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Рекомендовано до публгкацИ д-р фарм. наук, професор Краснопольский Ю. М.
Дата надходження рукопису 11.03.2016
Хижняк Оксана Сергивна, астрант, кафедра бютехнологи i аналогично! xiMii, Нацiональний техшчний ушверситет «Харшвський Полiтеxнiчний 1нститут», вул. Кирпичова, 21, м. Харшв, Укра!на, 61002 E-mail: Oksana.khizhnyak@gmail.com
UDC 547,792:547,856
DOI: 10.15587/2313-8416.2016.67685
PRIMARY ANTIMICROBIAL SCREENING OF NOVEL [1,2,4]TRIAZOLO[4,3-a]QUINAZOLIN-5(4#)-ONE DERIVATIVES
© S. Danylchenko, O. Drushlyak, S. Kovalenko, S. Kovalenko, A. Elliott, J. Zuegg
Aim. The aim of the given study was to conduct primary antimicrobial screening of novel [1,2,4]triazolo [4,3-a]quinazolin-5(4H)-one derivatives.
Methods. The set of 169 novel [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one derivatives has been tested for activity against 5 bacteria: Escherihia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeru-ginosa and Staphylococcus aureus, and 2 fungi: Candida albicans and Cryptococcus neoformans. Primary antimicrobial screening has been conducted by whole cell growth inhibition assays, using the provided samples at a single concentration. Samples were tested in water - 0.3 % DMSO solutions with final sample concentrations 32 ng/ml (70-80 yMol).
Results. [1,2,4]Triazolo[4,3-a]quinazolin-5(4H)-ones 5{1}, 7{1}, 7{2}, 7{3} showed more than 80 % inhibition of Acinetobacter baumannii growth and compounds 7{4} showed more than 80 % inhibition of growth fungi Cryptococcus neoformans.
Conclusions. For the first time conducted antimicrobial screening of novel [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones showed that compounds, which had no amide group exhibited no antimicrobial activity, but several [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one derivatives containing amide group attached by carbon or sulfur-carbon chain possess antimicrobial activity against Acinetobacter baumannii or fungi Cryptococcus neoformans Keywords: [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one, antimicrobial activity Escherihia coli, Klebsiella pneu-moniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, Cryp-tococcus neoformans
Мета. У даному до^дженш було поставлено за мету провести первинний с^тнг на aHmuMiKpo6Hy активтсть нових похiдних [1,2,4]триазоло[4,3-a]хiназолiн-5(4H)-ону.
Методи. Масив 169 нових похiдних [1,2,4]триазоло[4,3-a]хiназолiн-5(4H)-ону було тестовано на активтсть проти 5 видiв бактерш: Escherihia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa та Staphylococcus aureus, та 2 видiв грибiв: Candida albicans та Cryptococcus neoformans. Первинний скрттг на антимiкробну активтсть було проведено тестуванням усього масиву на подав-лення росту клтин, за умов однаково! концентрацИ сполук. Зразки сполук було тестовано у водних з 0.3 % ДМСО розчинах при остаточнт концентрацИ сполук 32 цг/мл (70-80 цМол).
Результати. noxidni [1,2,4]триазоло[4,3-a]хiназолiн-5(4H)-ону 5{1}, 7{1}, 7{2}, 7{3} показали бшьш нiж 80 % тамування росту Acinetobacter baumannii, та сполука 7{4} показала бшьш нiж 80 % тамування росту грибку Cryptococcus neoformans.
