INTRODUCTION:

An urgent task of the modern pharmaceutical industry is the creation of new medicinal products from plant raw materials based on alkaloids and their derivatives, the development of technologies for obtaining substances, and the improvement of existing technologies for their production.

As is known, with the help of chemical modification, it is possible to obtain biologically active substances or increase the activity of the original compound. Therefore, a number of chemical transformations were carried out on the basis of lupinine to obtain new biologically active substances on its basis. The modification capabilities of the structure of the lupinine molecule allow for targeted syntheses of new compounds and the study of their biological properties. Many of the derivatives of the alkaloid (-)-lupinine (1) turned out to be valuable biologically active substances^1-4, which served as an incentive for their comprehensive study, as well as the search for methods for constructing more complex structures. Lupinine extracted from the plant Anabasis salsa growing in central Kazakhstan. For the first time, we carried out a morphological study of the plant Anabasis salsa, growing in Central Kazakhstan, and determined the diagnostic characteristics of the plant^5-9.

Interest in lupinine is due to its broad spectrum of biological action. This alkaloid is bactericidal, slightly sedative, and has anthelmintic and hypotensive activities^10,11. Lupinine is not used in its pure form, but serves as a raw material for the production of hydrochloric lupicaine, which is used as a local anesthetic^11,12. Ester derivatives of lupinine have antiviral and hepatoprotective activity¹³.

Analysis of literary data on the chemical transformations of lupinine showed that various of its esters, amino, imide, halogen, thio- and O-acyl derivatives were previously synthesized and evaluated for their biological activity^14-26. Recently, based on the transformation of (-)-lupinine, we developed a preparative synthesis of (1S,9aR)-1-[(1,2,3-triazol-1-yl)-methyl]octahydro-1H-quinolizine with various substituents at the C-4 position in the lupinine molecule of the 1,2,3-triazole ring^27-31. Thus, the search for and development of convenient methods for modifying^33-42 lupinine to obtain its potentially bioactive 1,2,3-triazole derivatives is an important and urgent task.

The aim of this work is to obtain a 1,2,3-triazole derivative compound based on isolated lupinine with subsequent development of a technology for the production of the substance for pharmaceutical purposes. One of the important tasks in the production of medicinal substances is standardization.

MATERIAL AND METHODS:

Lupinine is an alkaloid isolated from the extract of the plant raw material of Anabasis salsa. M.p. - 69-71°C (EtOH, [α]_D - 30.5° (c 0.41, MeOH); (lit. data: m.p. 68-69°C (EtOH), [α]_D - 23.5°), C₁₀H₁₉NO^43-44.

Methanesulfonyl chloride, sodium azide, alkyne 4-benzyloxy-3-methoxyphenylacetylene were purchased from Alfa-Aesar.

Solvents (CH₃Cl, DMF), as well as Et₃N were purified by standard methods; DMF was additionally distilled in a stream of argon immediately before the reactions⁴⁵.

The synthesized structures were confirmed on the basis of analytical and spectral data. The purity of the sample was >99%.

Research methods:

¹H and ¹³C NMR spectra were recorded on a JNN-ECA Jeol 400 spectrometer (frequency 399.78 and 100.53 MHz, respectively) using DMSO-d₆ as a solvent. Chemical shifts were measured relative to the signals of residual protons or carbon atoms of deuterated dimethyl sulfoxide. The multiplicity of signals in the ¹³C NMR spectra was determined from the spectra recorded in the J-modulation mode (JMOD). The assignment of signals in the ¹H and ¹³C NMR spectra was confirmed based on two-dimensional homonuclear ¹H-¹H (COSY) and heteronuclear ¹H-¹³C spectroscopy (HMBC, HSQC), as well as based on literature data for quinolizines. High-resolution mass spectra were recorded on a DFS ThermoScientific spectrometer (evaporator temperature 200-250°C, EI ionization, 70 eV). Melting points were determined on a Mettler Toledo FP900 thermal system. The reaction progress was monitored by TLC on Sorbfil UV-254 plates using the following systems: CH₃Cl, CH₃Cl-EtOH, 10:1, visualization in iodine vapor and under UV light (254 nm). Purification of alkaloids was carried out by passing through a column of AI₂O₃ (II st. act.). The reaction products were isolated by column chromatography on Acros silicagel (0.035-0.240mm), eluents CHCl₃, CHCl₃-EtOH, 100:1 → 10:1.

