Manahelohe and Shikhaliev BMC Chemistry
https://doi.org/10.1186/s13065-024-01267-3(2024) 18:162

BMC Chemistry

Open Access

RESEARCH

Synthesis and PASS-assisted evaluationof new heterocyclic compounds containinghydroquinoline scaffolds
Gizachew Mulugeta Manahelohe1* and Khidmet Safarovich Shikhaliev2
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 thesecompounds possess. In this study, the synthesis of both linear and fused heterocyclic systems that incorporatehydroquinoline fragments was described. Furthermore, the pharmacological activity spectra of the synthesizedcompounds 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 thereaction 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-trimethyl1,2,3,4-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 withdimethylacetylenedicarboxylate (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 methyleneactive 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 acatalytic amount of piperidine in ethanol. The biological activities of the synthesized compounds were predictedusing 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 thatcompounds 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.

*Correspondence:
Gizachew Mulugeta Manahelohe
gizachewm75@gmail.com
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Manahelohe and Shikhaliev BMC Chemistry(2024) 18:162

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Keywords Heterocyclic compound, Hydroquinoline, Vilsmeier–Haack formylation, Quinolone
Graphical Abstract

Introduction
Currently, heterocyclic compounds have attracted agreat deal of research interest because of their numerous significant medical and biological applications[1–4]. Quinoline derivatives are N-containing heterocyclic compounds that are known for their applications inmedicinal chemistry as antimalarial, anti-inflammatory,
anti-asthmatic, antibacterial, antihypertensive, and tyrosine kinase inhibiting agents [5–11]. Hence, interest in
the synthesis of heterocyclic compounds containing aquinoline scaffold has increased tremendously [12–15].
Alkyl derivatives of 1,2-H-dihydroquinoline belong
to a large group of quinoline derivatives and are
known to have great practical importance [16–18].

2,2,4-Trimethyl-1,2-H-dihydroquinoline is one of themost important representatives and is considered anessential and effective antioxidant in rubber technologies[19]. The methods used for the synthesis of 1,2-quinoline derivatives are based on cyclization reactions, wellknown as the Skraup reaction, and various Skraup-based
modification reactions, such as Combes, Knorr, Doebnerand 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 awide range of biological activities [24–26] and haveManahelohe and Shikhaliev BMC Chemistry(2024) 18:162

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Fig. 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

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
Compound
3a
3b
3h
4a
4b
3e

R’
CH3
Bn
CH3
CH3
Bn
CH3

R1
H
H
H
H
H
H

R2
H
H
OH
H
H
OCH3

R3
H
H
H
H
H
H

industrial applications, such as photosensitizers in solar
cells [27–29] and additives to polymers [30, 31]. Hence,the construction of new heterocyclic assemblies andfunctionalization of hydroquinoline compounds haveattracted the attention of synthetic organic chemists tofurther 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, theproblem 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 indrug development from the initial stage to the approvalof the drug. Using in silico tools to predict the biologicalactivity and/or ADMET target for novel compounds has
been widely used, as it helps in decreasing the cost andtime related to drug discovery [32, 33].
Hence, in this study, the synthesis of new heterocyclic
compounds containing hydroquinoline moieties such ascarbonitriles, oxazolones, pyrazolo/triazolo[1,5-a]pyrimidines, and coumarins based on formylhydroquinolines
was described (Fig. 1). Moreover, the pharmacologicalactivity spectrum of the synthesized compounds was

Compound
5a
5b
5e
6a
6b
-

R’
CH3
Bn
CH3
CH3
Bn
-

R1
CHO

-

R2
H
H
OH
H
H
-

R3
H
H
H
H
H
-

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 VilsmeierHaack (VH) formylation reaction of 1,2,2,4-tetramethyl1,2-dihydroquinoline bearing an unsubstituted benzene
ring proceeded with the formation of 1,2,2,4-tetramethyl1,2-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
namelyN-alkyl-1,2-di(1,2,3,4-tetera)hydrohydroquinoline-6-carbaldehydes 5a, b, e and 6a, b and7-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.
Synthesis of N-alkyl-2,2,4-trimethylhydroquinolin-6-ylcarbonitriles 7 and 8

One of the most important functional group transformations in organic synthesis is the conversion of aldehyde

