Design, synthesis, computational study, and biological evaluation of new molecules for the treatment of age-related diseases

Abstract

Cerebral ischemia (CI) is a disease of aging and a cerebrovascular pathology that represents a major unmet medical and global socioeconomic problem. Currently, the only approved drug for CI is the recombinant tissue plasminogen activator (rtPA), that only dissolves the thrombus, limiting its effectiveness. Consequently, many patients show significant sequelae after CI. Moreover, the narrow therapeutic window of rt-PA (3 h) further worsens this issue. Therefore, the development of new drugs for the therapy of CI is urgent and necessary. One of the main events that characterizes CI is the oxidative stress (OS). Therefore, the development of antioxidant molecules and free radical scavengers is an objective for drug development in this area. Among antioxidant agents, nitrones have shown the great effectiveness, -phenyl-N-tert-butyl nitrone (PBN) being one of the most studied and used as a reference in this work. Thus, herein we have designed, synthesized, and tested a number of new nitrones as potential drugs for CI in vitro, in vivo, and in silico studies. Several nitrones bearing different organic cores have been synthesized to determine their antioxidant capacity to find hitnitrones for further development. In addition, several PBN-derived nitrones bearing similar two and three nitrone motives have been synthesized and analysed to observe if an increase in the number of nitrone moieties increases their antioxidant and neuroprotective capacities. Finally, different nitrone moieties have also been incorporated in the same molecule to determine if the resulting hetero-nitrones show improved antioxidant capacity. On the other hand, Alzheimer's disease (AD) is a neurodegenerative pathology, and a significant socioeconomic problem, being one of the leading causes of death, mainly among the eldest. The etiology of AD is still not fully understood, although several hypotheses have been proposed. Currently, there are several drugs approved by the Food and Drug Administration (FDA) in US for the therapy of AD, but they only reduce AD symptoms and do not cure AD patients. This problem is likely due to the multifactorial nature of the disease. This is why the multitargetdirect ligand (MTDL) strategy, able to provide molecules simultaneously acting on different biological targets involved in the disease, could provide perhaps more efficient drugs for AD. Moreover, the relationship between AD and CI is well known and has also been studied. Although the mechanisms that relate them are unknown, it has been established that CI contributes to the development of AD. Therefore, in this work, a series of nitrones have been developed for the combined treatment of AD and CI. To this end, nitrones with known antioxidant capacity have been designed bearing pharmacophoric groups, such as propargylamines or substituted piperidines, able to inhibit monoamino oxidase (MAO) or cholinesterase (ChE) enzymes, respectively, as biological targets clearly implemented in the progress of AD, resulting in multipotent and multifunctional drugs for the possible combined treatment of AD and CI.