It is widely accepted that palladium is one of the most useful catalysts in organic chemistry, and many palladium(0)-catalysed carbon–carbon bond-forming reactions have been developed over the years. In addition, the ever-growing need for more environmentally benign processes in the chemical industry has driven scientists to look for greener options while developing new methodologies for organic synthesis. This thesis describes a series of studies on Suzuki and Heck coupling reactions in water and the application of palladium(0) catalysis to the development of new HIV-1 integrase inhibitors. The previously described 'transition-metal-free Suzuki-type coupling' reaction was shown to take place due to sub-ppm levels of palladium contaminants present in the commercially available sodium carbonate base. Based on this finding, a new, microwave-assisted Suzuki protocol utilizing ppb/ppm levels of palladium in water was developed. This methodology was adapted to terminal Heck coupling, although the scope of the protocol was found to be rather limited. Finally, both Suzuki and Heck reaction processes were successfully scaled up to 100 mmol using an automated batch stop-flow microwave apparatus. As the methodologies utilizing ultralow palladium concentrations were not applicable to aryl chlorides, attention was shifted towards palladium on carbon. This simple catalyst, together with microwave heating employing simultaneous cooling, was found to be beneficial in the Suzuki coupling of aryl chlorides with phenylboronic acid in water. Ligand-controlled internal arylation of ethylene glycol vinyl ether with aryl halides was shown to be possible in water alone without any additives. Reactions were run under air, using conventional heating and the products formed were isolated as aryl methyl ketones in good to excellent yields. The electron-rich (dippp)2Pd complex was shown to be beneficial for the microwave-assisted internal arylation of some aryl chlorides. Furthermore, the active role of the hydroxyl group of ethylene glycol vinyl ether in the formation of a cationic intermediate leading to internal Heck coupling product was elucidated. Finally, to demonstrate the usefulness of palladium(0) catalysis in the development of new pharmaceutical entities, a series of HIV-1 integrase inhibitors was synthesised and evaluated in strand transfer assays and in vitro. Based on the results and docking studies performed, valuable information related to the structure–activity relationship was obtained.

Introducción: En pacientes con VIH en TARV y fallo virológico a primera línea, establecer un esquema terapéutico tras haber identificado la mutación M184V, que confiere resistencia, representa una disyuntiva. Objetivo: Comparar la respuesta virológica de los esquemas terapéuticos prescritos a pacientes con VIH que presentaron la mutación M184V en dos hospitales nacionales de Lima, Perú durante los años 2008 a 2019 y determinar los factores de riesgo asociados a una mala respuesta virológica. Métodos: Se desarrolló un estudio de cohorte retrospectivo. Resultados: Un total de 175 participantes fueron elegibles para el estudio. El sexo masculino predominó (75.4%), la mediana de edad actual fue 41 años (IQR 35.84 ; 47.47) y tiempo en TARV fue 89 meses (IQR 57.7 ; 124.53). La mediana de carga viral inicial fue 4.5 log10 (IQR 3.97 ; 5.09) y el tiempo entre la genotipificación y el cambio de terapia fue 2 meses (IQR 0 ; 3.57). El esquema antirretroviral más utilizado fue IP + 2 INTR (55.4%). Con el esquema IP + INI se obtuvo 69% menos riesgo de mala respuesta virológica [p=0.019 (IC 95% 0.117 ; 0.825)]. Conclusiones: En los pacientes con VIH y mutación M184V, el esquema IP + INI ha demostrado una mayor disminución de la carga viral de control y, así, una buena respuesta virológica. Los factores de riesgo asociados a una mala respuesta virológica fueron la demora entre la genotipificación y el cambio de terapia, niveles elevados de carga viral inicial y mala adherencia. / Introduction: In patients with HIV in ART and virological failure to the first-line regimen, establishing a therapeutic regimen after having identified the M184V mutation, which confers ART resistance, represents a dilemma. Objective: To compare the virological response of the therapeutic regimens prescribed to patients with HIV who presented the M184V mutation in two national hospitals in Lima, Peru during the years 2008 to 2019, and to determine the risk factors associated with poor virological response. Methods: A retrospective cohort study was developed based on the information of the HIV program participants with the M184V mutation. Results: A total of 175 participants were eligible for the study. The male sex predominated (75.4%), the current median age was 41 years (IQR 35.84, 47.47) and the time on ART was 89 months (IQR 57.7, 124.53). The median initial viral load was 4.5 log10 copies/ml (IQR 3.97, 5.09) and the time between genotyping and the change of therapy was 2 months (IQR 0; 3.57). The most used antiretroviral regimen was PI + 2 NRTIs (55.4%). With the PI + INI ART, 69% less risk of poor virological response was obtained [p=0.019 (CI 95% 0.117 ; 0.825)]. Conclusions: In patients with HIV and the M184V mutation, the PI + INI ART has shown a greater decrease in control viral load and, thus, a good virological response. The risk factors associated with a poor virological response were the delay between genotyping and change of therapy, high levels of initial viral load, and poor adherence among the participants. / Tesis