Висновки. Проведене вперше тестування на антимiкробну активнкть [1,2,4]триазоло[4,3-a]хiназолiн-5(4И)-ошв показало, що сполуки, що не мають амiдноi групи, не проявляють антимiкробноi дп, проте деяш [1,2,4]триазоло[4,3-a]хiназолiн-5(4H)-они, що мктять амiдну групу, приеднану за допомогою кар-бонового, або сульфур-карбонового ланцюгу, мають антимiкробну активтсть проти Acinetobacter baumannii або Cryptococcus neoformans
Ключовi слова: [1,2,4]триазоло[4,3-a]хiназолiн-5(4H)-он, антимкробна активтсть, Escherihia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, Cryptococcus neoformans
1. Introduction
The infection treatment was actual task of medicine both ancient and modern times. A lot of remedies were directed against infectious diseases. But massive use of antimicrobial agents leads to appear microbial resistance to popular drugs.
2. Formulation of the problem in a general way, the relevance of the theme and its connection with important scientific and practical issues
The growth of microbial resistance to drugs is serious problem in the infection treatment. The main solution to this problem is the search for new effective antimicrobial agents. Usually, the screening of assays of new derivatives potentially biologically active compounds for antimicrobial activity is efficient way to find new antimicrobial substances.
Derivatives of [1,2,4]triazolo[4,3-a]quinazolin-5(4#)-one, which are representatives of the important class of condensed heterocycles possessing wide range of the biological activity, attract particular interest in development of innovative drug substances.
3. Analysis of recent studies and publications in which a solution of the problem and which draws on the author
Derivatives of [1,2,4]triazolo[4,3-a]quinazolin-5(4#)-one showed the H1-antihistaminic [1-9], anticonvulsant [10], antiHIV [11], anticancer [12], anti-asthmatic [8, 13], antiallergic [13], anti-inflammatory [13, 14] bio-activities. 1 -Alkyl-3 -aryl[1,2,4]triazolo [4,3-a]quinazolin-5(4#)-ones demonstrated moderate antibacterial [11, 12] including antitubercular [12] and antifungal [11] properties. In the previous study [15] we found that containing amide group connected via carbon chain 4-benzyl-1-{4-[4-(4-methoxyphenyl)piperazin-1-yl]-4-oxobutyl}[1,2,4] triazolo[4,3-a]quinazolin-5(4H)-one showed noticeable antimalarial activity with IC50 0.25 ^Mol.
4. Allocation of unsolved parts of the general problem, which is dedicated to the article
Only a small part of the vast array of possible [1,2,4]triazolo[4,3-a]quinazolin-5(4#)-one derivatives,
namely, 1 -alkyl-3 -aryl[1,2,4]triazolo [4,3 -a]quinazolin-5(4#)-ones have been systematically screened for antimicrobial activity [11, 12].
5. Formulation of goals (tasks) of article
The aim of the given study was to conduct primary antimicrobial screening of novel [1,2,4]triazolo[4,3-a]quinazolin-5(4^)-one derivatives, namely, 1-aryl-3-aikyl[1,2,4]triazolo[4,3-a]quinazolin-5(4#)-ones and [1,2,4] triazolo[4,3-a]quinazolin-5(4^)-ones containing amide group.
6. Statement of the basic material of the study (methods and objects) with the justification of the results
We used formerly described [16] 2-hydrazino-quinazolin-4(3#)-ones 1 as starting materials for [1,2,4]triazolo[4,3-a]quinazolin-5(4^)-ones synthesis (Fig. 1).
1 -Aryl-3 -alkyl[1,2,4]triazolo[4,3-a]quinazolin-5 (4#)-ones 2 have been synthesized by reaction of 2-hydrazinoquinazolin-4(3^)-ones 1 with aromatic aldehydes followed by oxidation in the presence of FeCl3 according [17].
Amides of [(4-substituted-4,5-dihydro-5-oxo[1,2,4] triazolo[4,3-a]quinazolin-1-yl)thio]acetic acid 5 have been obtained according [15] by condensation of hydrazines 1 with CS2 resulted in 1-thioxo-2,4-di-hydro[1,2,4]triazolo[4,3-a]quinazolin-5(1^)-ones 3 formation. Consequent alkylation by chloroacetic acid amides 4 lead to [1,2,4]triazolo[4,3-a]quinazolin-5(4^)-ones 5, which contain sulfur-carbon chain.