RESULTS:

Obtaining a 1,2,3-triazole derivative based on the lupinine substance:

In this paper, we describe the synthesis of lupinyl azide (3) and the subsequent preparation of its potentially biologically active derivative containing a 1,2,3-triazole substituent.

Lupinine azide was prepared from lupinine in two steps. The interaction of lupinine (1) with methanesulfonyl chloride in the presence of Et₃N in CH₂Cl₂ led to octahydro-2H-quinolizin-1-yl)methyl methanesulfonate (2), the reaction of which with NaN₃ in DMF led to the formation of corresponding organic azide of the quinolizine type (3)^18,19.

The reaction of lupinyl azide (3) with arylalkyne [4-benzyloxy-3-methoxyphenylacetylene] proceeded smoothly in DMF in the presence of copper sulfate CuSO₄×5H₂O and sodium ascorbate (NaAsc) upon heating to 75°C (TLC control). After column chromatography on silicagel, 1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-1H-quinolizine (4) containing an aryl substituent at position C-4 of the 1,2,3-triazole ring was isolated (Scheme 1).

Scheme 1. Synthesis of 1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-1H-quinolizine (4) from

(-)-lupinine (1).

The structure of the synthesized compounds (2-4) was confirmed by ¹H and ¹³C NMR spectroscopy and mass spectrometry, as well as by two-dimensional NMR spectroscopy methods COSY (¹H-¹H), HMQC (¹H-¹³C) and HMBC (¹H-¹³C), which allows establishing spin-spin interactions of homo- and heteronuclear nature. The presence of an azide substituent in the structure of (3) was confirmed by IR-spectrum data (intense absorption band at 2096 cm^-1, corresponding to stretching vibrations of the azide group).

The ¹H and ¹³C NMR spectra of the synthesized quinolizine 1,2,3-triazole contained a characteristic set of signals of the quinolizine skeleton and the corresponding substituent. In the strong field region (δ 1.17-1.70 ppm) there were broad multiplet signals with an integral intensity of 8H, which included protons of the lupinine skeleton of both axial and equatorial orientation (H-2a, e, 8a, e, 9a, e, 3a, 7a). The multiplet signal (δ 1.70-1.92ppm) belonged to the equatorially oriented protons of H-3,7. Next, the axial protons 4,6 (δ 1.88-2.08ppm), nodal proton 9a (δ 2.05-2.18ppm) and proton C-1 (δ 2.18-2.30 ppm) resonated. Protons 4,6 of equatorial orientation were represented by a broaded multiplet in the region (δ 2.80-2.88ppm). Protons of the methylene group H-10 resonated as two doublets of doublets in the region δ 4.51-4.65ppm. The proton of the 1,2,3-triazole ring in the ¹H NMR spectra corresponded to a singlet signal located in the region δ 7.37-7.71ppm. The carbon atoms of the triazole ring in the ¹³C NMR spectra corresponded to signals at 119.3-122.4 (C-5) and 146.2-156.8ppm (C-4) doublet and singlet, respectively (spectra were recorded in the JMOD mode). These data confirm the formation of 1,4-disubstituted 1H-1,2,3-triazoles as a result of the CuAAC reaction.

Mass spectra of all compounds contained peaks of molecular ions of varying intensity. In the spectra of the synthesized quinolizidinotriazole there was a peak of the fragmentary ion C₁₀H₁₇N (m/z 150-151), corresponding to the splitting of the molecule at the C-10 atom of the quinolizidine skeleton.

1. Chemistry:

1.1.(Octahydro-2H-quinolizin-1-ylmethyl)methanesulfonate 2:

To an ice-cooled solution of lupinine (1) (10.0g, 59.08 mmol) and triethylamine (23.91g, 236.32mmol) in CH₂Cl₂ (600mL), a solution of methanesulfonyl chloride (13.53g, 118.16mmol) in 60mL of CH₂Cl₂ was added dropwise. The reaction mixture was stirred for 40 minutes at 0°C and then for 8hours at room temperature. It was subsequently washed with a saturated sodium chloride solution (2×60mL), dried over anhydrous MgSO₄, filtered to remove the drying agent, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: chloroform, then chloroform-ethanol, 50:1). Yield: 9.3g (93%). Cream-colored crystals, m.p. 57-58°C (from ether). [α]_D- 21.6 (с 1.4, СHCl₃).

IR-spectrum, (KBr), ν, cm^-1: 1184, 1336 (ОSO₂), 2740, 2757, 2798 (quinolizidine).