Manahelohe and Shikhaliev BMC Chemistry(2024) 18:162

functional groups into nitriles. Nitriles are a very versatilefunctional 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 ofreagents to give nitriles. There are also a few methods
known for the one-step conversion of aldehydes into
nitriles without separating the formed aldoxime [38–42].
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 ofwater. The formation of pyridinium chloride facilitates
aldoxime–nitrile conversion, making the presence of adehydrating agent unnecessary. The reaction between
6-formyl-N-methyl-2,2,4-trimethyl-1,2-dihydroquinoline

Page 4 of 16

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 weemployed was the treatment of the respective aldehydewith iodine in aqueous ammonia at room temperature[42]. We speculated that the reaction proceeded via theoxidation of an aldimine with iodine to give an N-iodoaldimine intermediate, which eliminated an HI moleculein an ammonia solution to afford the nitrile product. This
procedure was applicable in our case using 6-formyl-Nbenzyl-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).
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 theFig. 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

Manahelohe and Shikhaliev BMC Chemistry(2024) 18:162

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 thesynthesis of 4-arylidene-2-aryloxazol-5-ones has been
widely used in synthetic organic chemistry and consistsof 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 influenceof the cis-N = C-C6H5 moiety on the olefinic hydrogenatom, which shifts more downfield than when the olefinichydrogen 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.
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-Nalkyl-2,2,4-trimethyldihydroquinolines 5a, b; 6a, b with

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

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ethyl-7-methylpyrazolo/triazolo/[1,5-a]pyrimidine6-carboxylates 11a, b (Fig. 4).
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 basepotassium tert-butoxide, and the reaction product isaccompanied 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 1HNMR spectra at 13.31 and 13.50 ppm are assigned to thecarboxylic 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 and9.05 ppm, is 16 Hz, which is a typical characteristic oftrans-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(FigureS10-S12).

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Fig. 4 Synthesis of triazolo/pyrazolo[1,5-a]pyrimidin-6-yl carboxylic acids 12a, b

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

Dimethylacetylenedicarboxylate (DMAD) is an electrondeficient acetylenic compound that is widely used incyclization 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, withpyridine 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 underpyridine catalysis conditions. Since position 8 is relatively
sterically hindered compared with position 6, only one
cycling center remains, which is position 6 (Fig. 5).
The reaction of 7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline 3 h with DMAD in the presence of acatalytic amount of pyridine resulted in the formation ofcompound 16 with a reaction yield of 46%. The 1H NMR
spectrum of compound 16 displays a series of signalsthat correspond to the tricyclic structure of annulated
α-methylene-γ-butyrolactone (Figure S13). A plausible
reaction mechanism has been proposed, as depicted inFig. 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.
Subsequent intramolecular proton transfer leads tointermediate E, which decomposes with the regenerationof pyridine and the formation of a compound in which
the phenolic hydroxyl group and one of the ester groupsof the dimethyl maleate fragment are spatially closed. The
subsequent intramolecular transesterification leads to theelimination 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 varietyof coumarin derivatives [48]. Pechmann condensationof 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-pentamethyl8,9-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 thering, 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Manahelohe and Shikhaliev BMC Chemistry(2024) 18:162

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Fig. 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

Fig. 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

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].

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

Fig. 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

The condensation reaction of 7-hydroxy-1,2,2,4-tetramethyl-1,2-dihydroquinoline-6-carbaldehyde 5e withmethylene-active compounds, such as ethyl cyanoacetate(18а), dimethyl-3-oxopentanedioate (18b), ethyl acetoacetate (18с), and diethylmalonate (18d), in the presenceof a catalytic amount of piperidine in ethanol afforded
3-substituted dihydroquinoline containing coumarins
19a-d in 34–58% yields, as shown in Fig. 7.
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 anester functional group, which enters into the intramolecular transesterification reaction of arylidene derivative B,

which is formed after dehydration of Knoevenagel adductA.
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 atδ = 7.25 ppm belongs to the olefinic proton H-4, which isbeta 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 indicatesthat 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

Manahelohe and Shikhaliev BMC Chemistry(2024) 18:162

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 atδ = 2.51, which is integrable to three protons, belongs tothe acetyl protons (Figure S18).
The 1H-NMR spectrum of compound 19d indicatesthat 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 andJ = 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-1,2,2,4tetramethyl-1,2-dihydroquinoline-6-carbaldehyde 5e. In
this case, arylidene derivative B (Fig. 9) undergoes thefollowing 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].
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).

