and biological applications [1,2,3,4]. Quinoline derivatives are N-containing heterocyclic compounds that are known for their applications in medicinal chemistry as antimalarial, anti-inflammatory, anti-asthmatic, antibacterial, antihypertensive, and tyrosine kinase inhibiting agents [5,6,7,8,9,10,11]. Hence, interest in the synthesis of heterocyclic compounds containing a quinoline scaffold has increased tremendously [12,13,14,15].

Alkyl derivatives of 1,2-H-dihydroquinoline belong to a large group of quinoline derivatives and are known to have great practical importance [16,17,18]. 2,2,4-Trimethyl-1,2-H-dihydroquinoline is one of the most important representatives and is considered an essential and effective antioxidant in rubber technologies [19]. The methods used for the synthesis of 1,2-quinoline derivatives are based on cyclization reactions, well known as the Skraup reaction, and various Skraup-based modification reactions, such as Combes, Knorr, Doebner and Friedlander [20, 21]. Tetrahydroquinoline is one of the most important simple nitrogen heterocycles, being widespread and present in a broad variety of pharmacologically active compounds [22, 23].

It has been found that heterocyclic compounds containing hydroquinoline derivatives are the basis for a wide range of biological activities [24,25,26] and have industrial applications, such as photosensitizers in solar cells [27,28,29] and additives to polymers [30, 31]. Hence, the construction of new heterocyclic assemblies and functionalization of hydroquinoline compounds have attracted the attention of synthetic organic chemists to further realize their versatile potential. Although methods for the synthesis of annulated heterocyclic systems containing 1,2-dihydro- and 1,2,3,4-tetrahydroquinoline moieties have been described in the literature, the problem of synthesizing new classes of linear and fused heterocyclic systems with hydroquinoline fragments, including those containing a chiral center in a certain configuration and various substituents, has not been completely solved.

In silico studies are becoming increasingly important in drug development from the initial stage to the approval of the drug. Using in silico tools to predict the biological activity and/or ADMET target for novel compounds has been widely used, as it helps in decreasing the cost and time related to drug discovery [32, 33].

Hence, in this study, the synthesis of new heterocyclic compounds containing hydroquinoline moieties such as carbonitriles, oxazolones, pyrazolo/triazolo[1,5-a]pyrimidines, and coumarins based on formylhydroquinolines was described (Fig. 1). Moreover, the pharmacological activity spectrum of the synthesized compounds was predicted by the in silico method using the Prediction of Activity Spectrum of Substances (PASS) computer program [34].

Results and discussion

Chemistry

K. Tianet et al. previously reported that the Vilsmeier-Haack (VH) formylation reaction of 1,2,2,4-tetramethyl-1,2-dihydroquinoline bearing an unsubstituted benzene ring proceeded with the formation of 1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-carbaldehyde as the only product [35]. In our previous publication [36] and PhD dissertation [37], we reported the synthesis of the starting materials hydroquinolinecarbaldehydes.

Hence in this work, the starting materials namely- N-alkyl-1,2-di (1,2,3,4-tetera)hydrohydroquinoline-6-carbaldehydes 5a, b, e and 6a, b and 7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline 3 h (Fig. 1; Table 1) were used to synthesize the desired compounds due to their structural favorability to synthesis the intended cyclic compounds.

Fig. 1
figure 1

Synthesis of 6(8)-Formyl-N-alkyl-2,2,4-trimethyl-1,2-di(1,2,3,4-tetra)hydroquinolines 5a, b, e and 6a, b via a VH formylation reaction

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Table 1 Substituents of the synthesized 6(8)-formyl-N-alkyl-2,2,4-trimethyl-1,2-di(1,2,3,4-tetra)hydroquinolines 5 and 6
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Synthesis of N-alkyl-2,2,4-trimethylhydroquinolin-6-yl-carbonitriles 7 and 8

One of the most important functional group transformations in organic synthesis is the conversion of aldehyde functional groups into nitriles. Nitriles are a very versatile functional group that can be used as a starting material for the synthesis of a variety of biologically active compounds, such as thiazole derivatives, oxazolines, imidazoles, triazolopyrimidines, and benzamidines [38]. In the majority of cases, nitriles are obtained via the initial formation of aldoxime, which is obtained by the condensation of hydroxylamine hydrochloride with an aldehyde, which is then subjected to dehydration by a variety of reagents to give nitriles. There are also a few methods known for the one-step conversion of aldehydes into nitriles without separating the formed aldoxime [38,39,40,41,42].

Consequently, to further functionalize hydroquinoline carbaldehydes, we have endeavored to synthesize carbonitrile groups using two different methodologies. Initially, we employed a hydroxylamine hydrochloride, pyridine and toluene system with the azeotropic separation of water. The formation of pyridinium chloride facilitates aldoxime–nitrile conversion, making the presence of a dehydrating agent unnecessary. The reaction between 6-formyl-N-methyl-2,2,4-trimethyl-1,2-dihydroquinoline 5a and H2NOH HCl/C5H5N/C7H8 was completed within 3 h, yielding 48% 1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-nitrile 7 (Fig. 2). The absence of the aldehydic proton signal, which typically resonates between 9.88 and 10.22 ppm in the 1H-NMR spectrum of the starting material, serves as evidence that the reaction has reached its completion (Figure S1). The second methodology we employed was the treatment of the respective aldehyde with iodine in aqueous ammonia at room temperature [42]. We speculated that the reaction proceeded via the oxidation of an aldimine with iodine to give an N-iodoaldimine intermediate, which eliminated an HI molecule in an ammonia solution to afford the nitrile product. This procedure was applicable in our case using 6-formyl-N-benzyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline 6b, which afforded N-benzyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline-6-nitrile 8 (Figure S2).

