Synthesis of redox active neuroprotective therapeutic agents

Mitochondria are energy-producing organelles present in eukaryotic cells. Energy as adenosine triphosphate (ATP) is produced at the end of a series of electron transfers called the electron transport chain (ETC). Such a highly coordinated and regulated series of electron transfer reactions give rise to a small percentage of electron leakage which, by the subsequent reduction of molecular oxygen, produce superoxide anions (O2.-). These anions initiate the production of additional highly reactive oxygen-containing radicals commonly known as reactive oxygen species (ROS). Although cells are equipped with endogenous antioxidant systems to minimize ROS accumulation, these endogenous defense systems become inadequate when ROS generation is increased. When ROS production occurs in excess, the cell is said to be under oxidative stress. Unchecked ROS production causes damage to cellular macromolecules, which in turn leads to cell death. Dysfunctional mitochondria and subsequent cell degeneration are a common cause of neurodegenerative diseases such as Friedreich’s ataxia (FRDA) and Alzheimer’s disease (AD). Therefore, targeting the mitochondria by neuroprotective drugs is imperative for the treatment of such diseases. In Chapter 1, the functioning of the ETC is described. Moreover, excessive ROS production and its consequences are also described.

FRDA is a progressive neurodegenerative disease caused by insufficient expression of frataxin (FXN). FXN is instrumental in the assembly of iron-sulfur clusters, which in turn are critical for the functioning of the ETC enzyme complexes. Therapeutic agents which, in addition to being antioxidants also increase FXN, can be good drugs to counter FRDA. In Chapter 2, the synthesis of phenothiazine analogues are described. Moreover, their efficacy as antioxidants and their ability to increase FXN are described. Finally, the synthesis of a reduced salt form of one analogue and its ability to cross the blood brain barrier (BBB) in mouse models of the disease is also described.

In Chapter 3, to discover potent neuroprotective drugs, a pair of regioisomeric benzoquinone analogues has been synthesized. The compounds were tested for their efficacy as antioxidants. Additionally, two pyrimidinol based redox cores were analyzed electrochemically to enable a better understanding of the mechanism of action of the multifunctional radical quencher (MRQ) class of antioxidants.