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Synthesis, biological activity and molecular modelling studies of tricyclic alkylimidazo-, pyrimido- and diazepinopurinediones.

Drabczyńska A, Karcz T, Szymańska E, Köse M, Müller CE, Paskaleva M, Karolak-Wojciechowska J, Handzlik J, Yuzlenko O, Kieć-Kononowicz K - Purinergic Signal. (2013)

Bottom Line: The best derivative was compound 11, showing 100 % protection at a dose of 100 mg/kg without symptoms of neurotoxicity.In rat tests (p.o.), 9 was characterized by a high protection index (>13.3).AR affinity did not apparently correlate with the antiepileptic potency of the compounds.

View Article: PubMed Central - PubMed

Affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.

ABSTRACT
Syntheses and biological activities of imidazo-, pyrimido- and diazepino[2,1-f]purinediones containing N-alkyl substituents (with straight, branched or unsaturated chains) are described. Tricyclic derivatives were synthesized by the cyclization of 8-bromo-substituted 7-(2-bromoethyl)-, 7-(3-chloropropyl)- or 7-(4-bromobutyl)-theophylline with primary amines under various conditions. Compound 22 with an ethenyl substituent was synthesized by dehydrohalogenation of 9-(2-bromoethyl)-1,3-dimethyltetrahydropyrimido[2,1-f]purinedione. The obtained derivatives (5-35) were initially evaluated for their affinity at rat A1 and A2A adenosine receptors (AR), showing moderate affinity for both adenosine receptor subtypes. The best ligands were diazepinopurinedione 28 (K i = 0.28 μM) with fivefold A2A selectivity and the non-selective A1/A2A AR ligand pyrimidopurinedione 35 (K i A1 = 0.28 μM and K i A2A = 0.30 μM). The compounds were also evaluated for their affinity at human A1, A2A, A2B and A3 ARs. All of the obtained compounds were docked to the A2A AR X-ray structure in complex with the xanthine-based, potent adenosine receptor antagonist-XAC. The likely interactions of imidazo-, pyrimido- and diazepino[2,1-f]purinediones with the residues forming the A2A binding pocket were discussed. Furthermore, the new compounds were tested in vivo as anticonvulsants in maximal electroshock, subcutaneous pentylenetetrazole (ScMet) and TOX tests in mice (i.p.). Pyrimidopurinediones showed anticonvulsant activity mainly in the ScMet test. The best derivative was compound 11, showing 100 % protection at a dose of 100 mg/kg without symptoms of neurotoxicity. Compounds 6, 7, 8 and 14 with short substituents showed neurotoxicity and caused death. In rat tests (p.o.), 9 was characterized by a high protection index (>13.3). AR affinity did not apparently correlate with the antiepileptic potency of the compounds.

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Synthesis of substituted imidazo-, pyrimido- and diazepino[2,1-f]purinediones. Reagents and conditions: i appropriate primary amines, solvent (EtOH, n-PrOH, n-BuOH, DMF or without solvent), reflux; ii aminoethanol, reflux; iii PBr3, CHCl3, reflux; iv KOH, EtOH, reflux
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Fig2: Synthesis of substituted imidazo-, pyrimido- and diazepino[2,1-f]purinediones. Reagents and conditions: i appropriate primary amines, solvent (EtOH, n-PrOH, n-BuOH, DMF or without solvent), reflux; ii aminoethanol, reflux; iii PBr3, CHCl3, reflux; iv KOH, EtOH, reflux

Mentions: The synthesis of tricyclic imidazo-, pyrimido- and diazepinopurinediones (Table 1) was accomplished as shown in Fig. 2. As starting material for 1,3-dimethyl-imidazo[2,1-f]purinediones (33, 34), 7-(2-bromoethyl)-8-bromotheophylline (1) was used, the preparation of which had been described by Caccacae [21]. In our laboratory, a modified procedure was developed using a two-phase catalysis method [16]. The other starting compounds, 7-(3-chloropropyl)-8-bromotheophylline (2) for 1,3-dimethyl-pyrimido[2,1-f]purinediones (5–24) and 7-(4-bromobutyl)-8-bromo-theophylline (3) for 1,3-dimethyl-diazepino[2,1-f]purinediones (25–32), were obtained as previously described [22, 23]. 1,3-Dipropyl-7-(3-chloropropyl)-8-bromoxanthine (4) [16, 17] was used as starting material for the synthesis of pyrimido[2,1-f]purinedione (35). The cyclization reaction with amines possessing straight, branched or unsaturated chains was carried out under various conditions (excess of amine, solvent and different reaction time). The synthesis of compounds 8, 9 and 23 was described previously [24], but their structures had been confirmed only by UV spectra, and pharmacological tests had not been performed. Unsubstituted compounds 5, 25 and 33 were previously synthesized in our group [25, 26] and were now subjected to pharmacological tests to compare them with substituted derivatives. Compound 22 with an ethenyl moiety was obtained by dehydrohalogenation of 9-(2-bromoethyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[2,1-f]purinedione (21) [27] (formed from the appropriate hydroxy ethyl derivative 20 [28]) with ethanolic potassium hydroxide (Fig. 2). The structures of the synthesized compounds were confirmed by UV, IR and 1H NMR spectra: UV spectra showed a bathochromic shift typical for 8-aminoxanthine derivatives with λmax of about 300 nm [29]. The IR absorption bands were typical of xanthine derivatives [30], and in the 1H NMR spectra, the expected chemical shifts were observed. All compounds were purified by recrystallization.Table 1


Synthesis, biological activity and molecular modelling studies of tricyclic alkylimidazo-, pyrimido- and diazepinopurinediones.

