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Вронська Людмила BiKTopiBHa, кандидат х1м1чних наук, доцент, кафедра фармаци, Навчально-науковий шститут шслядипломно! освгги, ДВНЗ «Тернотльський державний медичний ушверситет iMe-m I. Я. Горбачевського МОЗ Укра1ни», майдан Волi, 1, м. Тернотль, Украша, 46001 E-mail: vronska_liudmyla@ukr.net
Грошовий Тарас Андpiйoвич, доктор фармацевтичних наук, професор, завщувач кафедри, кафедра управлшня та економiки фармацii з технолопею лiкiв, ДВНЗ «Тернопiльський державний медичний унь верситет iменi I. Я. Горбачевського МОЗ Укра1ни», майдан Вол^ 1, м. Тернопiль, Укра1на, 46001 E-mail: grochovuy.tern@mail.ru
UDC 547,792:547,856
DOI: 10.15587/2313-8416.2016.65166
THE SYNTHESIS, COMPUTER PREDICTION OF THE BIOLOGICAL ACTIVITY AND THE ACUTE TOXICITY OF
4-ARYL-5-OXO-4,5-DIHYDRO [1,2,4] TRIAZOLO [4,3-a] QUINAZOLINE-8-CARBOXAMIDES © S. Danylchenko, O. Drushlyak, S. Kovalenko, S. Kovalenko
Aim. The aim of present study was to conduct modelling of the virtual library of 4-aryl-5-oxo-4,5-dihyd-ro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides, to determine the most probable biological activity spectrum and the acute toxicity of studied compounds by PASS and GUSAR software, sort out the most perspective substances and develop preparative protocols for their synthesis.
Methods. Using the PASS program computer prediction of the biological activity of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides has been performed. Prediction of the acute toxicity has been carried out by the GUSAR software. The structure of the compounds synthesized has been proven by elemental analysis and 1H NMR spectroscopy data.
Results. The synthesis of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides has been conducted starting from corresponding methyl 3-aryl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxy-lates, which were converted into corresponding 3-aryl-2-hydrazino-4-oxo-3,4-dihydroquinazoline-7-carbohy-drazides by treatment with hydrazine hydrate. Heating of these 2-hydrazinoquinazolin-4(3H)-ones with acety-lacetone was resulted in 4-aryl-8-[(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl]-1-methyl[1,2,4]triazolo[4,3-a]qui-nazolin-5(4H)-ones formation. Following substitution of pyrazole moiety by interaction of these compounds with primary amines led to destinated 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides. The PASS program computer prediction of the biological activity of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides has allowed identifying the types of activity of studied compounds and sorting out the leaders with potential antineurotic activity, which are perspective for male reproductive and erectile dysfunction treatment. Prediction of the acute toxicity has been carried out by the GUSAR software, which allowed to refer them to slightly toxic (class 4) or practically nontoxic (class 5) substances.
Conclusions. The obtained compounds are perspective objects for further investigations as slightly toxic (nontoxic) substances with potential antineurotic activity, which are perspective for male reproductive and erectile dysfunction treatment.
Keywords: synthesis, 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides, computer prediction, biological activity, acute toxicity
Мета. У даному дослiдженнi було поставлено за мету провести моделювання eipmyanbHoi бiблiотеки 4-арил-5-оксо-4,5-дигiдро[l,2,4]триазоло[4,3-a]хiназолiн-8-карбоксамiдiв, за допомогою комп'ютерних програм PASS та GUSAR визначити найбшьш ймовiрний спектр бiологiчноi активностi та гостру ток-сичнкть дослiджуваних сполук, а також видшити найбшьш перспективнi сполуки та розробити препа-ративнi методи ix синтезу.
Методи. Комп'ютерне прогнозування бiологiчноi активностi 4-арил-5-оксо-4,5-дигiдро[1,2,4]триазо-ло[4,3-a]xiназолiн-8-карбоксамiдiв проведено за допомогою програми PASS. Комп'ютерне прогнозування гостро'1' токсичностi здтснено за програмним забезпеченням GUSAR. Будову синтезованих сполук доведено за допомогою елементного аналiзу та даних 1H ЯМР спектроскопа.