¹Н NMR spectrum (400 MHz, CDCl₃), δ, ppm (J, Hz): 1.12-1.26 (1Н, m, Н-2а); 1.28-1.51 (5Н, m, Н-2е,8а,8е,3а,7а); 1.54 (1Н, m, Н-9а); 1.59-1.77 (2Н, m, Н-3е,7е); 1.84-2.02 (5Н, m, Н-1,4а,6а,9е,9а); 2.73-2.80 (2Н, m, Н-4е,6е); 2.97 (3Н, s, СН₃); 4.37 (1Н, dd, J = 10.6, J = 9.8, Н-10); 4.47 (1Н, dd, J = 10.6, J = 5.3, H-10).

¹³C NMR spectrum (101 MHz, CDCl₃), δ, ppm: 20.6 (С-3); 24.7; 25.4 C-7,8); 26.3 (С-2); 29.8 (С-9); 37.0 (СН₃); 38.0 (С-1); 56.8; 57.1 (С-4,6); 64.0 (С-9а); 69.5 (С-10).

Mass spectrum, m/z (I_rel, %): 248 (1), 247 (7), 153 (10), 152 (100), 150 (3), 98 (6). Found, m/z: 247.1238 [M]⁺. C₁₁H₂₁NO₃S. Calculated, m/z: 247.1237.

1.2. 1-(Azidomethyl)octahydro-1H-quinolizine 3:

A mixture of compound (2) (6.0g, 24.25mmol) and sodium azide (4.93g, 75.92mmol) in DMF (100mL) was stirred at 75°C for 8hours (monitored by TLC). The reaction mixture was poured onto a Petri dish to allow the solvent to evaporate freely in air. The residue was dissolved in CH₂Cl₂, washed with a saturated sodium chloride solution, dried over anhydrous MgSO₄, filtered to remove the drying agent, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silicagel (eluent: chloroform-ethanol, 50:1). Yield: 5.0g (83.3%). Light-yellow mobile liquid. [α]_D- 29.85 (c 2.4, chloroform).

IR-spectrum, ν, cm^-1: 1269, 2096 (N≡N), 2744, 2762, 2804 (quinolizidine).

¹Н NMR spectrum (400 MHz, CDCl₃), δ, ppm (J, Hz): 1.12-1.26 (1Н, m, Н-2а); 1.30-1.57 (6Н, m, Н-8а, 8е, 9a, 9e, 3а, 7а); 1.58-1.76 (3Н, m, H-2e,3е,7е); 1.80-1.99 (4Н, m, Н-1,4а,6а,9а); 2.72-2.82 (2Н, m, Н-4е,6е); 3.42 (1Н, dd, J = 12.6, J = 9.6, СН₂-10); 3.54 (1Н, dd, J = 12.6, J = 5.3, СН₂-10).

¹³C NMR spectrum (125 MHz, CDCl₃), δ, ppm: 20.7 (С-3); 24.9 (C-8); 25.4 (C-7); 27.3 (С-2); 29.6 (С-9); 38.2 (С-1); 50.4 (C-10); 56.8; 57.2 (С-4,6); 64.3 (С-9а).

Mass spectrum, m/z (I_rel, %): 194 (2), 153 (10), 152 (100), 137 (7), 136 (5), 98 (12), 84 (7), 83 (9), 82 (6), 55 (10), 41 (14). Found, m/z: 194.1528 [M]⁺. C₁₀H₁₈N₄. Calculated, m/z: 194.1526.

1.3. Synthesis of compound 1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-1H-quinolizine 4:

4.0g (20.65mmol) of lupinine azide (3), 4.92g (20.65 mmol) of substituted acetylene 4-benzyloxy-3-methoxyphenylacetylene, 0.257g (1.03mmol) of CuSO₄×5H₂O, and 0.204g (1.03mmol) of sodium ascorbate were stirred in DMF (100mL) at 75°C for 7-8 hours (monitored by TLC). The precipitate formed upon cooling was filtered, washed with hexane, dried, and yielded triazole (4). To isolate triazole (4), the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: chloroform, then a mixture of chloroform and ethanol, 100:1 → 10:1). Yield: 3.0g (75.0%). White powder with a yellowish tint, m.p. 152-153°C. [α]_D - 15.1 (c 1.2, chloroform).

IR-spectrum, ν, cm^-1: 694, 740, 790, 812, 846, 1452, 1466, 1504, 1585, 1610, 3090 (С=С, С=N), 1001, 1036, 1132, 1222, 1232 (С-О); 2759, 2802 (quinolizidine).

