CC BY
10
332 CHEMICAL PROBLEMS 2024 no. 3 (22) ISSN 2221-8688
UDC 547.541.3
SYNTHESIS AND PHARMACEUTICAL ACTIVITY OF TRIAZOLE SCHIFF BASES WITH THEORETICAL CHARACTERIZATION
Bassam A. Hassan*, Fadil M. Hamed
Department of Pharmaceutical Chemistry, College of Pharmacy, University of Thi-Qar, Thi-Qar, 64001,
Iraq.
*E-mail: bassamalsafee@utq.edu.iq
Received 13.01.2024 Accepted 01.04.2024
Abstract: In the presence of ethanol solvent and glacial acetic acids, triazole reacted with different aromatic aldehydes such as 4-methoxybenzaldehyde, 4-hydroxybenzaldehyde, and benzaldehyde to form the imines group known as Schiff bases. Triazole Schiff bases are triazole hydrazone and their derivatives, VA, VB, and VC. The structures of these synthetic triazole hydrazone derivatives were characterized by means of FT-IR and mass spectrometry. The purities and quality of the compounds were evaluated using TLC. It was established, that the active ingredient in the synthesised triazole hydrazone was more effective against the infections than cefuroxime.
Key words: triazole, hydrazones, biological activities, synthesis, characterization. DOI: 10.32737/2221-8688-2024-3-332-341
1. Introduction
Triazoles are heterocyclic organic compounds with three nitrogen atoms arranged in a five-member ring molecular structure. Two kinds of triazoles exist: 1, 2, 4-triazole and 1, 2, 3-triazole. Triazole derivative chemistry has drawn attention because of its practical uses in business, agriculture, and medicine. Furthermore, it is acknowledged that some triazoles are employed in the manufacture of polymers, as well as dyes, photographic chemicals, and analytical reagents 13, 14, and 15. Several five-membered aromatic systems
with three heteroatoms arranged symmetrically have been investigated due to their intriguing physiological characteristics. Additionally, it is well known that a variety of 1,2,4-triazole and 1,3,4-thiadiazole derivatives show a wide range of pharmacological characteristics, including antifungal and antibacterial activity. Some examples of currently accessible therapeutically relevant medications that include one of these heterocyclic nuclear are ribavirin, cefazoline, fluconazole, terconazole, and itraconazole [1].
Fig. 1. Isomer structure of Triazoles [2]
CHEMICAL PROBLEMS 2024 no. 3 (22)
www.chemprob.org
1,2,4-Triazoles five-membered
heterocycles that include more than two heteroatoms are thought to be formed from pyrrole by the substitution of nitrogen (-N=) atoms of the pyridine type from various places for methine groups (-CH=). The cyclic hydrazidines known as 1,2,4-triazoles have hydrogen atoms (or substituents) on either amide nitrogen six or hydrazide nitrogen 5. 1,3,4-triazole (4H-form) and parent 1,2,4-triazole (lH-form) are in tautomeric equilibrium [2] (Figure 1).
Many of the 1,2,4-triazole system's compounds have been studied as potentially useful therapeutic options due to their dual roles as anti-acetyl cholinesterase and selective COX-2 inhibitors. Triazole Schiff bases' potential as effective DNA probes, antioxidants, antivirals, anti-inflammatories, and analgesics is due to additional heterocyclic groups in them. These substances also show notables cytotoxic qualities. The development of novel 1,2,4-triazole-derived Schiff base compounds based
on metals with biological properties including antioxidant, antifungal, and antibacterial properties as chemotherapeutic agents. After metal-ion chelation, their physical activity rises [3].
Functional groupss made up of an imine or azomethine (-C=N-) bond between a carbonyl group and an amine or ammoniac derivative distinguishes Schiff bases from other classes of organic compounds. Hugo Schiff [4], a German chemist who created them for the first time in 1864, is honored by their name. Applications for Schiff bases are many in pharmaceutical chemistry, chemical synthesis, and materials research [5]. They are often used as intermediates in the synthesis of several chemical compounds as well as ligands in coordination chemistry. Schiff bases have been investigated for their potential as anti-inflammatory, antibacterial, and anticancer medicines since they also show biological action [6].
2. Experimental part
Triazole Schiff bases and their new derivatives were investigated using the MS Model: 5973 Agilent Technology (HP) of mass spectral and the melting points equipment (UK). Elemental analysis was done on a flashing thermo analyser C, H, and N. FT-IR spectra were examined in the 200-4000 cm-1 range on an infrared spectrophotometer (Shimadzu).