Fig. 2
figure 2

Synthesis of 1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-carbonitrile 7 and 1-benzyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile 8

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We have also attempted to synthesize an amide from 6-formyl-N-benzyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline 6b via treatment with aqueous hydrogen peroxide at room temperature, reportedly resulting in the intermediate formation of peroxocarboxamic acid [43]. However, a 4-h exposure to hydrogen peroxide at room temperature did not lead to the formation of the expected corresponding amide, yet the isolated compound was identified as the previously obtained nitrile 8. This might be due to the antioxidant properties of the tetrahydroquinoline fragment.

Synthesis of 2-Phenyl-1,3-oxazol-5(4Н)-ones 9 and 10

Benzoxazole derivatives have been reported in the literature to possess anti-inflammatory, analgesic, antibacterial, trichomonacidal, anthelmintic, fungicidal, antiviral, and kinase inhibitory effects [44]. The method for the synthesis of 4-arylidene-2-aryloxazol-5-ones has been widely used in synthetic organic chemistry and consists of the condensation of aromatic/heterocyclic/aldehydes with hippuric acid or its heteroanalogues in glacial acetic acid in the presence of anhydrous sodium acetate [45]. In our case, we used a solution of acetic anhydride in acetic acid for the condensation of hydroquinolinecarbaldehydes 5a, b and 6a, b with hippuric acid, and we obtained 2-aryl-4-arylidene-5(4 H)-oxazolones 9a and b and 10a and b in moderate yields of 30–60% (Fig. 3 and Figure S3-S6). Sidhu and coworkers confirmed that the 1H-NMR spectra of oxazolones show the deshielding influence of the cis-N = C-C6H5 moiety on the olefinic hydrogen atom, which shifts more downfield than when the olefinic hydrogen is cis to the carbonyl group [45]. In our case, the olefinic protons were found to resonate in the chemical shift range of δ = 7.18–7.22 ppm, which is relatively more upfield than expected (nearly δ = 7.60–7.85 ppm). Hence, based on the 1H-NMR spectral data, these compounds were assigned the (Z) configuration at position 4.

Fig. 3
figure 3

Synthesis of 2-phenyl-1,3-oxazol-5(4 H)-ones 9 and 10

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Condensation of Hydroquinoline Carbaldehydes with Reagents Containing an Activated Methyl Group 12, 13, 14

To search for potential biologically active compounds, we extended our work by reacting 6-formyl-N-alkyl-2,2,4-trimethyldihydroquinolines 5a, b; 6a, b with ethyl-7-methylpyrazolo/triazolo/[1,5-a]pyrimidine-6-carboxylates 11a, b (Fig. 4).

Fig. 4
figure 4

Synthesis of triazolo/pyrazolo[1,5-a]pyrimidin-6-yl carboxylic acids 12a, b

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The condensation of N-alkyl-1,2,3,4-tetrahydroquinoline-6-carbaldehydes 6a, b with 7-methylazolopyrimidines 11a, b occurs in the presence of the strong base potassium tert-butoxide, and the reaction product is accompanied by the hydrolysis of the ester group under the action of the water released during the condensation reaction. The broad downfield signals observed in the 1H-NMR spectra at 13.31 and 13.50 ppm are assigned to the carboxylic acid protons of 12a and b, respectively. The resulting 7-[(E)-2,2,4-trimethylhydroquinolin-6-ylidenemethyl]triazolo/pyrazolo[1,5-a]pyrimidin-6-yl carboxylic acids 12a, b are red crystalline compounds that are sparingly soluble in water.

Analysis of the 1H NMR spectra of carboxylic acids 12a and b showed that they are trans isomers. This is evidenced by the fact that the coupling constant of the olefinic protons, which resonate as doublets at δ 8.23 and 9.05 ppm, is 16 Hz, which is a typical characteristic of trans-substituted alkenes (Figure S7-S8). The 13C NMR spectrum of 12b shows a signal at 166.78 ppm, which is assignable to the carbonyl carbon atom of the carboxylic acid functional group (Figure S9).

The condensation of N-alkylhydroquinoline-6-carbaldehydes 5a, b, 6a, and b with acetone proceeds under milder conditions and leads to the previously unknown 4-(2,2,4-trimethylhydroquinoline-6-yl)-3-buten-2-ones 13a, b and 14, which are promising synthons for synthesizing biologically active heterocyclic systems.

In the 1H NMR spectra of compounds 13a, b, and 14, olefinic proton signals are observed in the form of two doublets in the regions of 6.50–6.54 and 7.44–7.49 ppm, and the value of the coupling constant is 16.4 Hz. These are the typical characteristics of 1,2-disubstituted alkenes with a trans configuration. On this basis, the compounds obtained were assigned the structure (E)-4-(1,2,2-trimethylhydroquinolin-6-yl)but-3-en-2-ones (Figure S10-S12).

Cyclizations of 7-Hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline 3 h and 7-Hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-carbaldehyde 5e, with Methylene-active compounds 16, 17, 19, 21, and 22

Dimethylacetylenedicarboxylate (DMAD) is an electron-deficient acetylenic compound that is widely used in cyclization reactions. With phenol, DMAD usually forms adducts, which are the result of the addition of a hydroxyl group under both basic and acid catalysis. However, with pyridine in the presence of sufficiently strong CH-acids, DMAD forms stable 1,4-diionic compounds of the betaine type [46]. The formation of such compounds leads to the reaction between DMAD and various phenols being terminated by α-methylene-γ-butyrolactones [47].

