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New polycyclic heterocycles were synthesised and evaluated as potential inhibitors of thymidine phosphorylase (TP). Inspired by the pharmacophoric pyrimidinedione core of the natural substrate, four series have been designed in order to interact with large empty pockets of the active site: pyrimidoquinoline-2,4-diones (series A), pyrimidinedione linked to a pyrroloquinoline-1,3-diones (series B and C), the polycyclic heterocycle has been replaced by a pyrimidopyridopyrrolidinetetraone (series D). In each series, the tricyclic nitrogen heterocyclic moiety has been synthesised by a one-pot multicomponent reaction. Compared to 7-DX used as control, 2d, 2l, 2p (series A), 28a (series D), and the open intermediate 30 showed modest to good activities. A kinetic study confirmed that the most active compounds 2d, 2p are competitive inhibitors. Molecular docking analysis confirmed the interaction of these new compounds at the active binding site of TP and highlighted a plausible specific interaction in a pocket that had not yet been explored.

Novel (E) -3-(dimethylamino)-1-(quinolin-3-yl)prop-2-en-1-one and (E) -3-(dimethylamino)-1-(quinolin-3-yl)but-2-en-1-one (2) were synthesized in excellent yields by reacting 3-acetylquinoline with DMF-DMA and DMA-DMA respectively. Subsequently, 2 were used as the precursors for the synthesis of 3-(pyrazolo[1,5- a ]pyrimidin-7-yl)quinolines and 3-(5-methylpyrazolo[1,5- a ]pyrimidin-7-yl)quinolines ( 4 ). All the synthesized compounds were subjected to structure elucidation and evaluated for their antiparasitic potential with special reference to their anti-malarial properties. The in-vitro studies of the synthesized compounds revealed moderate anti-malarial efficacy for compounds 4b , 4c , 4d , 4k , 4l and 4m . Compounds 4g and 4i showed highest activity displaying IC 50 values of 2.10 and 2.77  μ M, respectively, for the chloroquine-sensitive strain of P . falciparum, and 4.26 and 2.87  μ M, respectively, for the chloroquine-resistant strain. The in-vitro cytotoxicity of the compounds showed CC 50 as >500  µ M and thus, found to be safe. Molecular docking of the novel series of ligand 4a – 4n against the target protein P. falciparum Pf LDH enzyme target (PDB ID 1LDG) revealed good binding energies ranging from –8.06 to –11.02 kcal/mol with low inhibition constants summed up as 1.04, 473.55, 352.51, 290.9, 437.86, 1.23, 41.18, 26.81, 162.76, 300.38, 70.2, 29.84, 4.14, 8.4  µ M, respectively. The lower the inhibition constant ( µ M), the greater is the binding affinity and lower the medication required to inhibit the activity of the target receptor. Graphical abstract (E) -3-(dimethylamino)-1-(quinolin-3-yl)but-2-en-1-one with 3-aminopyrazole under ultrasonic irradiation in aqueous medium yielded novel 3-(pyrazolo[1,5- a ]pyrimidin-7-yl)quinolines and 3-(5-methylpyrazolo[1,5- a ]pyrimidin-7-yl)quinolines. Antimalarial studies against Pf 3D7 strain resulted in moderate activity with compound 4g showing highest activity. Molecular docking analysis of the compounds reveals the potentiality of the series to serve as antimalarial agents against CQ-sensitive ( Pf 3D7) and multi-drug-resistant ( Pf K1).

To answer the still unresolved question of the possible leukemogenic effects of extremely low frequency magnetic fields (ELF-MFs) and of their harmonics on the incidence of B acute lymphoblastic leukemia in children, we used an animal model to explore the possible co-initiating or co-promoting effects of ELF-MFs on the development of leukemia. We used a rat model in which B acute lymphoblastic leukemia is chemically induced by a nitrosurea derivative. From the onset of the chemical treatment, the animals were also exposed to ELF-MFs (100 μT, sinusoidal 50 Hz MFs), with or without harmonics. The experiment was conducted on 280 rats. We compared body weight and survival time, percentage of bone marrow blast cells, cumulative incidence of leukemia and type of leukemia in the unexposed groups and in the groups exposed to 50 Hz MFs, with and without harmonics. The results showed no significant differences between exposed and unexposed rats for any of these parameters (p > 0.05). Significant changes in the leukemia type obtained after γ-irradiation of the leukemia model, showed its sensitivity to a physical agent. Our results do not support the hypothesis that ELF-MFs, with or without harmonics, affect the development of B acute lymphoblastic leukemia in children.

An environmentally benign, simple, efficient, and convenient route is described for the synthesis of novel pyrazolo[1,5-a]pyrimidine derivatives under ultrasound irradiation. Condensation of aminopyrazole 5 with formylated active proton compounds (6, 8, E-G, 12, and 15) furnished pyrazolopyrimidine (7, 9, 10, 13, and 16) in high-to-excellent yields. In comparison with conventional methods, ultrasound irradiation offers several advantages, such as shorter reaction time, higher yields, milder conditions, and environmental friendliness. The reaction is clean with excellent yields and reduces the use of solvents. X-ray crystallographic study of compound 7c confirmed the regioselectivity of the reaction. The antibacterial profile of the newly synthesized compounds was evaluated by cup and saucer method.

An environmentally benign, simple, efficient, and convenient route is described for the synthesis of novel pyrazolo[1,5-a]pyrimidine derivatives under ultrasound irradiation. Condensation of aminopyrazole 5 with formylated active proton compounds (6, 8, E-G, 12, and 15) furnished pyrazolopyrimidine (7, 9, 10, 13, and 16) in high-to-excellent yields. In comparison with conventional methods, ultrasound irradiation offers several advantages, such as shorter reaction time, higher yields, milder conditions, and environmental friendliness. The reaction is clean with excellent yields and reduces the use of solvents. X-ray crystallographic study of compound 7c confirmed the regioselectivity of the reaction. The antibacterial profile of the newly synthesized compounds was evaluated by cup and saucer method.