Результати. Синтез 4-арuл-5-оксо-4,5-дuгiдро[1,2,4]трuазоло[4,3-a]хiназолiн-8-карбоксамiдiв був проведений виходячи з eidnoeidHux метил 3-арuл-4-оксо-2-тiоксо-1,2,3,4-тетрагiдрохiназолiн-7-кар-6oKcrnamie, як були перетворенi у вiдповiднi 3-арuл-2-гiдразuно-4-оксо-3,4-дuгiдрохiназолiн-7-карбо-гiдразuдu пiд дieю гiдразuн гiдрату. Нагрiвання цих 2-гiдразuнохiназолiн-4(3Н)-онiв в ацетuлацетонi привело до утворення 4-арил-8-[(3,5-диметил-1И-тразол-1чл)карботл]-1-метил[1,2,4]триазоло[4,3-а]хтазолт-5(4И)-отв. Наступне замiщення залишку тразолу при взаемоди цих сполук з первинними амi-нами дало цiльовi 4-арuл-5-оксо-4,5-дuгiдро[1,2,4]трuазоло[4,3-a]хiназолiн-8-карбоксамiдu. Комп'ю-терне прогнозування бiологiчноi актuвностi 4-арuл-5-оксо-4,5-дuгiдро[1,2,4]трuазоло[4,3-a]хiназолiн-8-карбоксамiдiв за допомогою програми PASS дозволило визначити напрямок актuвностi до^джуваних сполук та видшити серед них лiдерiв з потенцтною антиневротичною актuвнiстю, ят можуть бути перспективними для л^вання чоловiчuх репродуктивних захворювань та еректильних дисфункцш. Комп 'ютерне прогнозування гостроi токсuчностi здшснено за програмним забезпеченням GUSAR, що дозволило вiднестu 1'х до малотоксичних (4 клас) або практично нетоксичних речовин (5 клас). Висновки. Отрuманi сполуки е перспективними об 'ектами для подальших до^джень як малотоксuчнi (нетоксична речовини з потенцтною антиневротичною активтстю, як можуть бути перспективними для лiкування чоловiчuх репродуктивних захворювань та еректильних дисфункцш
Ключовi слова: синтез, 4-арuл-5-оксо-4,5-дuгiдро[1,2,4]трuазоло[4,3-a]хiназолiн-8-карбоксамiдu, ком-п'ютерне прогнозування, бiологiчна активнкть, гостра токсичтсть
1. Introduction
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.
2. Formulation of the problem in a general way, the relevance of the theme and its connection with important scientific and practical issues
The possibility to synthesize a large amount of [1,2,4]triazolo[4,3-a]quinazolin-5(4.ff)-one derivatives leads to the necessity for the rational presynthetic selection the most perspective compounds from defined variety. One of the effective ways to solve this problem is computer prediction of various properties of [1,2,4]triazolo[4,3-a]quinazolin-5(4#)-one derivatives, such as biological activity and acute toxicity, that enables to eliminate unpromising substances at the early stages of the research.
3. Analysis of recent studies and publications in which a solution of the problem and which draws on the author
Among potential pharmacologically significant properties of [1,2,4]triazolo[4,3-a]quinazolin-5(4.ff)-one derivatives the H1-antihistaminic [1-9], anticonvulsant [10], antiHIV [11], antibacterial [11-13], antifungal [11, 12], antitubercular [11, 13], anticancer [13], anti-asthmatic [8, 14], antiallergic [14], anti-inflammatory [14, 15] bioactivities should be mentioned. In the previous study [16] we predicted potential antiasthmatic and antiallergic activity of compounds of the specified class.
4. Allocation of unsolved parts of the general problem, which is dedicated to the article
The presence of amide group may have a significant impact on biological behavior of compounds. Investigation of influence of amide moiety on the biological activity of [1,2,4]triazolo[4,3-a]quinazolin-5(4#)-ones is important for expancion of knowledge about pharmacological properties of this class of compounds.
5. Formulation of goals (tasks) of article
Taking into account actuality of searching biological active substances among [1,2,4]triazolo[4,3-a]quina-zolin-5(4#)-one derivatives and modern advances in software for virtual screening the goal of present study was to conduct modelling of the virtual library of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides, to determine the most probable biological activity spectrum and the acute toxicity of studied compounds by PASS and GUSAR software, sort out the most perspective substances and develop preparative protocols for their synthesis.
6. Statement of the basic material of the study (methods and objects) with the justification of the results
For design of the virual library of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides 2 randomization points (aryl substituent in position 4 and different amine residue) and fixed methyl substituent in position 1 of [1,2,4]triazolo[4,3-a]quinazolin-5(4#)-one were chosen.
The synthesis of studied 4-aryl-5-oxo-4,5-dihy-dro[1,2,4]triazolo [4,3-a]quinazoline-8-carboxamides was carried out by scheme, which were based on previously founded the formation of [1,2,4]triazolo[4,3-a]quina-zolin-5(4#)-ones by reaction of 2-hydrazinoquinazolin-4(3#)-ones with acetylacetone (Fig. 1) [17]. Starting methyl 3 -aryl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazo-line-7-carboxylates 1a, b were converted into corresponding 2-hydrazinoquinazolin-4(3#)-ones 2a, b by treatment with hydrazine hydrate according improved method [18]. Heating of hydrazines 2a, b with acetylacetone was resulted in 4-aryl-8-[(3,5-dimethyl-№ pyrazol-1-yl)carbonyl]-1-methyl[1,2,4]triazolo [4,3-a]qui-nazolin-5(4#)-ones 3a, b formation. Following substitution of pyrazole moiety by interaction of compounds 3a, b with primary amines led to destinated amides 4a-l. This way allows obtaining the library of final products in good yields.