Amides of 3-(4-substituted-5-oxo-4,5-dihydro [1,2,4]triazolo[4,3-a]quinazolin-1-yl)propanoic acid 7 have been obtained according [15, 18] by condensation of hydrazine 1 with succinic anhydride, that produced 3-(4-substituted-5-oxo-4,5-dihydro[1,2,4]triazolo [4,3-a]qui-nazolin-1-yl)propanoic acids 6. For amide formation we used activation of carboxylic group in obtained acid 6 via getting intermediate imidazolyl amide by carbonyldiim-idazole (CDI) in anhydrous dioxane with subsequent reaction with corresponding amine by reflux up to 2 hours.
1. ArCH=O
2. FeCl,
NH I
NH,
v>
/и
'Дм
—N
N 4nn
=N
26 compounds
N -N /
N
■CDI. ii- HN
'N -N /
N
4 compounds
138 compounds
Fig. 1. The synthesis of [1,2,4]triazolo[4,3-a]quinazolin-5(4.ff)-ones
Novel 4-benzyl-2-[2-(tert-butylamino)-2-oxoe-thyl] -N-isopropyl-1,5-dioxo-1,2,4,5 -tetrahydro [1,2,4]tri-azolo[4,3-a]quinazoline-8-carboxamide 11 has been synthesized by reaction of 3-benzyl-2-hydrazino-N-iso-propyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide 8 with CDI resulted in 4-benzyl-N-isopropyl-1,5-dioxo-1,2,4,5-tetrahydro[1,2,4]triazolo[4,3-a]quinazoline-8-car-boxamide 9 formation. Consequent alkylation by N-(tert-butyl)-2-chloroacetamide 10 lead to [1,2,4]triazolo [4,3-a]quinazolin-5(4^)-one 11.
The structures of obtained compounds have been confirmed by the :H NMR spectroscopy data. Formation of the [1,2,4]triazolo[4,3-a]quinazolin-5(4^)-one condensed system led to shift of H-6 protons signals to 8.269.22 ppm, that is in good correlation with the known data [19]. 1H NMR-spectra were recorded on Varian WXR-400 (200 MHz) spectrometer in DMSO-d6 solution with TMS as internal standard, chemical shifts are reported in ppm. Melting points were measured with a Buchi B-520 melting point apparatus. Elemental analysis was performed on Euro EA-3000 apparatus.
4-Benzyl-N-isopropyl-1,5-dioxo-1,2,4,5-tetrahy-dro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamide 9. Reflux the solution of 0.70 g (0.002 mol) 3-benzyl-2-hydrazino-N-isopropyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide 8 and 0.39 g (0.0024 mol) of CDI in anhy-
drous DMF (5 ml) during 6 hours. After cooling, dilute the reaction mixture with H2O (20 ml). Filter the precipitate formed, wash it with i-propanol (10 ml) and recrys-tallize from mixture of DMF (5 ml) and /-propanol (10 ml). Yields 0.64 g (85 %), white solids, m.p. >300 °C (dec.). 1H NMR (5, ppm, J, hz): 1.16 (6H, d, J=7.0, 2CH3); 4.02-4.12 (1H, m, CH(CH3)2); 5.18 (2H, s, CH2); 7.24-7.36 (3H, m, H-3,4,5 Bn); 7.48 (2H, d, J=7.8, H-2,6 Bn); 7.86 (1H, dd, J6,7=7.8, J7,9=2.0, H-7); 8.17 (1H, d, J6,7=7.8, H-6); 8.57 (1H, d, J=7.0, CONH); 9.00 (1H, d, J7,9=2.0, H-9); 12.00 (1H, s, NH-2). Found, %: C 63.54; H 5.05; N 18.48. C20H19N5O3. Calculated, %: C 63.65; H 5.07; N 18.56.
