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.

Discovery of 1,3,4,5-tetrasubstituted pyrazoles as anti-trypanosomatid agents: Identification of alterations in flagellar structure of L. amazonensis.

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.

Levels of phenylpropanoids and iridoids in extracts and infusions of Verbena minutiflora.

Herein we report for the first time the levels of phenylpropanoids and iridoids in extracts and infusions of V. minutiflora consumed in Brazil to treat urinary and infectious disorders. An in house validation study demonstrated good accuracy and precision to determine the bioactive compounds in V. minutiflora by HPLC-DAD. Phenylpropanoids varied in the extracts (leaves 139.70 to 221.20 mg g-1, flowers 106.43 to 227.22 mg g-1, stems 42.18 to 56.48 mg g-1). Verbascoside occurred in higher concentration in extracts of leaves (87.66 - 136.16) mg g-1 and flowers (58.12 - 148.96) mg g-1 than in stems (19.24 - 24.62) mg g-1. Iridoids in extracts were as follows: leaves (46.60 - 54.79) mg g-1, flowers (55.88 - 93.87) mg g-1 and stems (40.05 to 61.74) mg g-1. High levels of iridoids (314.70 - 415.10) µg mL-1, phenylpropanoids (1996.39 - 2674.13) µg mL-1 and verbascoside (1029.38 - 1456.42 µg mL-1) in infusions support the popular consume of V. minutiflora.

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%.