General procedure for synthesis of triazole Schiff bases hydrazones (VA-VC)
2.1. Synthesis of potassium 2-(2-hydroxybenzoyl)hydrazine-1-carbodithioate
(II)
In 25 milliliters of ethanol, substituted 2-hydroxybenzohydrazide (0.02 mol) and KOH (0.06 mol) were dissolved. The mixture was then stirred and 0.2 mol CS2 was added dropwise at room temperature and left there for 12 hours. The yellow of potassium 2-(2-hydroxybenzoyl)hydrazine-1-carbodithioate was produced, filtered, and thoroughly cleaned three times using 100% ethanol [7].
2.2. Synthesis of 2-(4-amino-5-sulfanyl-4#-1,2,4-triazol-3-yl)phenol (III)
After dissolving the intermediate potassium dithiocarbazinates in 25 mL of hot water, 0.2 mol of hydrazine hydrate was added. After heating and refluxing for three hours, this combination was put into cold water and acidified using strong hydrochloric acid. 2-(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)phenol [8] was produced as a pink precipitate after the precipitates were filtered, rinsed with water, and recrystallized from ethanol. The chemical was evaluated for purity using the TLC technique, yielding an RF Value of 0.75 and an eluent ratio of 7:3 (ethanol: hexane). Spot pigment may be clearly seen in an iodine chamber [8].
2.3. Synthesis of 2-(4-amino-5-hydrazinyl-4#-1,2,4-triazol-3-yl)phenoll (IV)
A combination of 2-(4-amino-5-sulfanyl-4H- 1,2,4-triazol-3 -yl)phenol (0.05mol) and hydrazine hydrate (0.05mol) in ethanol (100 mL) was boiled for 72 hours, cooled and condensed. After filtering and washing with cold water, the crude product was recrystallized from ethanol to generate 3-hydrazinyl-5-phenyl-4H-1,2,4-triazol-4-amine (III) as a brown crystal
with an 82% yield and a melting point of 210-220°C [9].
2.4. Synthesis of triazole Schiff bases hydrazones derivatives V
Hot solutions of aromatic aldehyde (1.52 g, 10 mmol) and 2-(4-amino-5-hydrazinyl-4H-1,2,4-triazol-3-yl)phenol (1.92 g, 10 mmol) were combined in 50 mL of ethanol with two drops of glacial acetic acid. The mixture was
then allowed to reflux for two hours. The resultant solid product was then filtered, refined by crystallizing it from ethanol, cleaned with diethyl ether, and vacuum-dried over anhydrous calcium chloride. The physiochemical data of synthesized derivatives VA, VB, VC are listed in Table 1. Spot pigment was visibly identified in an iodine chamber [10].
Table 1. Physiochemical data of synthesized derivatives VA , VB, and VC
Symbol Molecular formula M.W(gm/mole) Colour Melting points (°C) Yield (%)
VA C24H22N6O3 442 yellow 221-223 71 %
VB C22H18N6O3 414 Yellowish brown 220-222 68 %
VC C22H18N6O 382 Yellowish brown 222-224 63 %
Scheme 1. 2-(4-amino-5-hydrazinyl-4#-1,2,4-triazol-3-yl)phenol derivatives
Scheme 2. Triazoloof hydrazones derivatives VA,VB,VC
Theoretically H-NMR characterization of synthesized compound:
Scheme 3. Theoretical H-NMR characterization of VA,VB 3. Results and discussion
The physicochemical properties of the represented in Table 1 and (Fig. 2, 3, 4) of the synthesized triazole hydrazone derivative shown triazole hydrazine derivative VA FTIR, Hin Table 1 display the molecular weight, yield NMR, and Mass spectra showed good evidence percentage, colour, and melting temperatures of to identify the structure of synthesized triazole the synthesized compounds. All data hydrazone derivative.
Scheme 4. Theoretical H-NMR characterization of VC
FTIR (KBr, cm-1) of VA revealed 3404 (O-H), 3188 (N-H), 3091 (C-H) aromatic, 2910 (c-H)Ali, and 1623 (C=N) correspondingly. Hydrazone derivative VB FTIR (KBr, cm-1) revealed the following peaks: 3408 (O-H), 3193 (N-H), 3085 (C-H) aromatic, 2905 (C-H)Ali, and 1625 (C=N). Hydrazone derivative VC FTIR (KBr, cm-1) revealed, in that order, 3407 (O-H), 3194 (N-H), 3095 (C-H) aromatic, 2905 (C-H)Ali, and 1630 (C=N) [11].