4-Benzyl-2-[2-(teri-butylamino)-2-oxoethyl]-,N-isopropyl-1,5-dioxo-1,2,4,5-tetrahydro[1,2,4]triazolo [4,3-a]quinazoline-8-carboxamide 11. Dissolve 0.38 g (0.001 mol) of 4-benzyl-N-isopropyl-1,5-dioxo-1,2,4,5-tetrahydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxami-de 9 in 5 ml of DMF. Add 0.21 g (0.002 mol) of powder of anhydrous Na2CO3 with stirring. Add 0.18 g (0.0012 mol) of N-(fer/-butyl)-2-chloroacetamide 10. Heat the reaction mixture with stirring at 90 °C for 2 hours. After cooling, dilute the reaction mixture with H2O (20 ml). Filter the precipitate formed, wash it with /-propanol (10 ml) and recrystallize from mixture of DMF (5 ml) and /-propanol (10 ml). Yields 0.35 g (71 %),
O
O
R1
N
N
1
Ar
2
DMF. NEt
CS
O
O
R1
N
R3
DMF. NEt
R2
4
O
R3
S
O
R2
N-
O
R1
H
7
5
11
9
8
white solids, m.p. 294-296 °C. :H NMR (5, ppm, J, hz): 1.08 (9H, d, .7=7.0, 3CH3); 1.16 (6H, d, J=7.0, 2CH3); 4.02-4.12 (1H, m, CH(CH3)2); 5.20 (2H, s, CH2); 5.20 (2H, s, CH2); 7.24-7.36 (3H, m, H-3,4,5 Bn); 7.48 (2H, d, Jt=7.8, H-2,6 Bn); 7.86 (1H, dd, J6>7=7.8, J7,9=2.0, H-7); 8.05 (1H, d, 7=7.0, CONH); 8.17 (1H, d, J6,7=7.8, H-6); 8.57 (1H, d, 7=7.0, CONH); 9.00 (1H, d, J7,9=2.0, H-9). Found, %: C 63.54; H 6.18; N 17.08. C26H30N6O4. Calculated, %: C 63.66; H 6.16; N 17.13.
Hereby sinthesized set of 169 novel [1,2,4]tria-zolo[4,3-a]quinazolin-5(4#)-one derivatives consisted of 26 1-aryl-3-alkyl[1,2,4]triazolo[4,3-a]quinazolin-5(4#)-ones 2, 4 amides of [(4-substituted-4,5-dihydro-5-oxo [1,2,4]triazolo[4,3-a]quinazolin-1-yl)thio]acetic acid 5, 138 amides of 3-(4-substituted-5-oxo-4,5-dihydro[1,2,4] triazolo[4,3-a]quinazolin-1-yl)propanoic acid 7 and 4-benzyl-2-[2-(tert-butylamino)-2-oxoethyl]-^-isopropyl-1,5-dioxo-1,2,4,5-tetrahydro[1,2,4]triazolo[4,3-a]quina-zoline-8-carboxamide 11.
This set of compounds has been tested for activity against 5 bacteria: Escherihia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus, and 2 fungi: Candida albicans and Cryptococcus neoformans.
Samples of 2 mg of each compound were dissolved in 0.2 ml of DMSO that gave 10mg/ml solution in DMSO. An aliquot of each sample was diluted to 320 ^g/ml in water, and plated in 384-well polypropylene plates (PP), 5 ^l was plated in duplicate (n=2) into a 384-well non-binding surface plate (NBS) for each strain or cell type assayed against. Once cells were added this gave a final compound concentration range of 32 ^g/ml (70-80 ^Mol). Final concentration of DMSO was 0.3 %.
All bacteria were cultured in Cation-adjusted Mueller Hinton broth (CAMHB) at 37 °C overnight. The resultant mid-log phase cultures was added to each well of the compound containing plates, giving a cell density of 5105 CFU/ml. All the plates were covered and incubated at 37 °C for 18 h without shaking. Inhibition of bacterial growth was determined by measuring absorb-ance at 600 nm using a Tecan M1000 Pro monochroma-tor plate reader.