O
R1 = Ph, 4-FPh HN ^XX
R2 = /-C5H11, 4-MeBn, 4-MeOBn, Ph(CH2)3, 3-MePh, 3-MeOPh
O )=N
4a-l /
Fig. 1. The synthesis of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides
The general procedure for the synthesis of 3-aryl-2-hydrazino-4-oxo-3,4-dihydroqumazoline-7-car-bohydrazides (2a, b). Add the corresponding methyl 3-aryl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-car-boxylate 1a, b (0.05 mol) to stirred mixture of dioxane (100 ml) and hydrazine hydrate (40 ml). Reflux the obtained emulsion with stirring for 3 h. Separate the lower dioxane layer and dilute it with H2O (200 ml). Filter the precipitate, wash it with /-propanol (100 ml) and recrys-tallize from mixture of DMF (100 ml) and /-propanol (200 ml). Yields, melting points, elemental analysis and 1H NMR data are given in Table 1.
The general procedure for the synthesis of 4-aryl-8-[(3,5-dimethyl-1^-pyrazol-1-yl)carbonyl]-1-met-hyl[1,2,4]triazolo[4,3-a]quinazolin-5(4.ff)-ones (3a, b). Heat the suspension of corresponding 3-aryl-2-hydra-zino-4-oxo-3,4-dihydroquinazoline-7-carbohydrazi-de 2a, b (0.03 mol) in acetylacetone (100 ml) at 100 °C with stirring for 5 hours. After cooling dilute the reaction mixture with /-propanol (300 ml). Filter the precipitate, wash it with /-
propanol (50 ml) and recrystallize from mixture of DMF (50 ml) and /'-propanol (100 ml). Yields, melting points, elemental analysis and 1H NMR data are given in Table 1.
The general procedure for the synthesis of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]qumazolme-8-carboxamides (4a-l). Reflux the solution of corresponding 4-aryl-8-[(3,5-dimethyl-1^-pyrazol-1 -yl)carbo-nyl]-1 -methyl[ 1,2,4]triazolo [4,3-a]quinazolin-5(4^)-one 3a, b (0.002 mol) in anhydrous DMF (10 ml) and corresponding amine (0.003 mol) during 8 hours. After cooling dilute the reaction mixture with H2O (30 ml). Filter the precipitate formed, wash it with /-propanol (10 ml) and recrystallize from mixture of DMF (5 ml) and /-propanol (10 ml). Yields, melting points, elemental analysis and 1H NMR data are given in Table 1.
The structures of obtained compounds 4a-l have been confirmed by the 1H NMR spectroscopy data (Table 1). :H 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.
Table 1
Properties of the compounds 2a, b; 3a, b; 4a-l_
Comp. code R Yield, % M.p., °С Molecular formula, m.m C, % Calc./ found H, % Calc./ found N, % Calc./ found 'H NMR spectral data 5, ppm, J, hz
1 2 3 4 5 6 7 8 9
2a R1=Ph 78 >300 C15HMN6O2 310.31 58.06/ 57.97 4.55/ 4.58 27.08/ 27.13 4.55 br.s, (2H, CONHNH2); 5.70 s, (2H, NHNH2-2); 7.08 t, (J 7.8, 1H, H-4 Ph); 7.33 t, (J 7.8, 2H, H-3,5 Ph); 7.57 dd, (J5 6 7.8, J6 8 2.0, 1H, H-6); 7.75 d, (J6 8 2.0, lH, H-8); 7.88 d, (J 7.8, 2H, 2,6 Ph); 8.00 d, (J5 6 7.8, 1H, H-5); 9.40 s, (1H, NHNH2-2); ' 10.02 s, (1H, CONHNH2)