¹Н NMR spectrum (500 MHz, CDCl₃), δ, ppm (J, Hz): 1.18-1.29 (3Н, m, Н-2а,2e,8a); 1.45-1.65 (5Н, m, Н-8е,9a,9e,3а,7а); 1.77-1.88 (2Н, m, Н-3е, 7е); 1.91-2.06 (2Н, m, Н-4а,6а); 2.10-2.18 (1Н, m, Н-9а), 2.22-2.27 (1H, m, Н-1); 2.80-2.88 (2Н, m, Н-4е,6е); 3.95 (3Н, s, OСН₃ at C-3ʹʹ); 4.55 (1Н, dd, J = 13.8, J = 5.5, Н-10); 4.61 (1Н, dd, J = 13.8, J = 12.1, Н-10); 5.16 (2Н, s, ОСН₂); 7.86 (1Н, d, J = 8.3, Н-5ʹʹ); 8.16 (1Н, dd, J = 8.3, J = 2.0, Н-6ʹʹ); 7.26–7.30 (1Н, m, С₆Н₅, Н-р); 7.31–7.37 (2Н, m, С₆Н₅, Н-m); 7.38-7.44 (1Н, m, С₆Н₅, Н-о); 7.50 (1Н, d, J = 2.0, H-2ʹʹ); 7.62 (1Н, s, Н-5ʹ).

¹³C NMR spectrum (125 MHz, CDCl₃), δ, ppm: 20.5 (С-3); 24.7 (С-8); 25.3 (С-7); 26.1 (С-2); 29.5 (С-9); 39.1 (С-1); 48.5 (С-10); 55.9 (OСН₃); 56.7; 57.1 (С-4,6); 64.2 (С-9а); 70.9 (ОСН₂); 109.3 (C-2ʹʹ); 114.1 (C-5ʹʹ); 117.9 (С-6ʹʹ); 119.5 (С-5ʹ); 124.2 (C-1ʹʹ); 127.2 (C-2ʹʹʹ,6ʹʹʹ); 127.7 (C-4ʹʹʹ); 128.4 (С-3ʹʹʹ,5ʹʹʹ); 136.9 (С-1ʹʹʹ); 147.3 (C-4ʹ); 147.9 (С=4ʹʹ); 149.9 (С-3ʹʹ).

Mass spectrum, m/z (I_rel, %): 434 (2), 433 (12), 432 (41), 313 (18), 258 (15), 152 (50), 151 (52), 150 (38), 136 (17), 91 (100). Found, m/z: 432.2519 [M]⁺. C₂₆H₃₂N₄О₂. Calculated, m/z: 432.2520.

Thus, we have selected the conditions for the synthesis of 1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-1H-quinolizine (4), providing a yield of 75.0%, with a purity of at least 97%.

2. Technology:

The starting material for obtaining the substance 1,2,3-triazole derivative of lupinine was lupinine with a purity of at least 98%. Figure 1 shows the process flow chart for obtaining the substance of 1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-1H-quinolizine.

The development of quality specifications and the standardization of new synthesized compounds are critical steps in introducing high-quality, safe, and effective medicinal products into medical practice.

The standardization of the compound 1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl) methyl)octahydro-1H-quinolizine (4) was carried out on five laboratory sample batches. According to the description, the samples of compound (4) are fine light-yellow crystalline powders with no odor. The substance is soluble in chloroform, DMF, glacial acetic acid, and when heated, in ethanol and other lower alcohols. It is sparingly soluble in acetone, poorly soluble in acetonitrile and hexane, practically insoluble in acids, alkalis, ethyl acetate, and benzene, and completely insoluble in water and ether.

Identification was performed using chemical reactions for functional groups. The presence of a tertiary nitrogen atom in the molecule allowed for reactions with general alkaloid precipitation reagents (Dragendorff, Bouchardat, and Liebermann reagents).

The IR-spectrum of 1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro -1H-quinolizine (4) recorded in KBr pellets showed absorption bands at 3090 cm^-¹, characteristic of stretching vibrations of (C=C, C=N) groups, and at 2759 and 2802 cm^-¹, corresponding to the stretching vibrations of the quinolizidine ring.

The UV-spectrum of the substance exhibited a distinct absorption maximum in the UV region at 275±2nm, a minimum at 203±2nm, and a shoulder at 218nm in a neutral medium of 96% ethanol.

The melting point of samples of compound (4), pre-dried at 100-105°C, was in the range of 152-153°C. The specific rotation [α]_D - 15.1 (c 1.2, chloroform).