Fungi strains were cultured for 3 days on Yeast Extract-Peptone Dextrose (YPD) agar at 30 °C. A yeast suspension of 1106 to 5106 cells/ml (as determined by 0D530) was prepared from five colonies. These stock suspensions were diluted with Yeast Nitrogen Base (YNB) broth to a final concentration of 2.5'103 CFU/ml. Then, 45 ^l of the fungi suspension was added to each well of the compound-containing plates. Plates were covered and incubated at 35°C for 24 h without shaking. Growth inhibition of Candida albicans was determined measuring absorbance at 530 nm (0D530), while the growth inhibition of Cryptococcus neoformans was determined measuring the difference in absorbance between 600 and 570 nm (0D600-570), after the addition of resazurin (0.001 % final concentration) and incubation at 35 °C for additional 2 h. The absorbance was measured using a Biotek Synergy HTX plate reader.
Colistin and Vancomycin were used as positive bacterial inhibitor standards for Gramnegative and Grampositive bacteria, respectively. Fluconazole was used as a positive fungal inhibitor standard for Candida albicans and Cryptococcus neoformans.
The tests have been carried out in C0-ADD laboratory (Brisbane, Australia).
N H
5{1} CH3
7{1}
7{2}
Cl
H3C
HC
O 7{4}
Fig. 2. [1,2,4]triazolo[4,3-a]quinazolin-5(4#)-ones with antimicrobial activity
F
2-[(4-Benzyl-5 -oxo-4,5-dihydro [ 1,2,4]triazolo [4,3-a]quinazolin-1-yl)thio]-N-isopropylacetamide 5{1}, N-(4-fluorophenyl) -3-[5-oxo-4 -(2-phenylethyl) -4,5 -dihydro [1,2,4]triazolo[4,3-a]quinazolin-1-yl]propanamide 7{1}, 1-(3 -morpholin-4-yl-3 -oxopropyl)-4-(2-phenylethyl) [1,2,4] triazolo[4,3-a]quinazolin-5(4#)-one 7{2} and 3-[4-(4-fluorobenzyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]qu-inazolin-1-yl]-N-[2-(4-methylphenyl)ethyl]propanamide 7{3} showed more than 80 % inhibition of Acinetobacter baumannii growth and 3-[4-(4-chlorobenzyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazolin-1-yl]-N-{3-[3-me-thyl-4 -(3 -methylphenyl)piperazin-1 -yl]propyl} propana-mide 7{4} showed more than 80 % inhibition of growth fungi Cryptococcus neoformans (Fig. 2).
7. Conclusions
For the first time conducted antimicrobial screening of novel [1,2,4]triazolo[4,3-a]quinazolin-5(4^)-ones showed that compounds, which had no amide group exhibited no antimicrobial activity, but several [1,2,4]tri-azolo[4,3-a]quinazolin-5(4#)-one derivatives containing amide group attached by carbon or sulfur-carbon chain possess antimicrobial activity against Acinetobacter bau-mannii or fungi Cryptococcus neoformans.
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9. Gobinath, M. Synthesis of 1-substituted-4-(pyridin-4-yl)[1,2,4]triazolo[4,3-a]quinazolin-5(4#)-ones as a new class of H1-antihistaminic agents [Text] / M. Gobinath, N. Subramani-an, V. Alagarsamy, S. Nivedhitha, V. R. Solomon // Tropical Journal of Pharmaceutical Research. - 2015. - Vol. 14, Issue 2. - P. 271. doi: 10.4314/tjpr.v14i2.12
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11. Alagarsamy, V. AntiHIV, antibacterial and antifungal activities of some novel 1,4-disubstituted-1,2,4-triazolo[4,3-a]quinazolin-5(4#)-ones [Text] / V. Alagarsamy, R. Giridhar, M. R. Yadav, R. Revathi, K. Ruckmani, E. De Clercq // Indian Journal of Pharmaceutical Sciences. - 2006. - Vol. 68, Issue 4. - P. 532. doi: 10.4103/0250-474x.27840
12. Gobinath, M. Anticancer and antitubercular study of some 1,4-disubstituted[1,2,4]-triazolo[4,3-a]quinazolin-5(4#)-ones [Text] / M. Gobinath, N. Subramanian, V. Alagarsamy // International Journal of Research in Pharmaceutical Sciences. -2012. - Vol. 3, Issue 1. - P. 146-149.