2b R1= =4-FPh 80 >300 C15H13FN6Ü2 328.30 54.88/ 54.92 3.99/ 4.01 25.60/ 25,57 4.55 br.s, (2H, CONHNH2); 5.70 s, (2H, NHNH2-2); 7.20-7.41 m (4H, H Ar); 7.57 dd, (J5 6 7.8, J6 8 2.0, 1H, H-6); 7.75 d, (J6 8 2.0, 1H, H-8); 8.04 d, (J5 6 7.8, 1H, H-5); 9.40 s, (1H, NHNH2-2); 10.02 s, (1H, CONHNH2)
3a R1=Ph 74 296298 C22H18N6O2 398.42 66.32/ 66.39 4.55/ 4.52 21.09/ 21.16 2.12 s, (3H, CH3 Pyr-3); 2.36 s, (3H, CH3-1); 2.55 s, (3H, CH3 Pyr-5); 6.26 s, (1H, H Pyr-4); 7.52-7.76 m, (6H, H-7, 5H Ph); 8.00 d, (J79 2.0, 1H, H-9); 8.31 d, (1H, J67 7.8, 1H, H-6)
1 2 3 4 5 6 7 8 9
3Ь Ю= =4-ЕРИ 78 303304 С22НПГК6О2 416.41 63.46/ 63.51 4.11/ 4.09 20.18/ 20.22 2.12 8, (3Н, СН3 Руг-3); 2.36 8, (3Н, СН3-1); 2.55 8, (3Н, СН3 Руг-5); 6.26 8, (1Н, Н Руг-4); 7.50 1 . 7.6, 2Н, Н-3,5-Аг); 7.70-7.82 т, (3Н, Н 7, Н-2,6-Аг); 8.04 а, (17,9 2.0, 1Н, Н-9); 8.30 а, (16,7 7.8,' 1Н, Н-6)
4а Ю=РИ К2=г-С5Нц 84 >300 С22Н23К5О2 389.45 67.85/ 67.78 5.95/ 5.99 17.98/ 18.03 0.88 а, . 7.0, 6Н, 2СН3); 1.40 яг, . 7.0, 2Н, ЫНСН2СН2); 1.52-1.72 т, (1Н, СН(СН3)2); 2.36 8, (3Н, СН3-1); 3.25 яг, (I 7.0, 2Н, ЫНСН2СН2); 7.42-7.56 т, (5Н, Н РИ); 7.74 аа, (I 7 7.8, 17 9 2.0, 1Н, Н-7); 8.00 а, (179 2.0, 1Н, Н-9); 8.26 а, (167 7.8, 1Н, Н-6); 8.55 1, (I 7.0, 1Н, СОЫН)
4Ь Ю=РИ К2= =4-МеВп 86 >300 С25Н21К5О2 423.472 70.91/ 70.86 5.00/ 4.97 16.54/ 16.58 2.24 8 (3Н, СН3); 2.36 8, (3Н, СН3-1); 4.40 а (I 7.0, 2Н, СН2); 7.09 а, (I 7.8, 2Н, 3,5 Вп); 7.19 а, (I 7.8, 2Н, 2,6 Вп); 7.58-7.72 т, (5Н, Н РИ); 7.77 аа, (,Т67 7.8, ^ 2.0, 1Н, Н-7); 8.04 а, (,Т79 2.0, 1Н, Н-9); 8.26 а, (,Т67 7.8, 1Н, Н-6); 9.18 1, (I 7.0, 1Н, СОЫН)
4с Ю=РИ =4-МеОВп 85 >300 С25Н21К5О3 439.47 68.33/ 68.39 4.82/ 4.78/ 15.94/ 15.89 2.36 8, (3Н, СН3-1); 3.70 8 (3Н, ОСН3); 4.37 а (I 7.0, 2Н, СН2); 6.85 а, (I 7.8, 2Н, 3,5 Вп); 7.22 а, (I 7.8, 2Н, 2,6 Вп); 7.58-7.72 т, (5Н, Н РИ); 7.77 аа, д67 7.8, ,Т79 2.0, 1Н, Н-7); 8.04 а, (,Т79 2.0, 1Н, Н-9); 8.26 а, д6,7 7.8, 1Н, Н-6); 9.18 1, (I 7.0, 1Н, СОЫН)
4а Ю=РИ К2= =РИ-(СН2)з 75 282284 С26Н23К5О2 437.49 71.36/ 71.40 5.30/ 5.28 16.01/ 15.98 1.80 яп, (I 7.0, 2Н, 2-СН2); 2.36 8, (3Н, СН3-1); 2.59 1, (I 7.0, 2Н, 3-СН2); 3.25 яг, (I 7.0, 2Н, 1-СН2); 7.15-7.30 т, (5Н, Н РИ-3); 7.42-7.56 т, (5Н, Н РИ); 7.74 аа, (•Т67 7.8, ,Т79 2.0, 1Н, Н-7); 8.00 а, д79 2.0, 1Н, Н-9); 8.26 а, (,Т67 7.8, 1Н, Н-6); 8.66 1, (I 7.0, 1Н, СОЫН)
4е Ю=РИ К2=3-МеРИ 74 >300 С^Н^^Ог 409.44 70.40/ 70.35 4.68/ 4.71 17.10 17.05 2.24 8 (3Н, СН3); 2.36 8, (3Н, СН3-1); 6.90 а, (I 7.8, 1Н, Н-4 Аг'); 7.20 1, (I 7.8, 1Н, Н-5 Аг'); 7.60-7.72 т, (7Н, Н РИ, 2,6-Аг'); 7.83 аа, (,Т67 7.8, ,Т79 2.0, 1Н, Н-7); 8.14 а, (,Т79 2.0, 1Н, Н-9); 8.32 а, (,Т6,7 7.8, 1Н, Н-6); 10.28 8, (1Н, СОЫН)
