Assessment of the Activity of Nitroisoxazole Derivatives against Trypanosoma cruzi.

The development of new compounds to treat Chagas disease is imperative due to the adverse effects of current drugs and their low efficacy in the chronic phase. This study aims to investigate nitroisoxazole derivatives that produce oxidative stress while modifying the compounds' lipophilicity, affecting their ability to fight trypanosomes. The results indicate that these compounds are more effective against the epimastigote form of T. cruzi, with a 52 ± 4% trypanocidal effect for compound 9. However, they are less effective against the trypomastigote form, with a 15 ± 3% trypanocidal effect. Additionally, compound 11 interacts with a higher number of amino acid residues within the active site of the enzyme cruzipain. Furthermore, it was also found that the presence of a nitro group allows for the generation of free radicals; likewise, the large size of the compound enables increased interaction with aminoacidic residues in the active site of cruzipain, contributing to trypanocidal activity. This activity depends on the size and lipophilicity of the compounds. The study recommends exploring new compounds based on the nitroisoxazole skeleton, with larger substituents and lipophilicity to enhance their trypanocidal activity.

N-Arylation of 3-Formylquinolin-2(1H)-ones Using Copper(II)-Catalyzed Chan-Lam Coupling.

3-formyl-2-quinolones have attracted the scientific community's attention because they are used as versatile building blocks in the synthesis of more complex compounds showing different and attractive biological activities. Using copper-catalyzed Chan-Lam coupling, we synthesized 32 new N-aryl-3-formyl-2-quinolone derivatives at 80 °C, in air and using inexpensive phenylboronic acids as arylating agents. 3-formyl-2-quinolones and substituted 3-formyl-2-quinolones can act as substrates, and among the products, the p-methyl derivative 9a was used as a substrate to obtain different derivatives such as alcohol, amine, nitrile, and chalcone.

Synthesis of N-Arylcytisine Derivatives Using the Copper-Catalyzed Chan-Lam Coupling.

N-Arylcytisine derivatives are quite rare. We report here a practical methodology to obtain these compounds. Using the copper-catalyzed Chan-Lam coupling, we synthesized new N-arylcytisine derivatives at room temperature, in air and using inexpensive phenylboronic acids. Cytisine and 3,5-dihalocytisines can act as substrates, and among the products, the p-Br-derivative 2r was used as a substrate to obtain biaryl derivatives under Pd-coupling conditions; ester 2j was converted into its acid and amide derivatives using classical carbodiimide conditions. This shows that the Chan-Lam cross-coupling reaction can be included as a versatile synthetic tool in the derivatization of natural products.

Synthesis of ß-alkoxy-N-protected phenethylamines via one-pot copper-catalyzed aziridination and ring opening.

A regioselective, copper-catalyzed, one-pot aminoalkoxylation of styrenes using primary and secondary alcohols and three different iminoiodanes as alkoxy and nitrogen sources respectively, is reported. The ß-alkoxy-N-protected phenethylamines obtained were used to synthesise ß-alkoxy-N-benzylphenethylamines which are interesting new compounds that could act as possible neuronal ligands.

Copper-catalyzed intermolecular and regioselective aminofluorination of styrenes: facile access to ß-fluoro-N-protected phenethylamines.

A copper-catalyzed regio- and intermolecular aminofluorination of styrenes has been developed. In this reaction Ph-I=N-Ts and Et3N·3HF act as nitrogen and fluorine sources, respectively. The obtained ß-fluoro-N-Ts-phenethylamines can be N-alkylated with subsequent deprotection affording the corresponding ß-fluoro-N-alkylated phenethylamines, which are interesting building blocks for compounds acting on neuronal targets.

Antiproliferative and uncoupling effects of delocalized, lipophilic, cationic gallic acid derivatives on cancer cell lines. Validation in vivo in singenic mice.

Tumor cells principally exhibit increased mitochondrial transmembrane potential (ΔΨ(m)) and altered metabolic pathways. The therapeutic targeting and delivery of anticancer drugs to the mitochondria might improve treatment efficacy. Gallic acid exhibits a variety of biological activities, and its ester derivatives can induce mitochondrial dysfunction. Four alkyl gallate triphenylphosphonium lipophilic cations were synthesized, each differing in the size of the linker chain at the cationic moiety. These derivatives were selectively cytotoxic toward tumor cells. The better compound (TPP(+)C10) contained 10 carbon atoms within the linker chain and exhibited an IC50 value of approximately 0.4-1.6 µM for tumor cells and a selectivity index of approximately 17-fold for tumor compared with normal cells. Consequently, its antiproliferative effect was also assessed in vivo. The oxygen consumption rate and NAD(P)H oxidation levels increased in the tumor cell lines (uncoupling effect), resulting in a ΔΨ(m) decrease and a consequent decrease in intracellular ATP levels. Moreover, TPP(+)C10 significantly inhibited the growth of TA3/Ha tumors in mice. According to these results, the antineoplastic activity and safety of TPP(+)C10 warrant further comprehensive evaluation.