13. Gaudilliere, B. Nouvelles 1-aminotriazolo[4,3-a]quinazoline-5-ones inhibitrices de phosphodiesterases IV [Text] / B. Gaudilliere, R. Lavalette, C. Andrianjara // Patent France 2792938. - 2000.
14. Elansary, A. K. Design, synthesis and in vitro PDE4 inhibition activity of certain quinazolinone derivatives for treatment of asthma [Text] / A. K. Elansary, H. H. Kadry, E. M. Ahmed, A. S. M. Sonousi // Medicinal Chemistry Research. - 2011. - Vol. 21, Issue 11. - P. 3327-3335. doi: 10.1007/s00044-011-9846-3
15. Danylchenko, S. Yu. [1,2,4]Triazolo[4,3-a]quinazolin-5(4#)-one derivatives as antimalarial agents [Text] / S. Yu. Danylchenko, O. G. Drushlyak, S.S. Kovalenko, S. M. Kovalenko, L. Maes // Ukrainian biopharmaceutical journal. - 2016. -Vol. 1, Issue 42. - P. 78-83.
16. Danilchenko, S. Yu. Synthesis of substituted 2-hydrazinoquinazolin-4-ones as intermediates for heterocyclic compounds synthesis [Text] / S. Yu. Danilchenko, O. G. Drushlyak, S. M. Kovalenko // Journal of Organic and Pharmaceutical Chemistry. - 2014. - Vol. 12, Issue 3. - P. 66-73.
17. Danylchenko, S. Yu. Synthesis, computer prediction of biological activity and acute toxicity of 1-Ar-4-R-[1,2,4]triazolo[4,3-a]quinazolin-5(4#)-ones [Text] / S. Yu. Da-nylchenko, O. G. Drushlyak, S. M. Kovalenko // Journal of Organic and Pharmaceutical Chemistry. - 2015. - Vol. 13, Issue 3 (51). - P. 38-45.
18. The patent application «The [1,2,4]Triazolo[4,3-a]quinazolin-5(4#)-one derivatives» [Text] / Danylchenko S. Yu. , Drushlyak O. G., Kovalenko S. M., Kovalenko S. S. -№ u201509803. - on 09.10.2015.