4f Ю=РИ К2= =3-МеОРИ 73 >300 С24Н!9К5О3 425.44 67.76/ 67.80 4.50/ 4.49 16.46/ 16.42 2.36 8, (3Н, СН3-1); 3.70 8 (3Н, ОСН3); 6.60 а, (I 7.8, 1Н, Н-4 Аг'); 7.08-7.22 т, (2Н, Н-5,6-Аг');7.35 8, (1Н, Н-2 Аг'); 7.42-7.56 т, (5Н, Н РИ); 7.74 аа, (I 7 7.8, ,Т79 2.0, 1Н, Н-7); 8.14 а, д79 2.0, 1Н, Н-9); 8.32 а, (I 7 7.8, 1Н, Н-6); 10.10 8, (1Н,' СОЫН)
4ё Ю=4-РРИ К2=г-С5Нц 86 >300 С 2 2Н22-^МзО2 407.44 64.85/ 64.81 5.44/ 5.46 17.19/ 17.22 0.88 а, (I 7.0, 6Н, 2СН3); 1.40 яг, (I 7.0, 2Н, ЫНСН2СН2); 1.52-1.72 т, (1Н, СН(СН3)2); 2.36 8, (3Н, СН3-1); 3.25 яг, (I 7.0, 2Н, ЫНСН2СН2); 7.50 1 (I 7.6, 2Н, Н-3,5-Аг); 7.70-7.82 т, (3Н, Н 7, Н-2,6-Аг); 8.00 а, д79 2.0, 1Н, Н-9); 8.26 а, (,Т67 7.8, 1Н, Н-6); 8.55 1, (I 7.0, 1Н, СОЫН)
4Ь Ю=4-РРИ К2=4-МеВп 85 >300 С25Н20ГК5О2 441.46 68.02/ 67.97 4.57/ 4.60 15.86/ 15.88 2.24 8 (3Н, СН3); 2.36 8, (3Н, СН3-1); 4.40 а (I 7.0, 2Н, СН2); 7.09 а, (I 7.8, 2Н, 3,5 Вп); 7.19 а, (I 7.8, 2Н, 2,6 Вп); 7.50 1 (I 7.6, 2Н, Н-3,5-Аг); 7.70-7.82 т, (3Н, Н 7, Н-2,6-Аг); 8.04 а, (,Т79 2.0, 1Н, Н-9); 8.26 а, (,Т67 7.8, 1Н, Н-6); 9.20 1, (I 7.0, 1Н, СОЫН)
1 2 3 4 5 6 7 8 9
4i R1=4-FPh R2= =4-MeOBn 88 >300 C25H20FN5O3 457.47 65.64/ 65.59 4.41/ 4.39 15.31/ 15.34 2.36 s, (3H, CH3-1); 3.70 s (3H, OCH3); 4.37 d (J 7.0, 2H, CH2); 6.85 d, (J 7.8, 2H, 3,5 Bn); 7.22 d, (J 7.8, 2H, 2,6 Bn); 7.50 t (J 7.6, 2H, H-3,5-Ar); 7.70-7.82 m, (3H, H 7, H-2,6-Ar); 8.03 d, (J79 2.0, 1H, H-9); 8.26 d, (J67 7.8, 1H, H-6); 9.18 t, (J 7.0, ' 1H, CONH)
4j R1=4-FPh R2= =Ph-(CH2)3 77 294296 C26H22FN5O2 455.49 68.56/ 68.52 4.87/ 4.90 15.38/ 15.40 1.80 qn, (J 7.0, 2H, 2-CH2); 2.36 s, (3H, CH3-1); 2.59 t, (J 7.0, 2H, 3-CH2); 3.25 qr, (J 7.0, 2H, 1-CH2); 7.15-7.30 m, (5H, H Ph-3); 7.50 t (J 7.6, 2H, H-3,5-Ar); 7.70-7.82 m, (3H, H 7, H-2,6-Ar); 8.00 d, (J79 2.0, 1H, H-9); 8.26 d, ' (J67 7.8, 1H, H-6); 8.64 t, (J 7.0, 1H, CONH)
4k R1=4-FPh R2=3-MePh 70 >300 C24Hi8FN5O2 427.43 67.44/ 67.39 4.24/ 4.26 16.38/ 16.35 2.24 s (3H, CH3); 2.36 s, (3H, CH3-1); 6.90 d, (J 7.8, 1H, H-4 Ar'); 7.20 t, (J 7.8, 1H, H-5 Ar'); 7.44-7.70 m, (4H, H-3,5-Ar, 2,6-Ar'); 7.70-7.82 m, (3H, H 7, H-2,6-Ar); 8.14 d, (J79 2.0, 1H, H-9); 8.32 d, (J67 7.8, 1H, H-6); 10.30 s,' (1H, CONH)
41 R1=4-FPh R2= =3-MeOPh 72 >300 C24Hi8FN5O3 443.43 65.01/ 64.97 4.09/ 4.11 15.79/ 15.81 2.36 s, (3H, CH3-1); 3.70 s (3H, OCH3); 6.60 d, (J 7.8, 1H, H-4 Ar'); 7.08-7.22 m, (2H, H-5,6-Ar'); 7.35 s, (1H, H-2 Ar'); 7.50 t (J 7.6, 2H, H-3,5-Ar); 7.70-7.82 m, (3H, H 7, H-2,6-Ar); 8.14 d, (J79 2.0, 1H, H-9); 8.32 d, (J67 7.8, 1H, H-6); 10.10 s, (1H, CONH)
Formation of the [1,2,4]triazolo[4,3-a]quinazolin-5(4#)-ones condenced system led to shift of H-6 protons signals to 8.26-8.32 ppm, that is in good correlation with the known data [19]. Melting points were measured with a Buchi B-520 melting point apparatus. Elemental analysis was performed on Euro EA-3000 apparatus. Starting methyl 3 -aryl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-car-boxylates 1a, b have been obtained from commercial producer.
