Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer's Disease and Parkinson's Disease

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases in the elderly. The key histopathological features of these diseases are the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), along with a depleted antioxidant system, mitochondrial dysfunction, and intracellular Ca²⁺ dyshomeostasis, plays a vital role in the pathophysiology of these neurological disorders. Due to an improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. However, there is no effective protective treatment or therapy available but rather only very limited palliative treatment. Therefore, there is an urgent need for the development of preventive strategies and disease-modifying therapies to treat AD/PD. Because dysregulated Ca²⁺ metabolism drives oxidative damage and neuropathology in these diseases, the identification or development of compounds capable of restoring Ca²⁺ homeostasis and signaling may provide a neuroprotective avenue for the treatment of neurodegenerative diseases. In addition, a set of strategies to control mitochondrial Ca²⁺ homeostasis and signaling has been reported, including decreased Ca²⁺ uptake through voltage-operated Ca²⁺ channels (VOCCs). In this article, we review the modulatory effects of several heterocyclic compounds on Ca²⁺ homeostasis and trafficking, as well as their ability to regulate compromised mitochondrial function and associated free-radical production during the onset and progression of AD or PD. This comprehensive review also describes the chemical synthesis of the heterocycles and summarizes the clinical trial outcomes.

Keywords: Alzheimer’s disease; Parkinson’s disease; calcium; heterocyclic compounds; mitochondria; oxidative stress.

Figure 1

Heterocycles target Ca²⁺ dyshomeostasis leading to mitochondrial Ca²⁺ overload, oxidative damage, and neuronal degeneration in AD and PD.

Scheme 1

Unique total production of ANAVEX2-73 1.

Scheme 2

Synthesis of caffeine 2 from uracil 9.

Scheme 3

Novel approaches for the N-methylation of theophylline 14.

Scheme 4

Schwartz’s strategy for the synthesis of diltiazem 3.

Scheme 5

Enantiomerically pure key intermediate 18 for diltiazem 3 production.

Scheme 6

Chemoenzymatic synthesis of diltiazem 3.

Scheme 7

Zheng’s protocol to generate latrepirdine 4.

Scheme 8

Ruthenium(III) catalysis used in the synthesis of latrepirdine 4.

Scheme 9

Hantzsch reaction used in the preparation of nifedipine 5.

Scheme 10

Synthesis of nifedipine 5 via photoinduced iron-catalyzed ipso-nitration.

Scheme 11

First flow multicomponent synthesis of nifedipine 5.

Scheme 12

Generation of nifedipine 5 by using the green approach.

Scheme 13

Solid-phase production of nimodipine 6.

Scheme 14

Production of nimodipine 5 in pilot batches by Pharm. Sintez. Co (Moscow, Russian Federation).