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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-chromene3-carbonitrile is formed, the analog of which is intermediate C (Fig. 10). At an equimolar ratio of reactants andunder conditions of catalysis with metal halides [52] orion-exchange resins [53], this primary condensation
product can be isolated; however, with an excess of malononitrile, it enters into further condensation.
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 thecatalyst of the transformation.
However, the third equivalent of malononitrile [55]can act as a nucleophile, under the action of which F isformed, 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, asimilar 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 notobserved. 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 totalof four protons, is attributed to the two amine groups(Figure S21).

Fig. 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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Fig. 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

In silico studies
PASS predicted activity spectrum of the synthesizedcompounds

The predicted PASS activity spectra of the test compounds (Table 2) showed that 4-aryl-substituted 3-buten2-one compounds 13a, 13b, and 14 likely exhibit
gluconate 2-dehydrogenase (acceptor) inhibitor activity, with Pa values ranging from 0.849 to 0.870. Whereashydroquinoline carbonyl-containing compounds 7 and8 have a propensity to act as good antiallergic, antiasthmatic, antiarthritic, and progesterone antagonists (Pavalues of 0.276–0.827), phenyloxazolones 9, 10(a, b) havea low probability of being pharmaceutically active. Coumarins containing compounds 17, 19a, and 19c werepredicted to be good progesterone antagonists, with Pavalues of 0.710, 0.63, and 0.615, respectively.

Experimental section
GeneralThe 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 forthe solvents THF and DMF, where further purifications
were conducted. The reaction progress and purity of theindividual synthesized compounds were monitored using
precoated silica gel TLC plates (Merck TLC Silica gel 60
F254 plates, chloroform eluent, methanol, hexane, andethyl acetate in various proportions), and visualization of
the spots was carried out using a UV lamp. The 1Н and13
С NMR spectra were recorded in deuterated dimethyl

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Table 2 PASS-predicted activity of the test compounds
Compound

7
8
9a
9b
10a
10b
12a
12b
13a
13b
14
16
17
19a
19b
19c
19d
21
22

Probability of a Compound Being Active (Pa) or Inactive (Pi)
Antiallergic

Antiasthmatic

Antiarthritic

Pa
0.546
0.691
0.509
0.287
0.571
0.311
0.707
0.543
0.556
0.423
0.305
0.247
0.392
0.227
0.28
-

Pa
0.471
0.63
0.385
0.533
0.257
0.694
0.462
0.42
0.267
0.231
-

Pa
0.422
0.626
0.455
0.311
0.616
0.488
0.771
0.641
0.379
0.29
0.248
0.21
0.372

Pi
0.025
0.009
0.027
0.101
0.018
0.088
0.008
0.022
0.02
0.046
0.09
0.134
0.055
0.109
0.106
-

Pi
0.032
0.013
0.053
0.023
0.117
0.009
0.033
0.042
0.11
0.139
-

Pi
0.071
0.025
0.06
0.126
0.026
0.051
0.01
0.023
0.088
0.139
0.172
0.205
0.091

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 ofionization 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-6carbonitrile7

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 refluxedwith a Dean–Stark trap. Upon completion of the process(TLC, hexane/ethyl acetate 8:2), the reaction mixture wascooled and filtered from the precipitate of pyridinium
chloride, the filtrate was washed with distilled water anddried over anhydrous sodium sulfate, and the toluene wasremoved 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,Progesterone
Antagonist
Pa
0.827
0.276
0.367
0.18
0.266
0.212
0.142
0.06
0.515
0.217
0.145
0.506
0.71
0.63
0.394
0.615
0.429
0.493
0.305

Gluconate 2-Dehydrogenase (Acceptor)
Inhibitor
Pi
0.001
0.003
0.003
0.004
0.003
0.007
0.005
0.017
0.002
0.004
0.005
0.002
0.002
0.002
0.003
0.002
0.003
0.002
0.003

Pa
0.87
0.869
0.849
0.441
-

Pi
0.005
0.005
0.008
0.254
-

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-1,2,3,4tetrahydroquinoline-6-carbonitrile, 8a. 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, thesolution gradually became colorless as the iodine wasconsumed. 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 withmethylene chloride. The organic phase was washedwith water, dried, and evaporated. The residue wasrecrystallized from aqueous acetonitrile.
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, thesolution 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 withmethylene chloride. The organic phase was washedwith water, dried, and evaporated. The residue wasrecrystallized from aqueous acetonitrile.