The virtual screening for biological activity of virtual library of studied substances was performed by the PASS Online web-resource, which contains information about structure and biological activity more than 300000 organic compounds [20-22]. Computer prediction of the biological activity spectrum of virtual library of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carbo-xamides 4a-l was performed with probability of demons-ration of specific type of therapeutic action exceeding 50 % (Pa > 0,500).
Analysis of the computer prediction results for the virual library of 4-aryl-5-oxo-4,5-dihydro[1,2,4]tria-zo-
lo[4,3-a]quinazoline-8-carboxamides by PASS software showed the possibility of searching substances possessing potential antineurotic activity, and perspective for male reproductive and erectile disfunction treatment among these compounds and allowed to generate the library of the most perspective compounds 4a-l for further investigations (Table 2). However, the probability of antiasthmatic and antiallergic activity is diminished compared to previously described library of having no amide group compounds [23].
Prediction of acute toxicity of compounds 4a-l for different routes of administration (oral, subcutaneous, intravenous, intraperitoneal) has been carried out by GUSAR software [24, 25]. The training set of program was developed based on SYMYX MDL Toxicity Database, which contains information about acute toxicity more than 10000 chemical structures. Obtained data of acute toxicity of the studied compounds are presented by LD50 value (log 10 (mmol/kg) and mg/kg) and the toxicity class according to the OECD classification project of chemical substance by acute toxicity values [24, 26].
Table 2
Prediction of the biological activity spectrum of
4a 4b 4c 4d 4e 4f
Biological activity H3C^CH3 HN^X^ O SJO Л N я /=» H,C > XX -A «4s0 H3C H3C HN-X^ O AX) XI N N /=» H3C ......°vt O HC
Pa Pi Pa Pi Pa Pi Pa Pi Pa Pi Pa Pi
1 2 3 4 5 6 7 8 9 10 11 12 13
Antineurotic 0.569 0.083 0.534 0.096 0.605 0.070 0.730 0.032 0.306 0.241 0.456 0.131
Erectile dysfunction treatment 0.786 0.003 0.802 0.003 0.774 0.003 0.770 0.004 0.775 0.003 0.748 0.004
Male reproductive disfunction 0.733 0.004 0.746 0.004 0.722 0.004 0.736 0.004 0.742 0.004 0.715 0.004
treatment
Phobic disorders treatment 0.660 0.095 - - - - 0.346 0.279 - - - -
Fibrinogen receptor antagonist 0.533 0.033 0.424 0.073 0.380 0.092 0.499 0.044 - - - -
Tumour necro-
sis factor alpha release 0.493 0.009 0.469 0.009 0.477 0.009 0.456 0.010 0.540 0.007 0.524 0.007
inhibitor
Thiol protease inhibitor 0.451 0.016 - - - - - - - - - -
Anticonvulsant 0.440 0.050 0.345 0.092 - - 0.314 0.112 - - - -
Dysmenorrhea treatment 0.392 0.002 0.445 0.002 0.392 0.002 0.410 0.002 0.480 0.002 0.410 0.002
Antiasthmatic 0.426 0.041 0.567 0.019 0.579 0.018 0.541 0.022 0.611 0.014 0.615 0.014
Interleukin 2 antagonist 0.377 0.004 0.416 0.004 0.361 0.004 0.383 0.004 0.566 0.003 0.488 0.003
Platelet aggregation inhibitor 0.370 0.027 0.388 0.023 0.399 0.021 0.416 0.018 0.434 0.015 0.442 0.014
Antiallergic 0.390 0.056 0.501 0.028 0.528 0.024 0.495 0.029 0.581 0.017 0.591 0.016
HIV attachment inhibitor 0.321 0.034 0.387 0.014 0.375 0.017 0.305 0.042 0.320 0.035 0.315 0.037
Interferon alpha agonist 0.335 0.049 - - - - - - - - - -
CYP2C8 inhibitor 0.382 0.138 - - - - - - 0.312 0.214 - -
Kidney function stimulant - - 0.382 0.182 - - 0.321 0.232 - - - -
Gluconate 2-dehydrogenase (acceptor) inhibitor - - - - 0.398 0.300 - - - - - -
1 2 3 4 5 6 7 8 9 10 11 12 13
CYP2H substrate - - - - 0.360 0.270 - - - - - -