Drabczyńska A, Karcz T, Szymańska E, Köse M, Müller CE, Paskaleva M, Karolak-Wojciechowska J, Handzlik J, Yuzlenko O, Kieć-Kononowicz K - Purinergic Signal. (2013)

Synthesis of substituted imidazo-, pyrimido- and diazepino[2,1-f]purinediones. Reagents and conditions: i appropriate primary amines, solvent (EtOH, n-PrOH, n-BuOH, DMF or without solvent), reflux; ii aminoethanol, reflux; iii PBr3, CHCl3, reflux; iv KOH, EtOH, reflux
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3757144&req=5

Fig2: Synthesis of substituted imidazo-, pyrimido- and diazepino[2,1-f]purinediones. Reagents and conditions: i appropriate primary amines, solvent (EtOH, n-PrOH, n-BuOH, DMF or without solvent), reflux; ii aminoethanol, reflux; iii PBr3, CHCl3, reflux; iv KOH, EtOH, reflux
Mentions: The synthesis of tricyclic imidazo-, pyrimido- and diazepinopurinediones (Table 1) was accomplished as shown in Fig. 2. As starting material for 1,3-dimethyl-imidazo[2,1-f]purinediones (33, 34), 7-(2-bromoethyl)-8-bromotheophylline (1) was used, the preparation of which had been described by Caccacae [21]. In our laboratory, a modified procedure was developed using a two-phase catalysis method [16]. The other starting compounds, 7-(3-chloropropyl)-8-bromotheophylline (2) for 1,3-dimethyl-pyrimido[2,1-f]purinediones (5–24) and 7-(4-bromobutyl)-8-bromo-theophylline (3) for 1,3-dimethyl-diazepino[2,1-f]purinediones (25–32), were obtained as previously described [22, 23]. 1,3-Dipropyl-7-(3-chloropropyl)-8-bromoxanthine (4) [16, 17] was used as starting material for the synthesis of pyrimido[2,1-f]purinedione (35). The cyclization reaction with amines possessing straight, branched or unsaturated chains was carried out under various conditions (excess of amine, solvent and different reaction time). The synthesis of compounds 8, 9 and 23 was described previously [24], but their structures had been confirmed only by UV spectra, and pharmacological tests had not been performed. Unsubstituted compounds 5, 25 and 33 were previously synthesized in our group [25, 26] and were now subjected to pharmacological tests to compare them with substituted derivatives. Compound 22 with an ethenyl moiety was obtained by dehydrohalogenation of 9-(2-bromoethyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[2,1-f]purinedione (21) [27] (formed from the appropriate hydroxy ethyl derivative 20 [28]) with ethanolic potassium hydroxide (Fig. 2). The structures of the synthesized compounds were confirmed by UV, IR and 1H NMR spectra: UV spectra showed a bathochromic shift typical for 8-aminoxanthine derivatives with λmax of about 300 nm [29]. The IR absorption bands were typical of xanthine derivatives [30], and in the 1H NMR spectra, the expected chemical shifts were observed. All compounds were purified by recrystallization.Table 1

Bottom Line: The best derivative was compound 11, showing 100 % protection at a dose of 100 mg/kg without symptoms of neurotoxicity.In rat tests (p.o.), 9 was characterized by a high protection index (>13.3).AR affinity did not apparently correlate with the antiepileptic potency of the compounds.

View Article: PubMed Central - PubMed

Affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.

ABSTRACT
Syntheses and biological activities of imidazo-, pyrimido- and diazepino[2,1-f]purinediones containing N-alkyl substituents (with straight, branched or unsaturated chains) are described. Tricyclic derivatives were synthesized by the cyclization of 8-bromo-substituted 7-(2-bromoethyl)-, 7-(3-chloropropyl)- or 7-(4-bromobutyl)-theophylline with primary amines under various conditions. Compound 22 with an ethenyl substituent was synthesized by dehydrohalogenation of 9-(2-bromoethyl)-1,3-dimethyltetrahydropyrimido[2,1-f]purinedione. The obtained derivatives (5-35) were initially evaluated for their affinity at rat A1 and A2A adenosine receptors (AR), showing moderate affinity for both adenosine receptor subtypes. The best ligands were diazepinopurinedione 28 (K i = 0.28 μM) with fivefold A2A selectivity and the non-selective A1/A2A AR ligand pyrimidopurinedione 35 (K i A1 = 0.28 μM and K i A2A = 0.30 μM). The compounds were also evaluated for their affinity at human A1, A2A, A2B and A3 ARs. All of the obtained compounds were docked to the A2A AR X-ray structure in complex with the xanthine-based, potent adenosine receptor antagonist-XAC. The likely interactions of imidazo-, pyrimido- and diazepino[2,1-f]purinediones with the residues forming the A2A binding pocket were discussed. Furthermore, the new compounds were tested in vivo as anticonvulsants in maximal electroshock, subcutaneous pentylenetetrazole (ScMet) and TOX tests in mice (i.p.). Pyrimidopurinediones showed anticonvulsant activity mainly in the ScMet test. The best derivative was compound 11, showing 100 % protection at a dose of 100 mg/kg without symptoms of neurotoxicity. Compounds 6, 7, 8 and 14 with short substituents showed neurotoxicity and caused death. In rat tests (p.o.), 9 was characterized by a high protection index (>13.3). AR affinity did not apparently correlate with the antiepileptic potency of the compounds.

Show MeSH
Related in: MedlinePlus