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A simple, efficient and highly regioselective method for the preparation of 3,4- and 4,5-disubstituted N-methylpyrazoles in a one-pot procedure is reported. The methodology developed was based on the regiochemical control of the reaction of 4-acyl-1H-pyrrole-2,3-diones and methylhydrazine with an influence of the addition or absence of acid and the substrate structure.

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Trypanosoma cruzi and Leishmania species are causative agents of Chagas disease and Leishmaniasis, respectively, known as Neglected Tropical Diseases. Up to now, the treatments are inadequate and based on old drugs. Thus, we report herein the discovery of 1,3,4,5-tetrasubstituted pyrazole derivatives that presented potent and selective inhibition against promastigote forms of L. amazonensis, and epimastigote forms of T. cruzi. The structure-activity relationship led to the identification of three compounds (2m, 2n and 2p) with an in vitro IC50 of 7.4 µM (selective index - SI ≥ 133.0), 3.8 µM (SI in the range of 148.4 to 200.8), and 7.3 µM (SI in the range of 87.2 to 122.4) against L. amazonensis, respectively. Also, those compounds exhibited in vitro IC50 of 9.7 µM (SI ≥ 101.5), 4.5 µM (SI in the range of 125.3 to 169.6) and 17.1 µM (SI in the range of 37.2 to 52.2) against T. cruzi, respectively. A preliminary study about the reaction mechanism in promastigotes showed that 2n caused an increase of the production of ROS and of lipid storage bodies. Furthermore, 2n induced abnormalities in the flagellum that may have an impact on the parasite motility.

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In this article, a series of 29 new pyrimidine N-acylhydrazone hybrids were synthesized and evaluated in vitro against Leishmania amazonensis and Trypanosoma cruzi protozoa that cause the neglected diseases cutaneous leishmaniasis and Chagas disease, respectively. Eight of the target compounds showed significant antiprotozoal activities with IC50 values in 4.3-33.6 µM range. The more active compound 4f exhibited selectivity index greater than 15 and drug-like properties based on Lipinski's rule.

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A new one-pot two-step sequential methodology for synthesis of novel 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives is reported. One-pot transformation of ß-enamino diketones and arylhydrazines generated 4-iminium-N-arylpyrazole salt intermediates in situ, which were easily transformed into 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives by NaBH3CN. The products could be isolated in the free or hydrochloride salt forms. Also, it was possible to obtain the products in the zwitterionic form by ester group hydrolysis. Furthermore, all synthesised compounds were evaluated in vitro against a panel of eight human tumor cell lines. The 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives were much more powerful than the hydrochloride and zwitterionic forms. Moreover, the results suggest that the N-aryl group at the pyrazole ring is vital for modulating antiproliferative activity. The 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-phenylpyrazoles 3a-g exhibited higher inhibitory activities against OVCAR-3, with GI50 values of 0.013-8.78 µM, and lower inhibitory activities against normal human cell lines. Molecular docking was performed to evaluate the probable binding mode of 3a into active site of CDK2.

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An efficient one-pot method is described for the highly regioselective synthesis of α-ketoamide N-arylpyrazoles from secondary ß-enamino diketones. For this, the key intermediate, 4-acyl 3,5-dihydroxypyrrolone, was generated in situ and underwent bimolecular nucleophilic substitution at C-5 by arylhydrazine, with subsequent heterocyclization at the carbonyl carbon of the acyl group. This strategy allowed for regiochemical control of α-ketoamide N-arylpyrazoles from ß-enamino diketones and arylhydrazines.

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An alternative highly regioselective synthetic method for the preparation of 3,5-disubstituted 4-formyl-N-arylpyrazoles in a one-pot procedure is reported. The methodology developed was based on the regiochemical control of the cyclocondensation reaction of ß-enamino diketones with arylhydrazines. Structural modifications in the ß-enamino diketone system allied to the Lewis acid carbonyl activator BF3 were strategically employed for this control. Also a one-pot method for the preparation of 3,5-disubstituted 4-hydroxymethyl-N-arylpyrazole derivatives from the ß-enamino diketone and arylhydrazine substrates is described.

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[Hmim][HSO4] ionic liquid (IL) and bio-renewable sources as chitosan (CHT) and chondroitin sulfate (CS) were used to yield hydrogel-based materials (CHT/CS). The use of IL to solubilize both polysaccharides was considered an innovative way based on "green chemistry" principle, aiming the production of CHT/CS blended systems. CHT/CS hydrogels were carried out in homogeneous medium from short dissolution times. The hydrogels were characterized and achieved with excellent stabilities (in the 1.2-10pH range), larger swelling capacities, as well as devoid of cytotoxicity towards the normal VERO and diseased HT29 cells. The CHT/CS hydrogels carried out in [Hmim][HSO4] could be applied in many technological purposes, like medical, pharmaceutical, and environmental fields.

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