19. Saleh, M. A. Synthesis of aldehydo sugar (4-oxoquinazolin-2-yl)hydrazones and their transformation into 1-(alditol-1-yl)-1,2,4-triazolo[4,3-a]quinazolin-5(4#)-ones [Text] / M. A. Saleh, M. F. Abdel-Megeed, M. A. Abdo, A. M. Shkor // Journal of Heterocyclic Chemistry. - 2003. - Vol. 40, Issue 1. -P. 85-92. doi: 10.1002/jhet.5570400111
References
1. Alagarsamy, V., Giridhar, R., Yadav, M. R. (2005). Synthesis and pharmacological investigation of novel 1-
substituted-4-phenyl-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-on-es as a new class of H1-antihistaminic agents. Bioorganic & Medicinal Chemistry Letters, 15 (7), 1877-1880. doi: 10.1016/ j.bmcl.2005.02.016
2. Alagarsamy, V., Giridhar, R., Yadav, M. R. (2006). Synthesis and pharmacological investigation of novel 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones as a new class of H1-antihistamine agents. Journal of Pharmacy and Pharmacology, 58 (9), 1249-1255. doi: 10.1211/jpp.58.9.0012
3. Alagarsamy, V., Meena, S., Ramaseshu, K. V., Solomon, V. R., Kumar, T. D. A. (2007). 4-Cyclohexyl-1-substituted-4H-[1,2,4]triazolo [4,3-a] quinazolin-5-ones: Novel Class of H 1 -antihistaminic Agents . Chemical Biology & Drug Design, 70 (2), 158-163. doi: 10.1111/j.1747-0285. 2007.00544.x
4. Alagarsamy, V., Solomon, V. R., Murugan, M. (2007). Synthesis and pharmacological investigation of novel 4-benzyl-1-substituted-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones as new class of H1-antihistaminic agents. Bioorganic & Medicinal Chemistry, 15 (12), 4009-4015. doi: 10.1016/j.bmc.2007.04.001
5. Alagarsamy, V., Rupeshkumar, M., Kavitha, K., Meena, S., Shankar, D., Siddiqui, A. A., Rajesh, R. (2008). Synthesis and pharmacological investigation of novel 4-(2-methylphenyl)-1-substituted-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones as new class of H1-antihistaminic agents. European Journal of Medicinal Chemistry, 43 (11), 2331-2337. doi: 10.1016/j.ejmech.2007.10.001
6. Alagarsamy, V., Kavitha, K., Rupeshkumar, M., Solomon, V., Kumar, J., Kumar, D., Sharma, H. (2009). Synthesis and pharmacological investigation of novel 4-(3-ethylphenyl)-1-substituted-4H-[1,2,4]triazolo[4,3-a] quinazolin-5-ones as a new class of H1-antihistaminic agents. Acta Pharmaceutica, 59 (1). doi: 10.2478/v10007-009-0003-1
7. Alagarsamy, V., Sharma, H. K., Parthiban, P. et. al (2009). 4-(3-Methoxyphenyl)-1-substituted-4H-[1,2,4]triazolo [4,3-a]quinazolin-5-ones: new class of H1-antihistaminic agents. Pharmazie, 64, 5-9.
8. Gobinath, M., Subramanian, N., Alagarsamy, V. (2015). Design, synthesis and H1-antihistaminic activity of novel 1-substituted-4-(3-chlorophenyl)-[1,2,4] triazolo [4,3-a] quinazolin-5(4H)-ones. Journal of Saudi Chemical Society, 19 (3), 282-286. doi: 10.1016/j.jscs.2012.02.006
9. Gobinath, M., Subramanian, N., Alagarsamy, V., Nivedhitha, S., Solomon, V. (2015). Synthesis of 1-Substituted-4-(Pyridin-4-yl) [1,2,4] Triazolo [4,3-a] Quinazolin-5(4H)-ones as a
New Class of H1- Antihistaminic Agents. Tropical Journal of Pharmaceutical Research, 14 (2), 271. doi: 10.4314/tjpr.v14i2.12
10. Abdel Gawad, N. M., Georgey, H. H., Youssef, R. M., El Sayed, N. A. (2010). Design, synthesis, and anticonvulsant activity of novel quinazolinone analogues. Medicinal Chemistry Research, 20 (8), 1280-1286. doi: 10.1007/s00044-010-9465-4
11. Alagarsamy, V., Giridhar, R., Yadav, M., Revathi, R., Ruckmani, K., De Clercq, E. (2006). AntiHIV, antibacterial and antifungal activities of some novel 1,4-disubstituted-1,2,4-triazolo[4,3-a] quinazolin-5(4 h )-ones. Indian Journal of Pharmaceutical Sciences, 68 (4), 532. doi: 10.4103/0250-474x.27840
12. Gobinath, M., Subramanian, N., Alagarsamy, V. (2012). Anticancer and antitubercular study of some 1,4-disubs-titated[1,2,4]-triazolo[4,3-a]quinazolin-5(4#)-ones. International Journal of Research in Pharmaceutical Sciences, 3 (1). 146-149.
