The latest advances in the discovery of nitric oxide hybrid drug compounds

ABSTRACT

Introduction: There is a great interest in Nitric oxide (NO) within medicinal chemistry since it’s involved in human signaling pathways. Prodrugs or hybrid compounds containing NO-donor scaffolds linked to an active compound are valuable, due to their potential for modulating many pathological conditions due to NO’s biological properties when released in addition to the native drug. Compounds that selectively inhibit nitric oxide synthase isoforms (NOS) can also increase therapeutic capacity, particularly in the treatment of chronic diseases. However, search for bioactive compounds to efficiently and selectively modulate NO is still a challenge in drug discovery.

Areas covered: In this review, the authors highlight the recent advances in the strategies used to discover NO-hybrid derivatives, especially those related to anti-inflammatory, cardiovascular, anticancer and anti-microorganism activities. They also focus on: nitric oxide synthase inhibitors, NO delivery materials and other related activities.

Expert opinion: The process of molecular hybridization can be used to obtain NO-releasing compounds that also interact with different targets. The main problem with this approach is to control NO multiple actions in the right biological system. However, the use of NO-releasing groups with many different scaffolds leads to new molecular structures for bioactive compounds, suggesting synergies.

KEYWORDS:

• Drug discovery
• hybrid compounds
• immune system
• nitric oxide
• nitric oxide synthase inhibitors
• NO-donors
• prodrugs
• therapeutic potential

Article highlights

• Nitric oxide is a versatile molecule, which has been involved in treating many important diseases

• The NO-releasing scaffold-based approach has led to increased interest in the past five years.

• Exogenous and endogenous sources of NO can also be controlled in order to find new drugs

• Different NO-releasing groups can be used in order to obtain probable synergistic effects either through molecular hybridization or prodrug design

• Challenges relating to NO-releasing control have to be addressed in order to widen its application in drug design and discovery

This box summarizes key points contained in the article.

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.

Additional information

Funding

The authors are supported by the Sao Paulo Research Foundation (FAPESP), the Coordination for the Improvement of Higher Education Personnel (CAPES) and the Brazilian National Council for Scientific and Technological Development (CNPq). Specifically, EI Ferreira is supported by a CNPq fellowship No. 309989/2015-9, while FG Pernichelle is supported by a FAPESP scholarship award no. 2016/03124-0. Finally, RAM Serafim was awarded a CAPES scholarship.