Synthesis, Structure, and Biological Activity of Novel Bispidine Derivatives (original) (raw)
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1-Carbethoxy-2,4,6,8-tetraaryl-3,7-diazabicyclo[3.3.1] nonan-9-ones (1, 2) were synthesized and their 1 H and 13 C NMR data are reported. Chemical shifts and spectral assignments for 2,4,6,8-tetrakis(4-chlorophenyl)-3,7diazabicyclo[3.3.1]nonan-9-one (3), 2,4,6,8-tetraphenyl-3-thia-7-azabicyclo[3.3.1]nonan-9-one (4) and 2,4,6,8tetraaryl-3,7-diazabicyclo[3.3.1]nonanes (5-7) are also included.
Bioorganic & Medicinal Chemistry, 2010
Seven new 1,3-diazepinium chlorides exhibiting some structural similarities to the 1,4-benzodiazepines were synthesized. In a Hippocratic screen using mice, three of these salts, 3-methoxy-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8a), 3-methoxy-9-methyl-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8c) and 3-methoxy-11methyl-6-oxo-7,13-dihydro-6H-benzofuro[2,3-e]pyrido[1,2-a][1,3]diazepin-12-ium chloride (8e) were examined for their effect on the central nervous system, and their activities compared to that of diazepam. On their own, salts 8a, 8c and 8e solicited no sedative effects on the behaviour of the animals. However, they elicited significant effects in combination with diazepam on diazepam-induced activities such as decreased motor activity, ataxia and loss of righting reflex. Compounds 8a and 8c were fitted into the pharmacophore/receptor model developed by Cook et al. with interaction at the L 1 , H 1 and A 2 sites indicating that they are potential inverse agonists of the Bz receptor. The compounds displayed some affinity for the a1 isoform of the GABA A /BzR (L Di interaction) but are non-selective for a5 (no L 2 interaction). Results of binding affinity studies showed that compound 8a is mildly selective for the a1 receptor although not very potent (K i = 746.5 nM). The significant potentiation of diazepam-induced ataxia and decreased motor activity by compounds 8a and 8c in the Hippocratic screen may be associated with a1 selectivity.
European Journal of Medicinal Chemistry, 2011
Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by cyclization of 7-halogenoalkyl-8-bromo-1,3-dimethylxanthine derivatives with aminocycloalkanes. The obtained compounds (1–33) were evaluated for their affinity to rat adenosine A1 and A2A receptors. Selected compounds were additionally investigated for affinity to the human A1, A2A, A2B and A3 receptor subtypes. The results of the radioligand binding assays at adenosine A1 and A2A receptors showed that most of the compounds exhibited adenosine A2A receptor affinity at micromolar or submicromolar concentrations; an annelated pyrimidine ring was beneficial for A2A affinity. The most potent A2A ligands of the present series were compounds 6 (Ki 0.33 μM rat A2A, 0.31 μM human A2A), 8 (Ki 0.98 μM rat A2A, 0.42 μM human A2A) and 15 (Ki 0.24 μM rat A2A, 0.61 μM human A2A) with the latter one showing high A2A selectivity. In NaCl shift assay, 15 was shown to be an antagonist at A2A receptors. This result was confirmed for the best compounds 6, 8, 15 in cAMP accumulation studies. A 3D-QSAR equation with a good predicting power (q2 = 0.88) for A2A AR affinity was obtained. The compounds were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (i.p.). Most of them showed anticonvulsant activity in chemically induced seizures; among them the diazepinopurinediones were the best (e.g. 31) showing protection in both tests on short time symptoms, without signs of neurotoxicity. Five compounds, 8, 17, 20, 29, and 31, exhibited anticonvulsant activity after peroral application in rats. Structure–activity relationships are discussed including the analysis of lipophilic and spatial properties. The new compounds, which contain a basic nitrogen atom and can therefore be protonated, may be good starting points for obtaining A2A antagonists with good water-solubility.Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones are described. Most compounds exhibited adenosine A2A receptor (A2A AR) affinity at micromolar or submicromolar concentrations and showed anticonvulsant activity in chemically induced seizures without signs of neurotoxicity. A QSAR equation with a good predicting power for A2A AR affinity was obtained.► Novel cycloalkylimidazo-, pyrimido- and diazepinopurinediones (1–33) were obtained. ► Adenosine A1, A2A R affinities were evaluated in binding studies on rat brain tissues. ► Selected compounds were tested for their affinity to human A1, A2A, A2B and A3 R. ► Anticonvulsant activity (MES, scMet) was evaluated. ► QSAR analysis was performed.
Synthesis, antileukemic and antiplatelet activities of 2,3-diaryl-6,7-dihydro-5H-1,4-diazepines
European Journal of Medicinal Chemistry, 2008
The synthesis, antileukemic and antiplatelet activity evaluation of 2,3-diaryl-6,7-dihydro-5H-1,4-diazepines are described. In general, it was found that compound 17o showed moderate antileukemic activity against MOLT3 human leukemic cancer cell lines. An arachidonic acid induced platelet aggregation effect on washed rat platelets was studied. Compound 17i was found to be the most potent. The antiplatelet properties may be mediated by interference with the arachidonic acid pathway.
Journal of Medicinal Chemistry, 2000
A series of 4-(methylsulfonyl)aniline derivatives were synthesized in order to obtain new compounds as a potential anti-inflammatory agents with expected selectivity against COX-2 enzyme. In vivo acute anti-inflammatory activity of the final compounds 11-14 was evaluated in rat using an egg-white induced edema model of inflammation in a dose equivalent to 3 mg/Kg of diclofenac sodium. All tested compounds produced significant reduction of paw edema with respect to the effect of propylene glycol 50% v/v (control group). Moreover, the activity of compounds 11 and 14 was significantly higher than that of diclofenac sodium (at 3 mg/Kg) in the 120-300 minute time interval, while compound 12 expressed a comparable effect to that of diclofenac sodium in the 60-240 minute time interval time, and compound 13 showed a comparable effect to that of diclofenac sodium at all experimental times. The result of this study indicates that the incorporation of the 4-(methylsulfonyl)aniline pharamacophore into naproxen, indomethacine, diclofenac and mefanamic acid maintained their anti-inflammatory activity and may increase selectivity towards the COX-2 enzyme which will be confirmed in the future by assessing COX-2: COX-1 inhibitory ratios using a whole blood assay.
Journal of Combinatorial Chemistry, 2004
The design and synthesis of a library of novel families of 3-oxopiperazinium and perhydro-3-oxo-1,4diazepinium derivatives is reported. The library was composed of 44 3-oxopiperazinium derivatives (11 of these compounds had a spiranic skeleton) and 22 perhydro-3-oxo-1,4-diazepinium compounds. The synthetic procedure involved a 6-step sequence carried out in solution, along with the use of solid-phase linked scavengers and microwave activation for the rapid removal of the excess of amine reagents. A final cyclization step performed under mild conditions led to the charged heterocyclic moiety. Screening of this library in two biological assays identified active compounds that inhibit the activity of the vanilloid receptor TRPV1 and modulators of the multidrug resistance phenomenon. Thus, this synthetic sequence represents a facile and convenient entry to unprecedented libraries of this sort of tetraalkylammonium derivatives that may be of use for identification of novel scaffolds of diverse biological activity.