The target compounds of triazole hydrazone VA that were synthesised showed molecular ion peaks in their mass spectra at 442, 289, 191, 148, 118, 91, 77, 65, and 53. These peaks correspond to the molecular ion fragments C24H22N6O3, C24H21N6O2+, C10H8N6O2+, C8H9N5O, C8H6N3O+, C7H7N3O,
C7H6N2O, C7H8, C9H5NO3, C6H5+ C4H3, as shown in (Fig. 3) [12].
C5H5 , and
Fig. 2. FT-IR spectrum of triazole hydrazones VA
Fig. 3. Mass spectra of triazole hydrazones VA
VA
JUU
16 15 14 13 12 11
7 6
fl tppm)
Fig. 4. 1H-NMR spectrum of hydrazones VA
H-NMR Images Fig. 4 [15] show the 1H-NMR spectrum data of the synthesized compound of triazole hydrazine VA. Regarding the aromaticc portion of the spectrum, many signals that show up in the range of 6.07 to 8.12 ppm are thought to be related to the aromatic
ring. On the other hand, the second signal is a singlett that has reverted to the Azomethine group CH=N- chemical shift value that was seen in 9.1 ppm [16]. Additionally, we observed that singlet signals at (14.04 ppm) in the 1H-NMR spectrum were assigned to NH of triazolo
ring, respectively, while OH interference with aromatic ring. Additionally, we observed that two singlet signals at (3.1) ppm in the !H-NMR spectrum were assigned to six proton of OCH3 [17], [18].
The mass spectral analysis of the ion fragmentss confirmed the composition of the synthesised triazole schiff bases VB. The molecularr ion peaks at 414, 282, 191, 160, 149, 134, 108, 93, 65, and 53 are part of the
molecular ion fragments C22H18N6O3, C10H8N6O2+, C8H9N5O, C8H6N3O+, C7H7N3O, C7H8, C9H5NO3, C5H5+, and C4H3. The target of triazole hydrazone VC that was synthesised has molecular ion peaks in its mass spectrum at 382, 282, 191, 160, 149, 134, 108, 93, 65, 53 [13]. These peaks are part of the molecular ion fragments C22H18N6O, C10H8N6O2+, C8H9N5O, C8H6N3O+, C7H7N3O, C7H5N2O, C7H8, C9H5NO3, and C5H5+ [14].
4. Biochemical action
VA, VB, and VC, the active ingredientss of synthesised triazole hydrazones, were chemically producedd and evaluated in vitro using the agar cups methodd. The antimicrobiall properties of streptococcus [19], aeromonas [20], aureus [21], pseudomonas [22], klebsiellae [23], acinetobacter [24], and staphylococcus
[25] were assessedd. The data in Table 2 indicates that the activee component in the synthesised triazole schiff bases [26].was more efficientt against the pathogens thann CEFUROXIMEE, which was selectedd to combat Acinetobacter. The results are listed in Table 2 [27].
Table 2. The diameter zone of growth of bacteria inhibition (mm) by plant extracts
Types of Isolates Antimicrobial Agent
CEFUROXIMEE VA VB VC
Staphylococcuss aureus I R I S
E. colii R R S I
Streptococcuss R R S R
Pseudomonass I R S I
S - sensitivity; I - intermediate; R - resistance
5. Conclusion
In the current study, triazole hydrazones VA, VB, and VC were synthesized and characterized by various physical features, such as melting point and colour, as well as by various spectral techniques, such as IR and mass spectra. Additionally, it was shown, that, the IR spectra showed five significant bands on 3404 3188, 3091, 2910, 1623, and 1699, respectively, of IVA, which corresponded to (O-h), (N-H), (CH) Aromatic, (C-H)Ali, and (C=N). It provides strong backing for the synthesis of derivativess of triazole Schiff bases. The ion peak of the mass fragment was seen at the target
compounds that were synthesised and displayed molecular ion peaks at 442, 425, 282, 191, 160, 149, 134, 108, 93, 65, and 53. These molecular ion peaks are associated with the molecular ion fragment C24H22N6O3, C24H21N6O2+, C1oH8N6O2+,C8H9N5O, C8^^O+, C7H7N3O, C7H6N2O, C7H8, C9H5NO3, C5H5+, and C4H3, which is associated with the molecular ion of the synthesised structure triazole hydrazones VA. The composition of the synthesized triazole hydrazones VA was validated by the ion fragment mass data.
References
1. Bandaru R., et al. The Role of Artificial Intelligence and Machine Learning in Drug Discovery and Development // Asian Journal of Advances in Research, 2024, V. 7(1), p. 133-140.
