Cathepsin K is a papain-like cysteine protease and is responsible for collagen degradation in bone tissue and thus represents an important target for the development of new therapies for treating diseases such as osteoporosis. Quinolines are an important class of heterocyclic molecular leads with a great pharmacological potential and represent a relevant scaffold to explore the chemical space of cathepsin K (CatK) inhibitors. This study presents the synthesis of nine 2,4-diphenylquinolines, including five phthalonitrile quinolines dyads, and the evaluation of their CatK inhibitory activity. Among the evaluated compounds, 4b was the most potent inhibitor with an IC50 (half-maximal inhibitory concentration) value of 1.55 µM (against Z-Phe-Arg-MCA substrate) acting in an uncompetitive inhibition mode. Molecular docking studies provided important information on the interaction of the inhibitor with the enzyme showing that these quinoline derivatives can play an important role as CatK inhibitors.

ABSTRACT We present a comprehensive review of the advent and impact of continuous flow chemistry with regard to the synthesis of natural products and drugs, important pharmaceutical products and definitely responsible for a revolution in modern healthcare. We detail the beginnings of modern drugs and the large scale batch mode of production, both chemical and microbiological. The introduction of modern continuous flow chemistry is then presented, both as a technological tool for enabling organic chemistry, and as a fundamental research endeavor. This part details the syntheses of bioactive natural products and commercial drugs.

We present the occurrence, structures, biological activities, biosynthesis, and syntheses of the sesquiterpene alkaloids.

Neste trabalho é apresentada uma análise teórica detalhada da estabilidade relativa dos adutos endo/exo formados entre o ciclopentadieno (1) e a 1,4-benzoquinona (2). As coordenadas intrínsecas de reação (IRC) indicaram a presença de apenas um estado de transição para a reação, mostrando que se trata de um mecanismo concertado para ambos os adutos, endo 3 e exo 4. As energias dos adutos foram calculadas com um alto nível de teoria (CBS-Q) confirmando que o aduto endo é mais estável que o exo, o que está em desacordo com o que é observado para reações que usualmente seguem a regra de Alder. Uma análise estrutural eletrônica foi realizada através da metodologia NBO, a qual indicou que interações atrativas predominam sobre as interações estéricas repulsivas no aduto endo. Em resumo, para a reação de cicloadição estudada o aduto endo é o produto termodinâmico e cinético, o que pode ser confirmado também pelos dados experimentais mencionados neste trabalho.

In this work it is presented a detailed theoretical analysis of the relative stability of endo/exo Diels-Alder adducts formed by the reaction between cyclopentadiene (1) and 1,4-benzoquinone (2). The intrinsic reaction coordinate (IRC) showed the existence of only one transition state for the reaction studied, for both endo 3 and exo 4 adducts. The energies of both adducts were obtained at high level of theory (CBS-Q) confirming that the endo adduct is more stable than exo, which is in the opposite way to the observed in reactions that usually follow Alder's rule. An electronic structure analysis was performed through NBO methodology, indicating that the attractive delocalization interaction predominates over the steric repulsive interaction in the endo adducts. In summary, for the studied cycloaddition reaction the endo adduct is the thermodynamic and kinetic product, which can be also confirmed by experimental data mentioned in this work.