The mass loss on drying for the samples did not exceed 3%. A 1% ethanol solution of compound (4) was clear and colorless. Due to the use of alkali in the synthesis of (4), alkalinity was regulated, with the pH of the ethanol solution ranging between 7.5 and 8.0. Purity analysis for “related impurities” was performed using thin-layer and high-performance liquid chromatography (HPLC). The total allowable content of related impurities was limited to no more than 0.1%. Technological permissible impurities regulated in substance (4) included: chlorides (not more than 0.05%), sulfates (not more than 0.05%), iron (not more than 0.002%), and sulfate ash (not more than 0.1%). Microbiological analysis allowed for no more than 1,000 bacteria and 100 yeasts and molds per gram of substance (4). Quantitative determination of the compound was carried out using high-sensitivity UV-spectrophotometry and HPLC. The average recovery percentage was 98.12%, with all obtained values ranging between 97.33% and 99.71%. Given the synthetic nature of the compound, the presence of related impurities was expected, requiring the quantitative content of 1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-1H-quinolizine to be no less than 98%.

Based on accelerated aging studies, a guaranteed shelf life of two years was proposed for compound (4).

AChE Inhibition Assay:

The triazole derivative (4) exhibited the strongest mixed-type acetylcholinesterase (AChEI) inhibition. The AChE inhibitory activity of compound (4) was comparable to that of galantamine (IC₅₀=8.2±1.3 μM), a known AChE inhibitor used in the treatment of mild Alzheimer's disease.

The presence of a benzyloxy group in the para-position of the benzene ring resulted in the maximum activity of compound (4) (IC₅₀=7.2 μM). Compound (4) has a 4-benzyloxyphenyl fragment, which was also present in some other AChEI inhibitors.

So, compound (4) was identified as a new AChEI inhibitor and was shown to exhibit mixed-type inhibitory activity. Thus, the compound 1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-1H-quinolizine (4) may be a promising candidate for evaluation in experimental models of Alzheimer's disease.

CONCLUSIONS:

We have proposed and developed optimal conditions for modifying the structure of the alkaloid lupinine at position C-10 to obtain a potentially bioactive 1,2,3-triazole derivative. The developed conditions allowed us to synthesize the corresponding 1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-1H-quinolizine with a good yield. The synthesized new derivative of lupinine with a 1,2,3-triazole fragment can provide additional ligand-receptor interactions of the biologically active substrate, and thereby change the selectivity of the biological action of the substrate. The structures of the new compounds were confirmed by spectral methods. Also, a process flow chart for obtaining a 1,2,3-triazole derivative based on the lupinine substance was developed. The quality specification was determined and standardization of the substance 1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-1H-quinolizine was carried out according to the following parameters in accordance with the requirements of the State Pharmacopoeia of the Republic of Kazakhstan^46-47: description, solubility, melting point, loss in weight on drying, authenticity, transparency, color, pH value, alkalinity, chlorides, sulfates, iron, heavy metals, sulfate ash, microbiological purity, related impurities, quantitative content, on the basis of which a regulatory document was developed.

In conclusion, it should be noted that interest in lupinine and its derivatives has increased significantly in recent years, mainly due to the versatility of its pharmacological action and especially due to its use in the treatment of Alzheimer's disease. In this regard, both new plant sources of lupinine and methods for its separation from related compounds in plant extracts and synthesis based on it are being sought.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

T.c - Technological control; Ch.c – chemical control; M.c – microbiological control

REFERENCES:

1. Tlegenov R.T. Synthesis and anticholinesterase activites of a number of derivatives of the alkaloid lupinine. Chemistry of Natural Compounds. 1990; 26: 434-436.

2. Gusarova N.K and et al. Synthesis of novel alkaloid derivatives from vinyl ether of lupinine and PH-addends. ARKIVOC. 2009; (VII): 260-267.

3. Abduvakhabov A.A and et al. Synthesis of a component of the aggregation pheromone of the Khapra beetle, Trogoderma granarium. Chemistry of Natural Compounds. 1990; 26: 486-487.

