Enoyl acyl carrier protein reductase inhibitors: an updated patent review (2011 – 2015)

ABSTRACT

Introduction: Enoyl-(acyl-carrier-protein) reductase (ENR) is a limiting step enzyme in the Fatty Acid Synthase II system. In mammals, there is no homologue to ENR, which makes it an optimal candidate target for selective anti-infective drugs. Up-to-date, only two ENR inhibitors are used in clinical practice.

Area covered: This review is a survey on important patents on low molecular weight compounds with ENR inhibiting activity published in 2011–2015. Common patent databases (SciFinder, esp@cenet, WIPO) were used to locate patent applications on the proposed topic and in the timespan of 2011–2015.

Expert opinion: In 2011–2015, we have observed patents in previously known structural groups of diphenyl ethers and acrylamides as well as new structural classes, often identified by high-throughput screening campaigns. The spectrum of activity of applied derivatives covers significant bacteria, mycobacteria, and apicomplexan parasites (Plasmodia and Toxoplasma). Good news from research of ENR inhibitors: a) four selective anti-staphylococcal compounds applied in 2011–2015 or earlier were pushed to Phase I or Phase II clinical trials and some of them proved safety and tolerability after peroral and/or intravenous administration; b) big pharma companies have renewed their interest in the development of new anti-infective compounds against resistant strains of clinical relevance.

KEYWORDS:

• Acrylamide
• antibacterial
• antimycobacterial
• enoyl-acyl-carrier-protein reductase
• FabI
• InhA
• MRSA
• triclosan

Article highlights

• Enoyl-(acyl-carrier-protein) reductase (ENR) is an attractive antimicrobial target, useful in the development of agents active against bacteria, mycobacteria, and some protozoal parasites (Plasmodium sp., Toxoplasma sp.)

• Structurally diverse classes of inhibitors in most cases share a common interaction pattern with ENR

• Most patents on ENR inhibitors in 2011-2016 were in the class of anti-staphylococcal acrylamides

• Nanomolar inhibitors of mycobacterial ENR were found among isoxazole-3-carboxamides, 3-aminopyrazoles, and 4-hydroxy-2-pyridones

• First compounds started clinical trials with systemic administration (p.o., i.v.) and proved to be safe and effective in treating staphylococcal infections

• Big pharma companies are interested in the development of ENR inhibitors, especially as anti-staphylococcal and antitubercular agents.

This box summarizes key points contained in the article.

Declaration of interest

All ligand-enzyme interaction diagrams were created by using the online version of PoseView [94]. 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

This paper was not funded.