7-Hydroxy-1,2,3,4-tetramethyl-1,2-dihydroquinoline, 3 h, at positions 6 and 8, exhibits pronounced CH acidity associated with the coordinated orientation of the –OH and disubstituted amine groups, which made it possible to prepare the corresponding cyclic derivatives under pyridine catalysis conditions. Since position 8 is relatively sterically hindered compared with position 6, only one cycling center remains, which is position 6 (Fig. 5).

Fig. 5
figure 5

Synthesis of methyl (Z)-2-(5,7,7,8-tetramethyl-2-oxo-7,8-dihydrofuro[3,2-g]quinolin-3(2 H)-ylidene)acetate 16 and 4,6,8,8,9-pentamethyl-8,9-dihydro-2 H-pyrano[3,2-g]quinolin-2-one 17

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The reaction of 7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline 3 h with DMAD in the presence of a catalytic amount of pyridine resulted in the formation of compound 16 with a reaction yield of 46%. The 1H NMR spectrum of compound 16 displays a series of signals that correspond to the tricyclic structure of annulated α-methylene-γ-butyrolactone (Figure S13). A plausible reaction mechanism has been proposed, as depicted in Fig. 6. In the presence of pyridine, DMAD forms a betaine derivative of dimethyl maleate A, which is stabilized through interaction with the phenolic derivative 3 h.

Fig. 6
figure 6

Plausible reaction mechanism of methyl (Z)-2-(5,7,7,8-tetramethyl-2-oxo-7,8-dihydrofuro[3,2-g]quinolin-3(2 H)-ylidene)acetate 16

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Subsequent intramolecular proton transfer leads to intermediate E, which decomposes with the regeneration of pyridine and the formation of a compound in which the phenolic hydroxyl group and one of the ester groups of the dimethyl maleate fragment are spatially closed. The subsequent intramolecular transesterification leads to the elimination of methanol and the formation of lactone 16.

The Pechmann reaction is one of the most significant and simple methods for the synthesis of a variety of coumarin derivatives [48]. Pechmann condensation of 7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline 3 h with ethyl acetoacetate in the presence of a catalytic amount of sulfuric acid afforded 4,6,8,8,9-pentamethyl-8,9-dihydro-2 H-pyrano[3,2-g]quinolin-2-one 17 in 67% yield. The 1H-NMR spectrum of 17 indicates that there are two singlet signals at δ 6.36 and 7.16 ppm, in which each signal is attributed to one proton that is assignable to the H-10 and H-5 aromatic protons, respectively. This indicated that the condensation reaction occurred at position 6, not at position 8 of the aromatic ring of 3 h. If the condensation had occurred via position 8 of the ring, there would have been two ortho-substituted aromatic protons, which would have resulted in two doublet aromatic signals with each signal integrable to one proton with a J-value of nearly 7(8) Hz. The preference of position 6 over position 8 can also be rationalized by the relative steric hindrance of position 8 over position 6 of the aromatic ring of starting material 3 h (Figure S14).

Coumarins are natural plant species with diverse biological activities, including anti-inflammatory, antitumor, antioxidant, and antidiabetic effects. Coumarin derivatives are also considered neuroprotective agents against oxidative stress and free radical generation [49]. Several methods have been employed for the synthesis of coumarins, such as Von Pechmann, Perkin, Knoevenagel, Reformatsky, Wittig, and Claisen rearrangement reactions [50].

The condensation reaction of 7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-carbaldehyde 5e with methylene-active compounds, such as ethyl cyanoacetate (18а), dimethyl-3-oxopentanedioate (18b), ethyl acetoacetate (18с), and diethylmalonate (18d), in the presence of a catalytic amount of piperidine in ethanol afforded 3-substituted dihydroquinoline containing coumarins 19a-d in 34–58% yields, as shown in Fig. 7.

Fig. 7
figure 7

Condensation reaction of 7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-carbaldehyde 5e with methylene-active compounds

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A plausible reaction mechanism for the formation of 3-R-6,8,8,9-tetramethyl-8,9-dihydro-2 H-pyrano[3,2-g]quinolin-2-one 19a-d is shown in Fig. 8. Common to all methylene-active compounds 18a-d is the presence of an ester functional group, which enters into the intramolecular transesterification reaction of arylidene derivative B, which is formed after dehydration of Knoevenagel adduct A.

Fig. 8
figure 8

Plausible reaction mechanism for the formation of 3-R-6,8,8,9-tetramethyl-8,9-dihydro-2 H-pyrano[3,2-g]quinolin-2-one 19a-d

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The 1H-NMR spectrum of 19a shows that there are two singlets, each corresponding to one proton at δ = 6.44 and 8.48 ppm, which are attributed to the aromatic protons H-10 and H-5, respectively. The downfield signal at δ = 7.25 ppm belongs to the olefinic proton H-4, which is beta to the electron-withdrawing cyano group. The mass spectrum of compound 19a indicates that it has an [M]+ value of 280.12 (Figure S15).

The 1H-NMR spectrum of compound 19b indicates that the signals at δ = 8.53 and 6.43 ppm are attributed to the aromatic protons H-5 and H-10, respectively. The singlet signal at δ = 3.96 ppm, which is attributed to two protons, is attributed to the methylene protons, whereas the singlet signals at δ = 3.62 ppm and 7.46 ppm are attributed to the methoxy and olefinic (H-4) protons (Figure S16). The 13C-NMR spectrum of 19b shows chemical shifts at 189.14, 168.48, and 160.07 ppm, which are assigned to the carbonyl carbon of ketone, lactone, and acyclic ester, respectively (Figure S17). The 1H-NMR spectrum of compound 19c indicated that the signals at δ = 8.47 and 6.40 ppm were attributed to the aromatic protons H-5 and H-10, respectively. The singlet signal at δ = 2.51, which is integrable to three protons, belongs to the acetyl protons (Figure S18).