4. Sparatore A, Sparatore F. 2-(4-R-Phenoxy/phenylthio)alkanoic esters of l-lupinine. Farmaco. 2001; 56: 169-174.

5. Itzhanova Kh.I., Bekisheva P.Zh., Ishmuratova M.Yu., Nurmaganbetov Zh.S., Serikbay A.T., Ewa Poleszak. Histochemical analysis of plant raw materials of Anabasis salsa growing in the territory of the central Kazakhstan. Research Journal of Pharmacy and Technology. 2024; 17(7): 3334-3338. DOI: 10.52711/0974-360X.2024.00521

6. Itzhanova H.I., Remetova N.S., Ishmuratova M.Yu., Nogayeva A.N., Abdrakhmanova G.M., Medeshova A.T., Samorodov A.V. Histochemical analysis of Xanthium strumarium raw materials, growing on the territory of Kazakhstan. Research Journal of Pharmacy and Technology. 2023; 16(12): 5796-1. DOI: 10.52711/0974-360X.2023.00938

7. Sabiyeva A., Ishmuratova M. Yu., Atazhanova G. A., Smagulov M. K., Zhuravel I. A. Histochemical Analysis of Aerial part of Dracocephalum ruyschiana L. and Dracocephalum nutans L. growing in the Territory of Central Kazakhstan. Research Journal of Pharmacy and Technology. 2022; 15(9): 3831-3835.

8. Tulebayev Y.A., Ishmuratova M.Yu., Losseva I.V., Wirginia Kukuła-Koch, Poleszak E., Nadirbek K.S. Comparative Histochemical analysis of above-ground parts of Filipendula vulgaris and Filipendula ulmaria growing in Central Kazakhstan. Research Journal of Pharmacy and Technology, 2021; 14(9):4863-7. doi: 10.52711/0974-360X.2021.00845

9. Turdiyeva Zh. A, Ishmuratova M. Yu., Atazhanova G. A., Ramazanova A. Histochemical Analysis of The Aerial part of Ferula songarica growing in the Territory of the Karaganda Region (Central Kazakhstan). Research Journal of Pharmacy and Technology. 2023; 16(11): 5079-4. doi: 10.52711/0974 360X.2023.00823

10. Nurkenov O.A., Gazaliev A.M., Kabieva S.K., Takibaeva A.T. Alkaloid lupinine I ego proizvodnye. – Karaganda: Glasir, 2016. – 112 s.

11. Bekisheva P.Zh, Itzhanova Kh.I, Nurmaganbetov Zh.S. Anabasis L. as a source of biologically active alkaloids (literature review). Pharmacy of Kazakhstan. 2023; 5: 349-355.

12. Orazbekova S.O. Ecology of plant alkaloids in cell culture. Republican Scientific Journal .Bulletin of the Kazakhstani-American Free University. Devoted to Problems of Ecology, Mathematics and Information Technology. 2011; 6: 92-95.

13. Abduvakhabov A.A, Tlegenov R.T, Khaitbaev Kh.Kh, Vaizburg G.I. Syntheses of lupinine esters and their interaction with cholesterases. Chemistry of Natural Compounds. 1990; 1: 75-80.

14. Gusarova N.K and et al. Synthesis of novel alkaloid derivatives from vinyl ether of lupinine and pH-addends. ARKIVOC. 2009; (VII): 260-267. https://doi.org/10.3998/ark.5550190.0010.725

15. Tasso B and et al. Novel quinolizidinyl derivatives as antiarrhythmic agents: 2. Further investigation. Journal of Medicinal Chemistry. 2010; 53: 4668-4677. https://doi.org/10.1021/jm100298d

16. Tasso B and et al. Further quinolizidine derivatives as antiarrhythmic agents-3. Molecules. 2023; 28: 6916. https://doi.org/10.3390/molecules28196916

17. Turdybekov K.M and et al. Synthesis, crystal structure, and stability of N-lupinylphthalimide conformers. Journal of Structural Chemistry. 2020; 61: 1823-1826. https://doi.org/10.1134/S0022476620110153

18. Nurkenov OA and et al. Synthesis, structure and properties of new O-acyl derivatives of the lupinine alkaloid. Chemistry of Natural Compounds. 2019; 55: 506-508. https://doi.org/10.1007/s10600-019-02726-3

19. Nurmaganbetov Zh.S and et al. Synthesis and spatial structure of 3-phenylacrylic acid octahydroquinolizin-1-ylmethyl ester and 2-(octahydroquinolizin-1-ylmethyl)isoindole-1,3-dione. Eurasian Chemico-Technological Journal. 2024; 26: 175-183. https://doi.org/10.18321/ectj1641

20. Ranjit V. Gadhave, Bhanudas S. Kuchekar. Design, Synthesis, Characterization and Antioxidant activity of Novel Benzothiazole and Coumarin based 6-(3, 5-dimethylpyrazol-1-yl) pyridazin-3-one Derivatives. Research J. Pharm. and Tech. 2020; 13(12):5661-5667. doi: 10.5958/0974-360X.2020.00986.5