Platelet derived growth factor receptor kinase inhibitor - - - - - - - - 0.480 0.036 0.389 0.079
GABA receptor agonist - - - - - - - - - - - -
Antiinflammat ory - - - - - - - - - - - -
4g 4h 4i 4j 4k 41
Biological activity HN^X^- O / N »r1 O :x!rQr >=n' H,C > O Ä0 >=N H,C HCTp r O й0" N " H C r O XO kx N " hc
Pa Pi Pa Pi Pa Pi Pa Pi Pa Pi Pa Pi
Antineurotic 0.690 0.043 0.662 0.052 0.716 0.036 0.803 0.016 0.419 0.151 0.592 0.074
Erectile dysfunction treatment 0.763 0.004 0.777 0.003 0.751 0.004 0.736 0.004 0.740 0.004 0.713 0.004
Male reproductive disfunction 0.713 0.004 0.726 0.004 0.703 0.004 0.706 0.004 0.710 0.004 0.687 0.004
treatment
Phobic disorders treatment 0.476 0.187 - - - - - - - - - -
Fibrinogen receptor antagonist 0.353 0.106 - - - - - - - - - -
Tumour necro-
sis factor alpha release 0.512 0.008 0.493 0.009 0.497 0.008 0.468 0.010 0.542 0.006 0.527 0.007
inhibitor
Thiol protease inhibitor 0.393 0.024 - - - - 0.316 0.111 - - - -
Anticonvulsant 0.431 0.053 0.338 0.097 - - - - - - - -
Dysmenorrhea treatment 0.375 0.002 0.414 0.002 0.376 0.002 0.385 0.002 0.432 0.002 0.385 0.002
Antiasthmatic 0.409 0.045 0.541 0.022 0.557 0.020 0.510 0.026 0.575 0.018 0.583 0.017
Interleukin 2 antagonist 0.362 0.004 0.392 0.004 0.347 0.004 0.361 0.004 0.522 0.003 0.448 0.003
Platelet aggregation inhibitor 0.332 0.038 0.343 0.034 0.359 0.029 0.369 0.027 0.383 0.024 0.396 0.021
Antiallergic 0.383 0.058 0.487 0.030 0.513 0.026 0.477 0.033 0.554 0.020 0.566 0.019
HIV attachment inhibitor 0.337 0.028 0.397 0.012 0.385 0.014 0.325 0.033 0.339 0.027 0.333 0.029
1 2 3 4 5 6 7 8 9 10 11 12 13
Interferon alpha agonist - - - - - - - - - - - -
CYP2C8 inhibitor 0.331 0.192 - - - - - - - - - -
Kidney function stimulant - - - - - - - - - - - -
Gluconate 2-dehydro-genase (acceptor) inhibitor - - - - - - - - - - - -
CYP2H substrate - - - - - - - - - - - -
Platelet derived growth factor receptor kinase inhibitor - - 0.348 0.112 0.321 0.139 0.345 0.114 0.510 0.028 0.426 0.058
GABA receptor agonist 0.317 0.025 0.313 0.026 - - - - - - - -
Antiinflammat ory - - - - 0.301 0.159 - - 0.306 0.155 0.308 0.153
Results of investigation in silico by GUSAR software gave the possbility to predict acute toxicity values for different routes of administration of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-car-boxamides 4a-l (Table 3). The values LD50 by oral administration were between 511 to 1795 mg/kg, by
7. Conclusions
According to the result of computer prediction of the biological activity spectrum and acute toxicity of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides the selection of slightly toxic or non-toxic substances with the potential antineurotic activ i-
subcutaneous - 1057 to 3045 mg/kg. The values LD50 by intravenous administration were between 94 to 215 mg/kg, and by intraperitoneal - were between 315 to 769 mg/kg. The data obtained indicate that compounds 4a-l are slightly toxic (class 4) or practically nontoxic (class 5) [24, 26].
Table 3
ty, and perspective for male reproductive and erectile dysfunction treatment has been performed.
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The values of acute toxicity of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazohne-8-carboxamides 4a-l [26]
Compound code R LD50, mg/kg
Oral administration Subcutaneous administration Intravenous administration Intraperitoneal administration
4a R1=Ph; R2=/-C5H11 633 1361 94 425
4b R1=Ph; R2=4-MeBn 1795 1798 143 497
4c R1=Ph; R2=4-MeOBn 512 1057 177 654
4d R1=Ph; R2=Ph(CH2)3 998 1469 121 456.