The 1H-NMR spectrum of compound 19d indicates that there is a triplet signal at δ = 1.28 ppm with a spin‒spin coupling constant of 7.10 Hz, which is attributed to three protons that belong to the methyl protons of the ethoxy group. The quartet signal at δ = 4.22 ppm and J = 7.10 Hz is assignable to the methylene protons. The signals at δ = 8.54 and 6.37 ppm are attributed to the aromatic protons H-5 and H-10, respectively (Figure S19).

Another highly reactive methylene compound is Meldrum’s acid 20, which we also used in the Knoevenagel condensation reaction with 7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-carbaldehyde 5e. In this case, arylidene derivative B (Fig. 9) undergoes the following transformation: the intramolecular nucleophilic attack of the phenol hydroxyl group on the carbonyl group of Meldrum’s acid leads to the elimination of the acetone molecule and, after protonation, to the formation of acid 21. K. A. Undale et al. reported the analogous synthesis of 3-carboxy coumarins by the potassium phosphate-catalyzed reaction of salicylaldehyde with Meldrum’s acid [51].

Fig. 9
figure 9

Plausible reaction mechanism for the formation of 6,8,8,9-tetramethyl-2-oxo-8,9-dihydro-2 H-pyrano[3,2-g]quinoline-3-carboxylic acid 21

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The 1H-NMR spectrum of compound 21 indicates that there is a downfield singlet signal at δ = 7.39 ppm, which can be assigned to the olefinic proton H-4, which is beta to the electron-withdrawing carboxylic group (Figure S20).

Unlike other methylene-active compounds, malononitrile (CH2(CN)2) is capable of undergoing cascade condensation reactions with salicylaldehyde and its analogs. At the first stage of the cascade, 2-imino-2 H-chromene-3-carbonitrile is formed, the analog of which is intermediate C (Fig. 10). At an equimolar ratio of reactants and under conditions of catalysis with metal halides [52] or ion-exchange resins [53], this primary condensation product can be isolated; however, with an excess of malononitrile, it enters into further condensation.

Fig. 10
figure 10

Plausible reaction mechanism for the formation of 2,5-diamino-9,10,10,12-tetramethyl-9,10-dihydropyrido[4′,3′,2′:8,1]isochromeno[4,3-g]quinoline-1,4-dicarbonitrile 22

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2-Imino-2 H-chromene-3-carbonitrile, or its analog С, contains an electrophilic carbon atom at position 4, which reacts with N- and S-nucleophiles under mild conditions [54]. With an excess of malononitrile under basic catalysis, this reaction center enters into a Knoevenagel condensation with a C-nucleophile, which is the bridging carbon atom of malononitrile. As a result, intermediate D is formed, the further transformation of which requires the transformation of the nitrile group, for example, into an amidine group, which occurs when piperidine is the catalyst of the transformation.

However, the third equivalent of malononitrile [55] can act as a nucleophile, under the action of which F is formed, the next participant in the domino reaction, which is oxidized under the action of intermediate C or atmospheric oxygen to tetracyclic intermediate G, which is close to the final pentacyclic product 22. Previously, a similar scheme was proposed for the interaction of salicylaldehyde with an excess of malononitrile [56].

The molecular ion peak [M] + at m/z 408, which was expected in the mass spectrum of compound 22, was not observed. However, there are notable peaks at m/z (rel. intensity, %) 31(60), 44(100), 197(30), and 394(53). The heaviest peak at m/z 394 corresponds to [M-14]+. The broad singlet signal at δ = 7.28 ppm in the 1H-NMR spectrum of compound 22, which can be attributed to a total of four protons, is attributed to the two amine groups (Figure S21).

In silico studies

PASS predicted activity spectrum of the synthesized compounds

The predicted PASS activity spectra of the test compounds (Table 2) showed that 4-aryl-substituted 3-buten-2-one compounds 13a, 13b, and 14 likely exhibit gluconate 2-dehydrogenase (acceptor) inhibitor activity, with Pa values ranging from 0.849 to 0.870. Whereas hydroquinoline carbonyl-containing compounds 7 and 8 have a propensity to act as good antiallergic, antiasthmatic, antiarthritic, and progesterone antagonists (Pa values of 0.276–0.827), phenyloxazolones 9, 10(a, b) have a low probability of being pharmaceutically active. Coumarins containing compounds 17, 19a, and 19c were predicted to be good progesterone antagonists, with Pa values of 0.710, 0.63, and 0.615, respectively.

Table 2 PASS-predicted activity of the test compounds
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Experimental section

General

The starting materials of hydroquinolinecarbaldehydes were synthesized via the Vilsmeier–Haack formylation reaction of the corresponding N-alkylhydroquinolines. All other reacting materials were commercially accessible from Sigma‒Aldrich suppliers. In this study, analytical grade reagents and solvents were used, except for the solvents THF and DMF, where further purifications were conducted. The reaction progress and purity of the individual synthesized compounds were monitored using precoated silica gel TLC plates (Merck TLC Silica gel 60 F254 plates, chloroform eluent, methanol, hexane, and ethyl acetate in various proportions), and visualization of the spots was carried out using a UV lamp. The 1Н and 13С NMR spectra were recorded in deuterated dimethyl sulfoxide (DMSO-d6) at 500.13 and 125.03 MHz, respectively, on a Bruker DRX instrument. Chemical shifts (δH) are recorded relative to the internal standard, tetramethyl silane (TMS) (see also Supplementary Materials). Mass spectra were recorded using Agilent Technologies LCMS6230B (CA; USA (chemical ionization, 200 eV)) and GCMS7890B (CA, USA) (carrier gas, EI, energy of ionization 70 eV) instruments. Melting points (mp) were measured uncorrected using a Stuart SMP30 (Hanan Advanced Technology Group Co., Ltd., Jinan; China) melting point instrument.