21. Pathak A.V., Kawtikwar P. S., Sakarkar D. M. Formulation and Standardization of Asava from Carica papaya. Research Journal of Pharmacy and Technology. 2021; 14(4): 2211-5. doi: 10.52711/0974-360X.2021.00392

22. Shanaz Banu, Josephine Leno Jenita, Manjula. D, K. B. Premakumari. Pharmacognostical Studies and Isolation of an alkaloid from Barleria cristata Linn. roots. Research J. Pharm. and Tech. 2020; 13(1): 163-167. doi: 10.5958/0974-360X.2020.00033.5

23. Medeshova A., Orazbayeva P., Romanova A., Dildabekova N., Orazbayev B., Ashirbekova B., Ashirbekova A. Development and Rheological studies of gels with Essential oil of Chamomile (Chamomillae recutita L.). Research Journal of Pharmacy and Technology. 2023; 16(11): 5161-6. doi: 10.52711/0974-360X.2023.00836

24. Turdybekov К. M., Zhanymkhanova, P. Z., Mukusheva, G. K., & Gatilov, Y. V. Synthesis and Spatial Structure of (E)-1-(2-(4-Bromobutoxy)- 6-Hydroxy-4-Methoxyphenyl-3-Phenylprop-2-en-1-one. Eurasian Journal of Chemistry. 2023; 28; 2(110): 69-75 https://doi.org/10.31489/2959-0663/2-23-2

25. Turmukhambetov, A.Zh.; Agedilova, M.T.; Nurmaganbetov, Zh.S.; Kazantsev, A.V.; Shul'ts, E.E.; Shakirov, M.M.; Bagryanskaya, I.Y.; Adekenov, S.M. Synthesis of quaternary salts of Peganum harmala alkaloids. Chemistry of Natural Compounds. 2009; 45(4): 601-603. DOI: 10.1007/s10600-009-9381-3

26. Ismagulova, N.M.; Nurmaganbetov, Zh.S.; Turmukhambetov, A.Zh.; Seitembetov, T.S.; Adekenov, S.M. Synthetic derivatives of natural alkaloid harmine. Eurasian Chemico-Technological Journal. 2009, 11(3), 199-205. DOI:10.18321/ectj281

27. Nurmaganbetov Z.S, Savelyev V.A, Gatilov Y.V, Nurkenov O.A, Seidakhmetova R.B, Shulgau Z.T, Mukusheva G.K, Fazylov S.D, Shults E.E. Synthesis and analgesic activity of 1-[(1,2,3-triazol-1-yl)methyl]quinolizines based on the alkaloid lupinine. Chemistry of Heterocyclic Compounds. 2021; 57: 911-919. https://doi.org/10.1007/s10593-021-03000-7

28. Nurmaganbetov Z.S and et al. Synthesis and structure of 4-substituted (1S,9aR)-1-[(1,2,3-triazol-1-yl)methyl]octahydro-1H-quinolysines of Lupinine. Bulletin of the Karaganda University, Chemistry. 2022; 106: 12-22. https://doi.org/10.31489/2022Ch2/2-22-5

29. Nurkenov O.A and et al. Synthesis, structure and biological activity of (1S,9aR)-1Н-1,2,3-triazol-1-yl)methyl)octahydro-1H-quinolizine derivatives of lupinine. Archives of Razi Institute. 2022; 77: 2307-2317. https://doi.org/10.22092/ARI.2022.360091.2550

30. Schepetkin I.A and et al. Inhibition of acetylcholinesterase by novel lupinine derivatives. Molecules. 2023; 28: 3357. https://doi.org/10.3390/molecules28083357

31. Nurmaganbetov Z.S and et al. Antiviral activity of (1s,9ar)-1-[(1,2,3-triazol-1-yl)methyl]octahydro-1h-quinolizines from the alkaloid lupinine. Molecules. 2024; 29: 5742. https://doi.org/10.3390/molecules29235742

32. Kavita R. Chandramorе, Rohan S. Ahire. Synthesis of Ethyl 2-(4-halobenzyl)-3-oxobutanoate and determination of its Biological activity by using prediction of activity spectra for substance. Asian J. Res. Pharm. Sci. 2022; 12(2):102-106. DOI: 10.52711/2231-5659.2022.00017

33. Goyal PK, Bhandari A, Rana AC, Bele DS. synthesis and antimicrobial activity of some 3-substituted -4h-1,2,4-triazole derivatives. Asian J. Research Chem. 2010; 3(2): 355-358.

