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•New approaches to polyfluoroalkylated pyrido1,2-apyrimidinones, pyrido2,1-bquinazolinones and bis-cyclohexenones were developed.•One-pot method based on commercially available ...reagents.•Reactions are carried out under mild conditions•Some synthesized heterocycles showed moderate antiviral activity.
A one-pot three-component reactions between polyfluoroalkylated 3-oxo esters and methyl ketones with 1,3-diaminopropane result in 8-hydroxy-9a-alkyl(phenyl)-8-(polyfluoroalkyl)octahydro-6H-pyrido1,2-apyrimidin-6-ones, whereas a similar reaction with 1,4-diaminobutane forms a salt with trifluoroacetoacetic ester. In a two-component reaction, diamines with a long aliphatic chain (1,4-diaminobutane, 1,6-diaminohexane and 1,8-diaminooctane) react with an aldol derived from trifluoroacetoacetic ester and acetone, to give bis-cyclohexenones having an aliphatic linker. Using 2-(aminomethyl)aniline in a three-component reaction with polyfluoroalkyl-3-oxo esters leads to new 7-hydroxy-5a-alkyl(phenyl)-7-(polyfluoroalkyl)-5a,6,7,8-tetrahydro-5H-pyrido2,1-bquinazolin-9(11H)-ones. Regioisomeric and spatial structures of new heterocycles were studied, and the mechanism of their formation was proposed. Some synthesized heterocycles were found to have moderate antiviral activity against influenza A/Puerto Rico/8/34 (H1N1) and Coxsackie B3 viruses.
A procedure has been developed for the synthesis of
cis
- and
trans
-diastereoisomeric partially hydrogenated pyrido1,2-
a
pyrimidines and pyrido2,1-
b
quinazolines by the four-component cyclization ...of ethyl trifluoroacetoacetate with two acetaldehyde molecules and propane-1,3-diamine or 2-(aminomethyl)aniline. The reactions are accompanied by side formation of zwitterionic tetrahydropyrimidinium carboxylate in the reaction with propane-1,3-diamine and of 7-hydroxy-7-(trifluoromethyl)-5,5a,6,7,8,11-hexahydro-9
H
-pyrido2,1-
b
quinazolin-9-one in the reaction with 2-(aminomethyl)aniline; in the latter case, the cyclization involved one acetaldehyde molecule. The stereochemical structure of the synthesized compounds was determined by
1
H,
19
F, and
13
C NMR spectroscopy and X-ray analysis. A probable mechanism has been proposed for the formation of new hetero-fused pyridine derivatives.
Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety ...drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. Objective: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. Methods: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. Results: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of “open field” and “elevated plus maze” (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of “forced swimming” (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABAA receptor with a value of the scoring function that estimates free energy of binding (ΔG) at −7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT1A receptor. Conclusions: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.
The present review provides a study on the structural features, reactions, and synthetic methodologies of pyrido1,2-
a
pyrimidines. Thus, the synthetic procedures and organic reactions since 2000 are ...described. The aim of this review is to give an overview of the diverse methodologies that have been reported on the chemistry of pyrido1,2-
a
pyrimidines. The tautomeric forms of 2-methyl-3-chloro-9-hydroxypyrido1,2-
a
pyrimidin-4-one are discussed, as well as, the biological importance and mechanistic pathways.
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Hydrogenation (3atm) of readily available pyrido1,2-apyrimidines 10, 14, and 17 over 5% Rh/Al2O3 forms 1,5-diazabicyclo4.4.0dec-5-enes 9, 15, and 18 in >95% yield, providing a general ...route to this little-studied class of compounds. All attempts to form the tetrahydro-1,2,4-triazine moiety of cinachyramine (1) by rearrangement of amidinium dimethylhydrazone 8 using the procedures developed by Kamatori to convert hydrazone 3a to tetrahydro-1,2,4-triazine 4a were unsuccessful.
Data on the main types of biological activity of condensed pyridine derivatives with a bridgehead nitrogen atom, including the structures of the most promising molecules and the current stage of ...their study, are reviewed. The effect of substituents on the biological properties of the considered azaheterocycles is discussed in each section. Most of the studies are devoted to searches for promising drugs in the treatment of socially significant bacterial, viral, and malignant neoplastic diseases.
A new series of 4-oxo-4
H
-pyrido1,2-
a
pyrimidine derivatives containing 1,3,4-oxadiazole and 1,3,4-thiadiazole rings as a part of the metal chelation motif were synthesized and evaluated for their ...in vitro anti-HIV-1 activity. Most of the tested compounds displayed moderate inhibitory properties against HIV-1 virus (NL4-3) in Hela cell cultures. Compounds
11e
and
11b
exhibited the highest activity among the synthesized compounds with inhibition rate of 51 and 48 % at concentration of 100 μM, respectively. Molecular docking study using the later crystallographic data available for PFV integrase (IN) showed that the designed compounds bind into the active site of IN such that the keto oxygen atom at position of C-4 and nitrogen atom of thiadiazole or oxadiazole ring moiety chelate the Mg
2+
ion. Our results also showed that all tested compounds presented no significant cytotoxicity at concentration of 100 μM. Therefore, these compounds can provide a very good basis for the development of new hits.
An expeditious metal-free heteroannulation reaction for pyrido1,2-
a
pyrimidines/imidazo1,2-
a
pyridines was developed in green solvent under mild reaction conditions by using three-component ...reaction of 2-chloroquinoline-3-carbaldehyde, malononitrile and nitroketen aminals, which obtained from the reaction between 1,1-
bis
(methylthio)-2-nitroethylene and diamines in green solvent under EtOH reflux conditions. This one-pot strategy is very simple and occurs in two steps. The present sequence is visualized as an environmentally benign process with excellent purity and high yields.
Graphic abstract
An efficient, useful and general procedure for the synthesis of pyrido1,2-
a
pyrimidines/imidazo1,2-
a
pyridines via a one-pot three-component reaction of 2-chloroquinoline-3-carbaldehyde, malononitrile/ethyl 2-cyanoacetate and nitroketen aminals under mild and catalyst-free conditions in excellent yields is described. The major advantages of this protocol are high yields, mild and catalyst-free conditions, short reaction times and application of green solvent.
An environmentally friendly and effective method to construct 4H-pyrido1,2-apyrimidin-4-one, which are ubiquitous structural units in a number of biologically active compounds has been developed. In ...this process, the reaction using water as the solvent in absence of catalyst under the mild conditions makes transformations very green, practical, and attractive.
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