Synthesis of 1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-carbonitrile 7

1,2,2,4-Tetramethyl-1,2-dihydroquinoline-6-carbaldehyde 5а (2.0 g, 9.28 mmol) was added to a flask containing a solution of hydroxylamine hydrochloride (0.65 g, 9.28 mmol) in 2 mL of pyridine with continuous stirring. After 5 min of stirring using a magnetic stirrer, 10 mL of toluene was added, and the mixture was refluxed with a Dean–Stark trap. Upon completion of the process (TLC, hexane/ethyl acetate 8:2), the reaction mixture was cooled and filtered from the precipitate of pyridinium chloride, the filtrate was washed with distilled water and dried over anhydrous sodium sulfate, and the toluene was removed on a rotary evaporator. The product was recrystallized from aqueous acetonitrile.

Yield: 48%, Mp. 80–82 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.32 (s, 6 H, (CH3)2); 1.91 (s, 3 H, CH3-C4); 2.81 (s, 3 H, N-CH3); 5.43 (s, 1H, CH-C3); 6.54 (d, 1H, J = 8.67, H-8); 7.23 (d, 1H, J = 2.03, H-5); 7.41 (dd, 1H, J = 8.62, J = 2.04, H-7).

Synthesis of 1-benzyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile, 8

  1. a.

    Hydroquinolinecarbaldehyde 6b (5 mmol) was treated with iodine (5.5 mmol) in a mixture of aqueous ammonia (25% 30 mL) and THF (5 mL) at room temperature for 8 h. During the reaction, the solution gradually became colorless as the iodine was consumed. An aqueous solution of Na2S2O3 (1 M, 10 mL) was added dropwise to the reaction mixture, which was then stirred for 3 h and extracted with methylene chloride. The organic phase was washed with water, dried, and evaporated. The residue was recrystallized from aqueous acetonitrile.

  2. b.

    Hydroquinolinecarbaldehyde 6b (5 mmol) was treated with iodine (5.5 mmol) in a mixture of aqueous ammonia (25% 30 mL) and THF (5 mL) at room temperature for 8 h. During the reaction, the solution gradually became colorless as the iodine was consumed. An aqueous solution of H2O2 (35%, 3 mL) was added dropwise to the reaction mixture, which was then stirred for 4 h and extracted with methylene chloride. The organic phase was washed with water, dried, and evaporated. The residue was recrystallized from aqueous acetonitrile.

Yields: 62% (Method A) and 51% (Method B), Mp. 115–117 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.26 (s, 6 H, (CH3)2); 1.34 (d, 3 H, J = 6.60, CH3-C4); 1.63 (t, 1H, J = 13.01, CH2A-C3); 1.92 (dd, 1H, J = 13.14, J = 4.61, CH2B-C3); 2.95 (m, 1H, CH-C4); 4.36 (d, 1H, J = 18.12, Bn-Ha); 4.83 (d, 1H, J = 17.99, Bn-Hb); 6.24 (d, 1H, J = 8.78, arom. ); 7.15–7.45 (m, 7 H, arom. ).

Synthesis of 2-Phenyl-1,3-oxazol-5(4Н)-ones 9 and 10 (general procedure)

A solution of the corresponding hydroquinolinecarbaldehyde 5 or 6 (3.4 mmol) in 3 mL of acetic acid was added dropwise to a stirred solution of hippuric acid (3.4 mmol), acetic anhydride (20 mL), and acetic acid. The reaction mixture was stirred at 70 °C for 3 h, poured into crushed ice, and stirred for 30 min. The product was extracted with chloroform and washed, the chloroform was evaporated using a rotary evaporator, and the residue was recrystallized from isopropanol.

(Z)-2-Phenyl-4-((1,2,2,4-tetramethyl-1,2-dihydroquinolin-6-yl)methylene)oxazol-5(4 H)-one (9a) Yield: 60%, Mp. 180–182 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.37 (s, 6 H, C(CH3)2); 2.02 (s, 3 H, CH3-4); 2.91 (s, 3 H, N-CH3); 5.48 (s, 1H, CH-3); 6.64 (d, 1H, J = 8.8, arom. ); 7.21 (s, 1H, CH-methylene); 7.60–8.20 (m, 7 H, arom. ).

(Z)-4-((1-Benzyl-2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)methylene)-2-phenyloxazol-5(4 H)-one (9b) Yield: 30%, Mp. 130–132 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.41 (s, 6 H, C(CH3)2); 2.08 (s, 3 H, CH3-4); 4.73 (s, 2 H, CH2-Bn); 5.57 (s, 1H, CH-3); 6.33 (d, J = 8.86, 1H, arom. ); 7.18 (s, 1H, CH-methylene); 7.21–8.20 (m, 12 H, arom.)

(Z)-2-Phenyl-4-((1,2,2,4-tetramethyl-1,2,3,4-tetrahydroquinolin-6-yl)methylene)oxazol-5(4 H)-one (10a) Yield: 41%, Mp. 140–142 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.25 (s, 3 H, C(CH3)2 A), 1.32 (s, 3 H, C(CH3)2B); 1.39 (d, J = 6.56, 3 H, CH3-4); 1.45 (t, J = 13.12, 1H, CH2A-3); 1.89 (dd, J = 13.12, J = 4.20, 1H, CH2B-3); 2.85 (m, 1H, CH-4); 2.92 (s, 3 H, N-CH3); 6.67 (d, J = 8.86, 1H, arom. ); 7.22 (s, 1H, CH-methylene); 7.55–8.20 (m, 7 H, arom. ).