Manahelohe and Shikhaliev BMC Chemistry(2024) 18:162

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)-ones9and10(generalprocedure)

A solution of the corresponding hydroquinolinecarbaldehyde 5 or 6 (3.4 mmol) in 3 mL of acetic acid wasadded 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, CH34); 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-dihydroquinolin6-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, CH34); 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(4H)-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, CH2ABn); 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. ).

Page 12 of 16

Synthesis of (E)-7-[2,2,4-trimethylhydroquinolin-6ylidenemethyl]triazolo(pyrazolo)[1,5-a]pyrimidin-6ylcarboxylic acid12(general procedure)

A mixture of 2 mmol of 6-formyltetrahydroquinoline(6a, b), 2 mmol of 7-methylazolopyrimidine (11a, b), 2.2mmol of potassium tert-butoxide, and 20 mL of methanol was refluxed for 6 h, cooled, and poured into 100 mLof 10% acetic acid solution. The precipitate formed wasfiltered off, washed with water, and after drying, it wasrecrystallized 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).
13
C 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)-3buten-2-ones13and14

To a solution of 2 mol of the corresponding N-alkylhydroquinoline-6-carbaldehyde, 5,6,15 mL of acetone wasslowly added to a stirring solution of 1 g of potassiumhydroxide in 20 mL of water. The solution was stirred atroom temperature for 5 h. The precipitate formed wasManahelohe and Shikhaliev BMC Chemistry(2024) 18:162

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-dihydroquinolin6-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, CH3CO-); 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, CH2AC’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-7,8dihydrofuro[3,2-g]quinoline-3(2 H)-ylidene)acetate16

To a stirred solution of 7-hydroxy-1,2,2,4-tetramethyl1,2-dihydroquinoline-6-carbaldehyde 5e (5 mmol) anddimethylacetylenedicarboxylate (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 theresidue 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-8,9dihydro-2 H-pyrano[3,2-g]quinolin-2-one17

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 (2mL) until reaction completion. After completion of thereaction (monitored by TLC), the mixture was cooled toroom temperature and extracted with ethyl acetate (2X).

Page 13 of 16

The solution was concentrated, and the crude productwas 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-tetramethyl8,9-dihydropyrano[3,2-g]quinolin-2-ones19, 21, and22

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 andmalononitrile (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 temperatureand 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[3,2g]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-8,9dihydro-2
H-pyrano[3,2-g]quinolin-3-yl)propanoate(19b) Yield: 58%, Mp. 179–181 °C. 1H NMR (DMSOd6, 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).
13
C 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, CH36); 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 (DMSOd6, 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, CH36); 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).

Manahelohe and Shikhaliev BMC Chemistry(2024) 18:162

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 thesynthesized 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) andprobable inactivity (Pi) of ‘drug-like’ substances.

Conclusion
In this study, heterocyclic compounds containinghydroquinoline fragments, such as carbonitriles, oxazolones, azolo[1,5-a]pyrimidines, and coumarins, weresynthesized.
The potential biological activities of the synthesizedcompounds 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, andantiasthmatic effects. It was also found that hydroquinoline carbonyl compounds 7 and 8 tend to act as goodprogesterone 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.
Supplementary Information

The online version contains supplementary material available at https://doi.
org/10.1186/s13065-024-01267-3.
Supplementary Material 1
Acknowledgements
The authors acknowledge the Ministry of Science and Higher Education of theRussian Federation.

Page 14 of 16

Author contributions
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 reagentsand materials, and supersized the entire work. All authors have read andagreed to the published version of the manuscript.
Funding
This work was financially supported by the Ministry of Education and Scienceof the Russian Federation (Project No. 4.2100.2014/К).
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.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Author details
1
Department of Chemistry, University of Gondar, P.O. Box 196, Gondar,
Ethiopia2
Department of Chemistry, Voronezh State University, Universitetskaya pl.
1, Voronezh 394006, Russian Federation
Received: 3 May 2024 / Accepted: 13 August 2024

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