34. Shantaram G. Khanage, Popat B. Mohite, S. Appala Raju. Synthesis, anticancer and antibacterial activity of some novel 1, 2, 4-triazole derivatives containing pyrazole and tetrazole rings. Asian J. Research Chem. 2011; 4(4): 567-573.

35. Vipul Singh, Arvind Kumar Singh, Rohit Tripathi, Preeti Mishra, Roopes Kumar Maurya. 1, 2, 4- triazole derivatives and its pharmacological activities. Asian J. Research Chem. 2013; 6(5): 429-437.

36. Dinesh R. Godhani, Anand A. Jogel, Vishal B. Mulani, Anil M. Sanghani, Nipul B. Kukadiya, Jignasu P. Mehta. Effect of temperature and solvent on molecular interactions of 1,2,4-triazole derivative. Asian J. Research Chem. 2018; 11(1): 32-36.DOI: 10.5958/0974-4150.2018.00007.X

37. Md Akram, Abdul Sayeed, Mohd Waseem Akram. Studies on the synthesis of some new 1,2,4-triazoles derivatives and evaluation for their anti-tubercular activity profiles. Research J. Pharm. and Tech. 2018; 11(1): 153-164. DOI: 10.5958/0974-360X.2018.00029.X

38. Igor V. Sych, Iryna V. Drapak, Marharyta M. Suleiman, Maryna V. Rakhimova, Natalya P. Kobzar, Irina A. Sych, Lina O. Perekhoda. Search for biologically active substances with antimicrobial and antifungal action in the series of 2.5-disubstituted 1, 3, 4-tiadiazoles. Research J. Pharm. and Tech. 2019; 12(6): 2871-2876. DOI: 10.5958/0974-360X.2019.00483.9

39. Semaa Yousif Khadum, Dina S. Ahmed, Emad Yousif. Chemical modification of pvc with schiff base containing a thiadiazole moiety and its influence on the physicochemical and morphological properties. Research J. Pharm. and Tech. 2019; 12(9): 4518-4522. DOI: 10.5958/0974-360X.2019.00778.9

40. Vijayakumar V., Radhakrishnan N., Vasantha-Srinivasan P. Molecular docking analysis of triazole analogues as inhibitors of human neutrophil elastase (hne), matrix metalloproteinase (MMP 2 and MMP 9) and Tyrosinase. Research J. Pharm. and Tech. 2020; 13(6): 2777-2783. DOI: 10.5958/0974-360X.2020.00493.X.

41. O.A. Bihdan, V.V. Parchenko. Chemical modification and Physicochemical properties of new derivatives 5-(thiophen-3-ilmethyl)-4-R1-1,2,4-triazole-3-thiol. Research J. Pharm. and Tech. 2021; 14(9): 4621-4629. DOI: 10.52711/0974-360X.2021.00803

42. Krishna Chandra Panda, B.V.V Ravi Kumar, Biswa Mohan Sahoo. Microwave induced synthesis of 1,2,4-triazole derivatives and study of their anthelmintic and anti-microbial activities. Research J. Pharm. and Tech. 2022; 15(12): 5746-5750. DOI: 10.52711/0974-360X.2022.00969

43. Sadykov A.S. Chemistry of alkaloids from Anabasis aphylla. Tashkent, 1956.

44. In Min Hwang and et al. Rapid and Simultaneous Quantification of Five Quinolizidine Alkaloids in Lupinus angustifolius L. and Its Processed Foods by UPLC–MS/MS. American Chemical Society. 2020; 5: 20825-20830. https://pubs.acs.org/doi/10.1021/acsomega.0c01929

45. Gordon A, Ford R. Сhemist's satellite. Physico-chemical properties, methods, bibliography. Moscow, 1976. http://www.vixri.ru/d2/Gordon%20A._SPUTNIK%20XIMIKA.pdf

46. Ermukhanbetova A.D., Kudaibergenova A.Zh., Kadyrbaeva G.M., Kashananova K.T., Bagiyarova F.A. Medicine and ecology. 2024; №4(113): 152-158.

47. State Pharmacopoeia of the Republic of Kazakhstan. Almaty: Publishing House “Zhibek Zholy”, 2008.

Received on 24.12.2024 Revised on 26.03.2025

Accepted on 02.06.2025 Published on 05.09.2025

Available online from September 08, 2025

Research J. Pharmacy and Technology. 2025;18(9):4281-4288.

DOI: 10.52711/0974-360X.2025.00615

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