(Z)-4-((1-Benzyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)methylene)-2-phenyloxazol-5(4 H)-one (10b) Yield: 47%, Mp. 195–197 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.29 (s, 3 H, C(CH3)2 A); 1.32 (s, 3 H, C(CH3)2B); 1.44 (d, J = 6.54, 3 H, CH3-4); 1.69 (t, J = 13.05, 1H, CH2A-3); 1.96 (dd, J = 13.18, J = 4.47, 1H, CH2B-3); 3.03 (m, 1H, CH-4); 4.48 (d, J = 18.19, 1H, CH2A-Bn); 4.88 (d, J = 18.21, 1H, CH2B-Bn); 6.33 (d, J = 8.91, 1H, arom. ); 7.18 (s, 1H, CH-methylene); 7.20–8.30 (m, 12 H, arom. ).

Synthesis of (E)-7-[2,2,4-trimethylhydroquinolin-6-ylidenemethyl]triazolo(pyrazolo)[1,5-a]pyrimidin-6-ylcarboxylic acid 12 (general procedure)

A mixture of 2 mmol of 6-formyltetrahydroquinoline (6a, b), 2 mmol of 7-methylazolopyrimidine (11a, b), 2.2 mmol of potassium tert-butoxide, and 20 mL of methanol was refluxed for 6 h, cooled, and poured into 100 mL of 10% acetic acid solution. The precipitate formed was filtered off, washed with water, and after drying, it was recrystallized from ethanol.

(E)-7-(2-(1,2,2,4-Tetramethyl-1,2,3,4-tetrahydroquinolin-6-yl)vinyl)- [1, 2, 4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (12a) Yield: 67%, Mp. 255–257 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.04 (d, 3 H, J = 6.7, CH3); 1.23 (s., 3 H, CH3); 1.31 (s, 3 H, CH3); 1.39–1,48 (m, 1H, СН2а); 1,88 (dd, 1H, J = 13.0, J = 4.2 CH2b); 2.80–2.86 (m, 1H, CH); 2,88 (s, 3Н, N-СН3); 6.45 (d, 1H, J = 8.5, CH arom. ); 7.42–7.46 (m, 2 H, СН arom. ); 8.23 (d, 1H, J = 16.0, СН vinyl); 8,81 (s, 1Н, СНtriazol. ); 9,05 (d, 1Н, J = 16.0, СН vinyl); 9,14 (s, 1Н, СН pyrim. ); 13,31 (s, 1Н, СООН).

(E)-7-(2-(1-Benzyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)vinyl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (12b) Yield: 60%, Mp. 291–293 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.29 (s, 6 H, (CH3)2); 1.41 (d, 3 H, J = 6.7, CH3); 1.68 (t, 1H, J = 12.8, CH2A); 1.94 (dd, 1H, J = 12.9, J = 4.7, CH2B); 3.02 (p, 1H, J = 5.8, CH-4); 4.41 (d, 1H, J = 18.0, Bn-СH2а); 4.81 (d, 1H, J = 18.0, Bn-СH2b); 6.32 (d, 1H, J = 8.6, СН arom. ); 6.80 (d, 1H, J = 2.4, СHpyraz. ); 7.20–7.28 (m, 7 H аrom. ); 7.50 (s, 1H, СH arom. ); 8.23 (d, 1Н, J = 16.0, СН vinyl); 8.43 (d, 1Н, J = 2.4, СН pyriaz. );8.87 (s, 1Н, СН pyrim. ); 9.05(d, 1Н, J = 16.0, СН vinyl); 13.50 (s, 1Н, СООН).

13C NMR (DMSO-d6, 125.03 MHz, δ(ppm): 19.69 (1С, СН3); 24.90 (1С, СН3); 26.65 (1С, СН3); 28.75 (1С, СН); 45.58 (1С, СН2); 48.38 (1С, СН2); 55.14 (1С, С(СН3)2); 96.86 (1С, СНpyraz. ); 109.20 (1С, С-6pyrim. ); 110.27 (1С, СНbenz. ); 112.63 (1С, СНvinyl); 123.42 (1С, СНbenz. ); 125.96 (2С, о-СН phenyl); 126.46 (1С, p-СН phenyl); 126.57 (1С, Сpyraz-pyrim. ); 126.96 (1С, Сbenz); 126.96 (1С, Сbenz); 127.72 (1С, С-СООН); 128.65 (2С, m-СНphenyl); 128.99 (1С, СНbenz); 139.60 (1С, СНpyraz. ); 144.55 (1С, Сphenyl); 146.96 (1С, Сbenz); 147.57 (1С, Сbenz-pyr. ); 149.64 (1С, СНvinyl; 150.12 (1С, Сpyrim. ); 166.78 (1С, СООН).

Synthesis of (E)-4-(2,2,4-trimethylhydroquinolin-6-yl)-3-buten-2-ones 13 and 14

To a solution of 2 mol of the corresponding N-alkylhydroquinoline-6-carbaldehyde, 5,6,15 mL of acetone was slowly added to a stirring solution of 1 g of potassium hydroxide in 20 mL of water. The solution was stirred at room temperature for 5 h. The precipitate formed was filtered off, washed with water, dried, and recrystallized from a mixture of acetone and water (1:1).

