Advances in the discovery of heterocyclic-based drugs against Alzheimer’s disease

ABSTRACT

Introduction

Alzheimer’s disease is a multifactorial neurodegenerative disorder characterized by beta-amyloid accumulation and tau protein hyperphosphorylation. The disease involves interconnected mechanisms, which can be clustered into two target-packs based on the affected proteins. Pack-1 focuses on beta-amyloid accumulation, oxidative stress, and metal homeostasis dysfunction, and Pack-2 involves tau protein, calcium homeostasis, and neuroinflammation. Against this background heterocyclic system, there is a powerful source of pharmacophores to develop effective small drugs to treat multifactorial diseases like Alzheimer’s.

Areas covered

This review highlights the most promising heterocyclic systems as potential hit candidates with multi-target capacity for the development of new drugs targeting Alzheimer’s disease. The selection of these heterocyclic systems was based on two crucial factors: their synthetic versatility and their well-documented biological properties of therapeutic potential in neurodegenerative diseases.

Expert opinion

The synthesis of small drugs against Alzheimer’s disease requires a multifactorial approach that targets the key pathological proteins. In this context, the utilization of heterocyclic systems, with well-established synthetic processes and facile functionalization, becomes a crucial element in the design phases. Furthermore, the selection of hit heterocyclic should be guided by a full understanding of their biological activities. Thus, the identification of promising heterocyclic scaffolds with known biological effects increases the potential to develop effective molecules against Alzheimer’s disease.

KEYWORDS:

• Alzheimer’s disease
• benzopyrane scaffold
• benzothiazole
• heterocyclic building blocks
• multi-target direct ligand
• pyridine scaffold
• small drug

Article highlights

• The design of drugs against Alzheimer’s disease (AD) should be approached from a multifactorial perspective.

• Heterocyclic systems provide an excellent opportunity for rapid and safe development of small multi-target drugs for Alzheimer’s disease.

• Heterocyclic systems with well-known, easy, and versatile synthetic pathways are fundamental in the design of small-molecule drugs.

• Fused heterocyclic systems, containing pyridine or pyran are privileged structures for the design of multitarget drugs.

• Overall, the integration of multifactorial targeting, utilization of heterocyclic systems with well-known synthesis processes, and informed selection will lead to the accelerated and efficient development of new molecules for pre-clinical evaluation against AD.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.