Controlled Pyrazole-Hydrazone Annulation: Regiodivergent Synthesis of 1H- and 2H-Pyrazolo[3,4-d]pyridazinones.

An efficient and controlled site-selective annulation of 3,5-diethoxycarbonyl 4-hydrazonyl pyrazoles is described. The relative proportion of the products is affected by hydrazone intermediate configuration, reaction temperature, and Lewis acid employed. At a temperature of 110-120 °C, the reaction preferentially afforded 1H-pyrazolo[3,4-d]pyridazin-7(6H)-ones, whereas using Yb(OTf)3 in MeCN reflux, 2H-pyrazolo[3,4-d]pyridazin-7(6H)-ones were favored. Computational investigations were performed to clarify the mechanism and the origin of the regiodivergence.

Synthesis and Antiprotozoal Profile of 3,4,5-Trisubstituted Isoxazoles.

Invited for this month's cover picture is the group of Prof. Fernanda Andreia Rosa at the State University of Maringá (Brazil). The cover picture shows the contribution of the SINTHET research group to the synthesis and discovery of new antiprotozoal compounds. The synthetic methodology allowed the construction of 60 new isoxazole derivatives with structural variations on the 3-, 4-, and 5-positions. The authors acknowledge Ms. Jeniffer do Nascimento Ascencio Camargo and Ms. Julia Caroline Manzano Willig for the Cover picture creation. Read the full text of their Full Paper at 10.1002/open.202100141.

Synthesis and Antiprotozoal Profile of 3,4,5-Trisubstituted Isoxazoles.

A series of 60 4-aminomethyl 5-aryl-3-substituted isoxazoles were synthesized by an efficient method and evaluated in vitro against Leishmania amazonensis and Trypanosoma cruzi, protozoa that cause the neglected tropical diseases leishmaniasis and Chagas disease, respectively. Thirteen compounds exhibited a selective index greater than 10. The series of 3-N-acylhydrazone isoxazole derivatives bearing the bithiophene core exhibited the best antiparasitic effects.

Antiparasitic Behavior of Trifluoromethylated Pyrazole 2-Amino-1,3,4-thiadiazole Hybrids and Their Analogues: Synthesis and Structure-Activity Relationship.

A series of trifluoromethylated pyrazole thiosemicarbazone, trifluromethylated pyrazole isothiosemicarbazone, and trifluoromethylated pyrazole 2-amino-1,3,4-thiadiazole hybrids were synthesized and evaluated in vitro against the promastigote form of Leishmania amazonensis and the epimastigote form of Trypanosoma cruzi, the pathogens causing the neglected tropical diseases leishmaniasis and Chagas disease, respectively. The results show the potential of these compounds regarding their antiparasitic properties. Studies on the structure-activity relationship demonstrated that compounds containing a bulky group at the para position of the phenyl ring attached to the 5-position of the pyrazole core had better antiparasitic effects. Among the substituents attached at the 3-position of the pyrazole ring, the insertion of the 2-amino-1,3,4-thiadiazole nucleus led to the most potent compounds compared to the thiosemicarbazone derivative.

1,2-Addition to trifluoromethylated ß-enamino diketones: regioselective synthesis of trifluoromethyl-containing azomethine pyrazoles and isoxazoles.

A simple and efficient methodology for highly regioselective synthesis of azomethine pyrazoles and isoxazoles containing a trifluoromethyl group is reported. The cyclocondensation of trifluoromethylated ß-enamino diketones (TBED) with phenylhydrazine and hydroxylamine hydrochloride, in the presence of BF3, provided 5-aryl-4-[(tert-butyl)iminomethyl]-3-trifluoromethylazoles by aza-Michael-type 1,2-addition. The scope of the reaction was expanded by transimination with arylamines in a one-pot method starting from TBED. Thus, 83 novel 4-[(alkyl/aryl)iminomethyl]-3-trifluoromethylazoles were obtained with high regioselectivity and in yields of 51 to 89%.

In vitro anti-Leishmania activity of T6 synthetic compound encapsulated in yeast-derived ß-(1,3)-d-glucan particles.

The objective of this study was to encapsulate a synthetic compound, the 4-[(2E)-N'-(2,2'-bithienyl-5-methylene)hydra-zinecarbonyl]-6,7-dihydro-1-phenyl-1H-pyrazolo[3,4-d]pyridazin-7-one (T6) in glucan-rich particles mainly composed by the cell wall of Saccharomyces cerevisiae (GPs) and to study their individual and combined activity on Leishmania infantum. The possible mechanism of action of T6 was also investigated. Our results showed the activity of T6 compound in both promastigote (IC50 = 2.5 µg/mL) and intracellular amastigote (IC50 = 1.23 µg/mL) forms. We also found activity against intracellular amastigote forms (IC50 = 8.20 µg/mL) when the T6 compound was encapsulated in GPs. Another interesting finding was the fact that T6 encapsulated in GPs showed a significant decrease in J774A1 macrophage toxicity (CC50 ≥ 18.53 µg/mL) compared to the T6 compound alone (IC50 = 2.27 µg/mL). Through electron microscopy and biochemical methodologies, we verified that the activity of T6 in promastigote forms of L. infantum was characterized by events of cell death by apoptosis like increased ROS production, cell shrinkage, phosphatidylserine exposure and DNA fragmentation. We conclude that T6 can be considered a promising anti-Leishmania compound, and that the use of GPs for drug encapsulation is an interesting approach to the development of new effective and less toxic formulations.