(E)-4-(1,2,2,4-Tetramethyl-1,2-dihydroquinolin-6-yl)but-3-en-2-one (13a) Yield: 76%, Mp. 68–70°C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.30 (s, 6H, (CH3)2); 1.96 (s, 3H, CH3-C’4); 2.26 (s, 3H, CH3-CO-); 2.81 (s, 3H, N-CH3); 5.40 (s, 1H, CH-DHQ); 6.52 (d, 1H, J = 8.67, H’-8); 6.55 (d, 1H, J = 16.14, CH-C3); 7.28 (d, 1H, J = 2.14, H’5); 7.39 (dd, 1H, J = 8.56, J = 2.14, H’7); 7.49 (d, 1H, J = 16.17, CH-C4).

(E)-4-(1-Benzyl-2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)but-3-en-2-one (13b) Yield: 80%, Mp. 70–72 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.35 (s, 6 H, (CH3)2); 2.01 (s, 3 H, CH3-C’4); 2.23 (s, 3 H, CH3-CO-); 4.60 (s, 2 H, N-CH2); 5.49 (s, 1H, CH-C’3); 6.22 (d, 1H, J = 8.67, H’8); 6.50 (d, 1H, J = 16.15, H-3); 7.15–7.35 (m, 7 H, аrom. ); 7.44 (d, 1H, J = 16.17, H-4).

(E)-4-(1-Benzyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)but-3-en-2-one (14) Yield: 84%, Mp. 100–102 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.25 (s, 3 H, (CH3)2 A); 1.26 (s, 3 H, (CH3)2B); 1.37 (d, 3 H, J = 6.59, CH3-C’4); 1.62 (t, 1H, J = 12.97, CH2A-C’3); 1.91 (dd, 1H, J = 13.05, J = 4.61, CH2B-C’3); 2.23 (s, 3 H, CH3-CO-); 2.97 (m, 1H, CH-C’4); 4.33 (d, 1H, J = 18.09, Bn-Ha); 4.80 (d, 1H, J = 18.06, Bn-Hb); 6.21 (d, 1H, J = 8.72, Arom. ); 6.50 (d, 1H, J = 16.12, H-3); 7.15–7.40 (m, 7 H, аrom. ); 7.45 (d, 1H, J = 16.27, H-4).

Synthesis of Methyl (Z)-2-(5,7,7,8-Tetramethyl-2-oxo-7,8-dihydrofuro[3,2-g]quinoline-3(2 H)-ylidene)acetate 16

To a stirred solution of 7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-carbaldehyde 5e (5 mmol) and dimethylacetylenedicarboxylate (5 mmol), ml of anhydrous THF/DMF (4:1) was added dropwise to pyridine (0.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min, and the mixture was refluxed until the reaction was complete. The solvent was removed on a rotary evaporator, and the residue was separated by column chromatography using n-hexane/ethyl acetate (4:1) as the eluent.

Yield: 46%, Mp. 195–197 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.35 (s, 6 H, C(CH3)2); 1.93 (s, 3 H, CH3-5); 2.87 (s, 3 H, N-CH3); 3.91 (s, 3 H, CH3O-); 5.50 (s, 1H, CH-6); 6.38 (s, 1H, H-9); 6.43 (s, 1H, H-4); 7.63 (s, 1H, CH-2).

Synthesis of 4,6,8,8,9-pentamethyl-8,9-dihydro-2 H-pyrano[3,2-g]quinolin-2-one 17

A mixture of 7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline 3 h (1 mmol) and ethylacetoacetate (1.2 mmol) was heated to 80 °C in the presence of sulfuric acid (2 mL) until reaction completion. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and extracted with ethyl acetate (2X). The solution was concentrated, and the crude product was recrystallized from ethanol to afford pure 4-substituted hydroquinoline containing coumarin 4,6,8,8,9-pentamethyl-8,9-dihydro-2 H-pyrano[3,2-g]quinolin-2-one 17.

Yield: 68%, Mp. 170–172 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.32 (s,6 H, (CH3)2); 1.98 (s, 3 H. C6-CH3); 2.35 (s, 3 H, C4-CH3); 2.83 (s, 3 H, N-CH3); 5.46 (s, 1H, H-10); 5.94 (s, 1H, H-3); 6.36 (s, 1H, H-10 (arom. ); 7.16 (s, 1H, H-5 (arom.)).

General procedure for the synthesis of 6,8,8,9-tetramethyl-8,9-dihydropyrano[3,2-g]quinolin-2-ones 19, 21, and 22

A mixture of 7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-carbaldehyde 5e (8.65 mmol), the corresponding active methylene compounds 18, 20 and malononitrile (8.64 mmol/ 25.95 mmol in the case of synthesis 21), and a few drops of piperidine in 10 mL of ethanol was boiled until the end of the reaction, after which the reaction mixture was cooled to room temperature and poured into 5 mL of chilled water. The resulting precipitate was filtered off and recrystallized from ethanol.

6,8,8,9-etramethyl-2-oxo-8,9-dihydro-2 H-pyrano[3,2-g]quinoline-3-carbonitrile (19a) Yield: 51%, Mp. 190–192 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.38 (s, 6 H, C(CH3)2); 1.94 (s, 3 H, CH3-6); 2.94 (s, 3 H, N-CH3); 5.54 (s, 1H, CH-7); 6.44 (s, 1H, H-10); 7.25 (s, 1H, H-5); 8.48 (s, 1H, H-4).

Methyl-3-oxo-3-(6,8,8,9-tetramethyl-2-oxo-8,9-dihydro-2 H-pyrano[3,2-g]quinolin-3-yl)propanoate (19b) Yield: 58%, Mp. 179–181 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.39 (s, 6 H, C(CH3)2); 1.95 (s, 3 H, CH3-6); 2.95 (s, 3 H, N-CH3); 3.62 (s, 3 H, CH3O-); 3.96 (s, 2 H, CH2); 5.53 (s, 1H, CH-7); 6.43 (s, 1H, H-10); 7.46 (s, 1H, CH-5); 8.53 (s, 1H, H-4).