2. Palekar V.S., Damle A.J., Shukla SR. Synthesis and antibacterial activity of some novel bis-1, 2, 4-triazolo [3, 4-b]-1, 3, 4-thiadiazoles and bis-4-thiazolidinone derivatives from terephthalic dihydrazide // European journal of medicinal chemistry, 2009, V. 44 (12), p. 5112-5116.
3. Fischer G. Recent progress in 1, 2, 4-triazolo [1, 5-a] pyrimidine chemistry // Advances in heterocyclic chemistry, 2007, V.95, p. 143219.
4. Abdulridha M.M., Hassan B.A., Hamed F.M. Synthesis And Antibacterial Evaluation of 1, 3, 4-Thiadiazole Containing 1, 3, 4-Oxadiazole Bearing Schiff Bases // International Journal Of Pharmaceutical Research, 2018, V. 10(4), p.
5. Hassan B.A., Abdulridha M.M., Hamed F.M. Design and antibacterial activity of 3, 6-diphenyl-1, 5, 6, 7, 8, 8 ahexahydro [1, 2, 4] triazolo [4, 3-B][1, 2, 4, 5] tetrazine as fused heterocyclic compounds // Biochemical & Cellular Archives, 2020, V. 20(1), p. 14991502.
6. Hassan B.A., Baqer F.M., Abdulridha MM. Design, Synthesis and Characterization of BenzoxazepineThiourea New Derivatives // International Journal of Drug Delivery Technology, 2021, V. 11(3), p. 874-876.
7. Hassan B.A., Nasera H.N., Abdulridha MM. Synthesis and antimicrobial evaluation of fused heterocyclic compound [1, 2, 4] triazolo [4, 3-b][1, 2, 4, 5] tetra zine // International Journal of Research in Pharmaceutical Sciences, 2019, V.10(2), p.1254-1258.
8. Hamed F.M., Hassan B.A., Abdulridha MM. The antitumor activity of sulfonamides derivatives // Int. J. Pharm. Res, 2020, V. 12, p. 2512-2519.
9. Hassan B.A., Baqer F.M., Abdulridha MM. Design, Synthesis and Characterization of Benzoxazepine Thiourea New Derivatives // International Journal of Drug Delivery
Technology, 2021, V. 11(3), p. 874-876.
10. Witczak Z.J., Bielski R. New developments and strategies. Click chemistry in glycoscience. John Wiley & Sons, 2013.
11. Hussain M.Y., Hassan B.A., Hanan Z.K. Synthesis and Characterization of a new Schiff basses (3Z, 3Z)-3, 3'-((oxybis (4, 1-phenylene)) bis (azanylylidene)) bis (indolin-2-one) // Turkish Journal of Computer and Mathematics Education (TURCOMAT), 2021, V. 12(14), p.3341-3351.
12. Bassam A., Hasan A. Preparation and characterisation of some transition metal complexes of new 4-[(5-ethyl-1, 3, 4-oxadiazol-2-yl) sulfanyl] aniline // The Swedish Journal of Scientific Research, 2014, V.1(6), p. 11-23.
13. Hasan B.A., Abdulridha M.M. Preparation and Characterisation of Sometransation Metal Complexes of New [Butanal (5-Ethyl-1, 3, 4-Oxadia-Zol-2-Yl) Hydrazone] // The Swedish Journal of Scientific Research, 2014, V. 1(5), p. 23-36.
14. Abass A.A., et al. Efficacy study of Captopril on some liver function tests in hypertensive patients // Revista Latinoamericana de Hipertension, 2023, V. 18(3), p. 142-146.
15. Shalaal S.H. et al. Maceration techniques extraction of thymus vulgaris and laurel (Laurus Nobilis) Leaves with antibacterial study // Plant Archives, 2019, V. 19(2), p. 4041-4044.
16. Abdulridha M.M. et al. Phytochemical and Antibacterial Activity of the Pegnum harmala Seeds and its Alkaloids // Plant Archives, 2019, V. 19(1), p.1439-1444.
17. Hassan B.A., Hamed F.M., Alyaseen F.F. Phytochemical screened, characterization and antibacterial activity of hesperetin and hesperidin extracted and isolated from dried oranges peels // International Journal of Research in Pharmaceutical Sciences, 2018, 9.4: 1362-1367.
18. Alyaseen F.F. et al. Extraction, isolation and chemical identification of piperine alkaloid from black pepper seeds and its
antibacterial activity // Plant Archives, 2018, V. 18(2), p. 2171-2176.