4e R1=Ph; R2=3-MePh 995 1695 210 507
4f R1=Ph; R2=3-MeOPh 970 1840 202 672
4g R1=4-FPh; R2=/-C5H11 693 1393 115 455
4h R1=4-FPh; R2=4-MeBn 1119 1686 216 651
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4j R1=4-FPh; R2=Ph(CH2)3 805 1760 189 316
4k R1=4-FPh; R2=3-MePh 1668 2045 186 769
4l R1=4-FPh; R2=3-MeOPh 589 1763 187 353
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Дата надходженнярукопису 17.02.2016
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 Oleksander, 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 Sergiy, Doctor of chemical sciences, professor, Department of Organic Chemistry, V. N. Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv, Ukraine, 61022 E-mail: kovalenko. sergiy.m@gmail.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
UDC 615.012:615.28]-092.4
DOI: 10.15587/2313-8416.2016.65209
SYNTHESIS OF THE ROW OF NEW FUNCTIONAL DERIVATIVES OF 7-ARYLALKYL -8-HYDRAZINE THEOPHYLLINES
© D. Korobko
Hydrazine functional derivatives are widely used in medical practice as remedies applied for pharmacotherapy of depression, infection diseases, hypertension, diabetes, etc. It is worth mentioning that among obtained 7-R-8-hydrazine derivatives of 1,3-dimethylxantine promising substances have been identified. Due to the fact that literature sources display only results of occasional studies of the reactions between 7-R-8-hydrazine theophyllines and mono- or dicarbonyle substances, the use of other keto reagents for xanthine bicycle at 8th position function-alization will allow to explore synthetic potential of the last one, and with high probability may lead to obtaining original biologically active substances.
Aim. To study types of reaction between 8- hydrazinyl-1,3-dimethyl-7-aryl alkyl-1H-purine-2,6(3H,7H)-diones and a number of carbonyl containing reagents.
Methods. A nucleophilic addition reaction followed by dehydration or ethanol splitting was used, as well as the complex of the modern analysis methods to confirm the structure and individuality of the synthesized substances. Results. Different directions of 8-hydrazinyl-1,3,-dimethyl-7(fenetyl-, 3-phenylpropyl-, 3-phenylalyl)- lH-purine-2,6(3H,7H)-diones chemical transformations in reactions with the appropriate carbonyl containing compounds have been studied experimentally. The structure of synthesized substances was confirmed by chromatog-raphy/mass and 1H NMR spectroscopy.
Conclusion. The group of 7-arylalkyl-8-(3,5-R,R1-pyrazole-1-yl)theophyllines, consisting of two functionally substituted bioactive heterocycles, has been synthesized by reaction between initial substances and selected mono- and dicarbonyl compounds
Keywords: synthesis, 7,8-disubstituted of 1,3-dimethylxantine, hydrazine derivatives, spectral analysis methods
ФунщюнальЫ noxidHi гiдразину набули широкого застосування в медичнш практицi як лiкарськi засоби для фармакокорекцП депресш, iнфекцiйниx уражень, запальних nрoцесiв, гinертензивниx статв, цукро-вого дiабету тощо. Варто зазначити, що серед вже одержаних 7-R-8-гiдразинonoxiдниx 1,3-диметилксантину також iдентифiкoванi перспективы у фармакoлoгiчнoму вiднoшеннi субстанци. Осюльки з лiтератури вiдoмo лише про спорадичн дoслiдження взаемодИ 7-R-8-гiдразинoтеoфiлiнiв з моно- та дикарбонтьними сполуками, використання тших кетовмсних реагентiв з метою функцioналiзацii 8 положення ксантинового бщиклу дозволить не ттьки вивчити синтетичний потен^ал останнього, але може з високою вирoгiднiстю призвести до одержання нових бioлoгiчнo активнихречовин. Мета. До^дити напрямки взаемодИ 8-гiдразинiл-1,3-диметил-7-арилалкiл-1H-nурин-2,6(3H,7H)-дioнiв з рядом карбоншвмкних реагентiв.
Методи. Використано реакцт нуклеофшьного приеднання з наступною дегiдратацiею чи вiдщеnленням етанолу, а також комплекс сучасних спектральних метoдiв анал1зу для тдтвердження структури й iндивiдуальнoстi синтезованих речовин.
Результати. Експериментально встанoвленi oкремi напрямки xiмiчниx перетворень 8^дразитл-1,3-диметил-7-(фенетил-, 3-фетлпротл-, 3-фенiлалiл)-1H-nурин-2,6(3H,7H)-дioнiв в реакцiяx з вiдnoвiдними карботлвмкними сполуками. Структуру синтезованих речовин тдтверджено даними хромато-мас-та 1Н ЯМР-сnектрiв.
Висновки. Ряд 7-арилалюл-8-(3,5^Дгтразол-1-ш)теофШтв, що складаються з двох функцюнально-замщених бioактивниx гетероци^в, синтезоваш шляхом взаемодИ виxiдниx речовин з окремими пред-ставниками моно- та дикарбоншьних сполук
Ключовi слова: синтез, 7,8-дизамiщенi 1,3-диметилксантину, noxiднi гiдразину, сnектральнi методи аналiзу