13C NMR (DMSO-d6, 125.03 MHz, δ(ppm): 18.19, 28.67, 28.74, 32.04, 48.11, 51.74, 58.41, 95.14, 107.83, 113.42, 119.97, 124.73, 125.09, 130.30, 148.15, 151.40, 158.81, 160.02, 168.48, 189.14.

3-Acetyl-6,8,8,9-tetramethyl-8,9-dihydro-2 H-pyrano[3,2-g]quinolin-2-one (19c) Yield: 39%, Mp. 200–202 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.38 (s, 6 H, C(CH3)2); 1.94 (s, 3 H, CH3-6); 2.51 (s, 3 H, CH3-CO-); 2.93 (s, 3 H, N-CH3); 5.51 (s, 1H, CH-7); 6.40 (s, 1H, H-10); 7.42 (s, 1H, H-5); 8.47 (s, 1H, H-4).

Ethyl 6,8,8,9-tetramethyl-2-oxo-8,9-dihydro-2 H-pyrano[3,2-g]quinoline-3-carboxylate (19d) Yield: 34%, Mp. 130–132 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.28 (t, 3 H, J = 7.1, CH3CH2O-); 1.37 (s, 6 H, C(CH3)2); 1.94 (s, 3 H, CH3-6); 2.91 (s, 3 H, N-CH3); 4.22 (q, 2 H, J = 7.1, CH3CH2O-); 5.58 (s, 1H, CH-7); 6.37 (s, 1H, H-10); 7.41 (s, 1H, CH-5); 8.54 (s, 1H, H-4).

6,8,8,9-. Tetramethyl-2-oxo-8,9-dihydro-2 H-pyrano[3,2-g]quinoline-3-carboxylic acid (21) Yield: 45%, Mp. > 250 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.36 (s, 6 H, C(CH3)2); 1.94 (s, 3 H, CH3-6); 2.90 (s, 3 H, N-CH3); 5.49 (s, 1H, CH-7); 6.39 (s, 1H, H-10); 7.39 (s, 1H, CH-5); 8.51 (s, 1H, H-4).

2,5-. Diamino-9,10,10,12-tetramethyl-9,10-dihydropyrido[4′,3′,2′:8,1]isochromeno[4,3-g]quinoline-1,4-dicarbonitrile (22) Yield: 30%, Mp. > 250 °C. 1H NMR (DMSO-d6, 500.13 MHz, δ(ppm), J (Hz)): 1.38 (s, 6 H, C(CH3)2); 1.95 (s, 3 H, CH3-12); 2.89 (s, 3 H, N-CH3); 5.51 (s, 1H, CH-11); 6.37 (s, 1H, H-8); 7.28 (bro. s, 4 H, 2xNH2); 8.44 (s, 1H, H-13). MS (EI, 70 eV), m/z (Irel (%)): 394 [M-14]+ (53), 197 (30), 44 (100), 31 (60).

In silico PASS prediction

Prediction of the activity spectra of substances (PASS) was used to predict the pharmacological activities of the synthesized compounds. The synthesized compounds were first converted into the SMILES format using ChemBioDraw 14.0 by PerkinElmer, Inc., and then predicted using the PASS online web tool http://www.way2drug.com/PASSOnline/predict.php (Way2Drug.com © 2011–2024 • Version 2.0), URL accessed on the 20th of July 2023). PASS indicates the probable activity (Pa) and probable inactivity (Pi) of ‘drug-like’ substances.

Conclusion

In this study, heterocyclic compounds containing hydroquinoline fragments, such as carbonitriles, oxazolones, azolo[1,5-a]pyrimidines, and coumarins, were synthesized.

The potential biological activities of the synthesized compounds were predicted using the PASS program. According to the prognosis, compounds 13a, 13b, and 14 are most likely to have inhibitory effects on gluconate dehydrogenase, as well as antiarthritic, antiallergic, and antiasthmatic effects. It was also found that hydroquinoline carbonyl compounds 7 and 8 tend to act as good progesterone antagonists and have antiallergic, antiasthmatic, and antiarthritic effects, with Pa values ranging from 0.276 to 0.827. Among the coumarin moieties containing hydroquinolines, compounds 17, 19a, and 19c were predicted to be good progesterone antagonists, with Pa values of 0.710, 0.630, and 0.615, respectively.

Data availability

All spectra for the compounds’ characterization are provided as Additional material. Similarly, the raw data are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors acknowledge the Ministry of Science and Higher Education of the Russian Federation.

Funding

This work was financially supported by the Ministry of Education and Science of the Russian Federation (Project No. 4.2100.2014/К).

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  1. Department of Chemistry, University of Gondar, P.O. Box 196, Gondar, Ethiopia

    Gizachew Mulugeta Manahelohe

  2. Department of Chemistry, Voronezh State University, Universitetskaya pl. 1, Voronezh, 394006, Russian Federation

    Khidmet Safarovich Shikhaliev

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GMM developed the methodology, performed the experimental section, collected data, interpreted data, and wrote the draft manuscript. KSS conceptualized the study, validated the work, supplied the necessary reagents and materials, and supersized the entire work. All authors have read and agreed to the published version of the manuscript.

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Manahelohe, G.M., Shikhaliev, K.S. Synthesis and PASS-assisted evaluation of new heterocyclic compounds containing hydroquinoline scaffolds. BMC Chemistry 18, 162 (2024). https://doi.org/10.1186/s13065-024-01267-3

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