19. Zhou H.C., Wang Y. Recent researches in triazole compounds as medicinal drugs // Current medicinal chemistry, 2012, V.19(2), p. 239-280.
20. Kharb R., Chander S.P., Yar M.S. Pharmacological significance of triazole scaffold // Journal of enzyme inhibition and medicinal chemistry, 2011, V. 26(1), p. 121.
21. Juricek M., Kouwer P.H.J, Rowan A.E. Triazole: a unique building block for the construction of functional materials // Chemical communications, 2011, V. 47(31), p. 8740-8749.
22. Zhang S. et al. Triazole derivatives and their anti-tubercular activity // European journal of medicinal chemistry, 2017, V. 138, p. 501-513.
23. Sathish K.S.P., Kavitha H. Synthesis and biological applications of triazole
derivatives-a review // Mini-Reviews in Organic Chemistry, V. 2013, V. 10(1), p. 40-65.
24. Saravolatz L.D., Johnson L.B., Kauffman C.A. Voriconazole: a new triazole antifungal agent // Clinical infectious diseases, 2003, V. 36(5), p. 630-637.
25. Abdulridha M.M., Hassan B.A., Neamah I.J. Theoretical study of synthesis and pharmaceutical study of Tetrazine derivatives // Annals of the Romanian Society for Cell Biology, 2022, V. 26(1), p.1657-1669.
26. Kaplancikli Z.A. et al. New triazole and triazolothiadiazine derivatives as possible antimicrobial agents // European journal of medicinal chemistry, 2008, V. 43(1), p. 155-159.
27. Torres H.A. et al. Posaconazole: a broad-spectrum triazole antifungal // The Lancet infectious diseases, 2005, V. 5(12), p. 775785.
NOZOM XARAKTERiSTiKALI TRIAZOL §iFF OSASLARININ SiNTEZi УЭ
FARMASEVTiK AKTiVLiYi
Bassam A. Hassan*, Fadil M. Hamed
dczagiliq Kimyasi Departamenti, dczagiliq Kolleci, Thi-Qar Universiteti, Thi-Qar, 64001, iraq.
*E-pogt: bassamalsafee@utq.edu.iq
Xülasa: Triazol etanol halledicisi va buzlu sirka tur§usunun i§tiraki ila 4-metoksibenzaldehid, 4-hidroksibenzaldehid va benzaldehid kimi müxtalif aromatik aldehidlarla reaksiyaya girarak §iff asaslari kimi taninan iminlar qrupunu amala gatirir. Triazol §hiff asaslari triazol hidrazon va onlarin töramalari, VA, VB va VC-dir. Bu sintetik triazol hidrazon töramalarinin strukturlari FT-iR va kütla spektrometriyasi vasitasila xarakteriza edilmi§dir. Birla§malarin tamizliyi va keyfiyyati TLC-dan istifada edarak qiymatlandirilmi§dir. Müayyan edilmi§dir ki, sintez edilmi§ triazol hidrazonun tarkibindaki aktiv tarkib sefuroksima nisbatan infeksiyalara qar§i daha tasirlidir. A?ar sözlar: triazol, hidrazonlar, bioloji aktivlik, sintez, xarakteristika.
СИНТЕЗ И ФАРМАЦЕВТИЧЕСКАЯ АКТИВНОСТЬ ТРИАЗОЛЬНЫХ ОСНОВАНИЙ ШИФФА С ТЕОРЕТИЧЕСКОЙ ХАРАКТЕРИСТИКОЙ
Басам А. Хасан*, Фадил М. Хамед
Кафедра фармацевтической химии, Фармацевтический колледж, Университет Ти -Кар, Ти-Кар,
64001, Ирак. *Электронная почта: bassamalsafee@utq.edu.iq
Аннотация: В присутствии растворителя этанола и ледяной уксусной кислоты триазол взаимодействовал с различными ароматическими альдегидами, такими как 4-метоксибензальдегид, 4-гидроксибензальдегид и бензальдегид, с образованием иминной группы, известной как основания Шиффа. Триазольные основания Шиффа представляют собой триазолгидразон и их производные VA, "УЪ и VC. Структуры этих синтетических производных триазолгидразона были охарактеризованы с помощью ИК-Фурье и масс-спектрометрии. Чистоту и качество соединений оценивали с помощью ТСХ. Установлено, что действующее вещество синтезированного триазолгидразона более эффективно против инфекций, чем цефуроксим.
Ключевые слова: триазолы, гидразоны, биологическая активность, синтез, характеристика.