An environmentally benign, simple, efficient, and convenient route is described for the synthesis of novel pyrazolo[1,5- a ]pyrimidine derivatives under ultrasound irradiation. Condensation of aminopyrazole 5 with formylated active proton compounds ( 6 , 8 , E–G , 12 , and 15 ) furnished pyrazolopyrimidine ( 7 ,  9 ,  10 , 13 , and 16 ) in high-to-excellent yields. In comparison with conventional methods, ultrasound irradiation offers several advantages, such as shorter reaction time, higher yields, milder conditions, and environmental friendliness. The reaction is clean with excellent yields and reduces the use of solvents. X-ray crystallographic study of compound 7c confirmed the regioselectivity of the reaction. The antibacterial profile of the newly synthesized compounds was evaluated by cup and saucer method.

An environmentally benign, simple, efficient, and convenient route is described for the synthesis of novel pyrazolo[1,5-a]pyrimidine derivatives under ultrasound irradiation. Condensation of aminopyrazole 5 with formylated active proton compounds (6, 8, E-G, 12, and 15) furnished pyrazolopyrimidine (7, 9, 10, 13, and 16) in high-to-excellent yields. In comparison with conventional methods, ultrasound irradiation offers several advantages, such as shorter reaction time, higher yields, milder conditions, and environmental friendliness. The reaction is clean with excellent yields and reduces the use of solvents. X-ray crystallographic study of compound 7c confirmed the regioselectivity of the reaction. The antibacterial profile of the newly synthesized compounds was evaluated by cup and saucer method.An environmentally benign, simple, efficient, and convenient route is described for the synthesis of novel pyrazolo[1,5-a]pyrimidine derivatives under ultrasound irradiation. Condensation of aminopyrazole 5 with formylated active proton compounds (6, 8, E-G, 12, and 15) furnished pyrazolopyrimidine (7, 9, 10, 13, and 16) in high-to-excellent yields. In comparison with conventional methods, ultrasound irradiation offers several advantages, such as shorter reaction time, higher yields, milder conditions, and environmental friendliness. The reaction is clean with excellent yields and reduces the use of solvents. X-ray crystallographic study of compound 7c confirmed the regioselectivity of the reaction. The antibacterial profile of the newly synthesized compounds was evaluated by cup and saucer method.

Functionalized pyrimido[4,5-b]quinoline-2,4 (1H,3H)-diones were synthesized by a three-component one-pot reaction involving barbituric acid, aldehydes, and anilines. The use of commercially available anilines allowed the facile syntheses of pyrimido[4,5-b]quinolinediones substituted in all the positions on the benzene ring with electron donor or electron withdrawing groups. This straightforward method circumvents the preparation of unstable substituted 2-aminobenzaldehydes that limits the scope of previously described syntheses. Furthermore, access to the 5-substituted derivatives is now also possible starting from aliphatic or aromatic aldehydes. Our strategy and methodology offer significant and practical improvements over other methodologies.

Functionalized pyrimido[4,5-b]quinoline-2,4 (1H,3H)-diones were synthesized by a three-component one-pot reaction involving barbituric acid, aldehydes, and anilines. The use of commercially available anilines allowed the facile syntheses of pyrimido[4,5-b]quinolinediones substituted in all the positions on the benzene ring with electron donor or electron withdrawing groups. This straightforward method circumvents the preparation of unstable substituted 2-aminobenzaldehydes that limits the scope of previously described syntheses. Furthermore, access to the 5-substituted derivatives is now also possible starting from aliphatic or aromatic aldehydes. Our strategy and methodology offer significant and practical improvements over other methodologies.Functionalized pyrimido[4,5-b]quinoline-2,4 (1H,3H)-diones were synthesized by a three-component one-pot reaction involving barbituric acid, aldehydes, and anilines. The use of commercially available anilines allowed the facile syntheses of pyrimido[4,5-b]quinolinediones substituted in all the positions on the benzene ring with electron donor or electron withdrawing groups. This straightforward method circumvents the preparation of unstable substituted 2-aminobenzaldehydes that limits the scope of previously described syntheses. Furthermore, access to the 5-substituted derivatives is now also possible starting from aliphatic or aromatic aldehydes. Our strategy and methodology offer significant and practical improvements over other methodologies.

To answer the still unresolved question of the possible leukemogenic effects of extremely low frequency magnetic fields (ELF-MFs) and of their harmonics on the incidence of B acute lymphoblastic leukemia in children, we used an animal model to explore the possible co-initiating or co-promoting effects of ELF-MFs on the development of leukemia. We used a rat model in which B acute lymphoblastic leukemia is chemically induced by a nitrosurea derivative. From the onset of the chemical treatment, the animals were also exposed to ELF-MFs (100μT, sinusoidal 50 Hz MFs), with or without harmonics. The experiment was conducted on 280 rats. We compared body weight and survival time, percentage of bone marrow blast cells, cumulative incidence of leukemia and type of leukemia in the unexposed groups and in the groups exposed to 50 Hz MFs, with and without harmonics. The results showed no significant differences between exposed and unexposed rats for any of these parameters (p＞0.05). Significant changes in the leukemia type obtained after γ-irradiation of the leukemia model, showed its sensitivity to a physical agent. Our results do not support the hypothesis that ELF-MFs, with or without harmonics, affect the development of B acute lymphoblastic leukemia in children.