13. Gaudilliere, B., Lavalette, R., Andrianjara, C. (2000). Nouvelles 1-aminotriazolo[4,3-a]quinazoline-5-ones inhibitrices de phosphodiesterases IV. Patent France 2792938.
14. Elansary, A. K., Kadry, H. H., Ahmed, E. M., Sonousi, A. S. M. (2011). Design, synthesis and in vitro PDE4 inhibition activity of certain quinazolinone derivatives for treatment of asthma. Medicinal Chemistry Research, 21 (11), 3327-3335. doi: 10.1007/s00044-011-9846-3
15. Danylchenko, S. Yu., Drushlyak, O. G., Kovalen-ko, S. S., Kovalenko, S.M., Maes, L. (2016). [1,2,4]Triazolo[4,3-a]quinazolin-5(4#)-one derivatives as antimalarial agents. Ukrainian biopharmaceutical journal, 1 (42), 78-83.
16. Danilchenko, S. Yu., Drushlyak, O. G., Kovalenko, S. M. (2014). Synthesis of substituted 2-hydrazinoquinazolin-4-ones as intermediates for heterocyclic compounds synthesis. Journal of Organic and Pharmaceutical Chemistry, 12 (3), 66-73.
17. Danylchenko, S. Yu., Drushlyak, O. G., Kovalenko, S. M. (2015). Synthesis, computer prediction of biological activity and acute toxicity of 1-Ar-4-R-[1,2,4]triazolo[4,3-a]quinazolin-5(4#)-ones. Journal of Organic and Pharmaceutical Chemistry, 13/3 (51), 38-45.
18. Danylchenko, S. Yu., Drushlyak, O. G., Kovalenko, S. M., Kovalenko, S. S. (2015). The patent application «The [1,2,4]Triazolo[4,3-a]quinazolin-5(4#)-one derivatives» № u201509803. on 09.10.2015.
19. Saleh, M. A., Abdel-Megeed, M. F., Abdo, M. A., Shkor, A.-B. M. (2003). Synthesis of Aldehydo Sugar (4-oxoquinazolin-2-yl)hydrazones and their transformation into 1-(alditol-1-yl)-1,2,4-triazolo-[4,3-a]quinazolin-5(4H)-ones. Journal of Heterocyclic Chemistry, 40 (1), 85-92. doi: 10.1002/jhet.5570 400111
Дата надходження рукопису 17.03.2016
Danylchenko Svitlana, Scientific Secretary of scientific and research department, National University of Pharmacy, 53 Pushkinska str., Kharkiv, Ukraine, 61002 E-mail: povstenko@gmail.com
Drushlyak Oleksandr, Candidate of chemical sciences, associate professor, Department of Quality Management, National University of Pharmacy, 53 Pushkinska str., Kharkiv, Ukraine, 61002 E-mail: aldry18@hotmail.com
Kovalenko Svitlana, Candidate of chemical sciences, associate professor, Department of Quality Management, National University of Pharmacy, 53 Pushkinska str., Kharkiv, Ukraine, 61002 E-mail: claire82@mail.ru
Kovalenko Sergiy, Doctor of chemical sciences, professor, Department of Organic Chemistry, V. N. Karazin Kharkiv National University, 4 Svobody squ., Kharkiv, Ukraine, 61022 E-mail: kovalenko.sergiy.m@gmail.com
Elliott Alysha, Institute for Molecular Bioscience, The Univercity of Queensland, Brisbane QLD 4072 Australia E-mail: a.elliott@imb.uq.edu.au
Zuegg Johannes, Institute for Molecular Bioscience, The Univercity of Queensland, Brisbane QLD 4072 Australia
E-mail: j.zuegg@imb.uq.edu.au
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