Synthesis and evaluation of N-alkyl-9-aminoacridines with antibacterial activity

Adam R Benoit; Charles Schiaffo; Christine E Salomon; John R Goodell; Hiroshi Hiasa; David M Ferguson

doi:10.1016/j.bmcl.2014.05.037

Synthesis and evaluation of N-alkyl-9-aminoacridines with antibacterial activity

Bioorg Med Chem Lett. 2014 Jul 15;24(14):3014-7. doi: 10.1016/j.bmcl.2014.05.037. Epub 2014 May 22.

Authors

Adam R Benoit¹, Charles Schiaffo¹, Christine E Salomon², John R Goodell³, Hiroshi Hiasa⁴, David M Ferguson⁵

Affiliations

¹ Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, United States.
² Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, United States.
³ Department of Chemistry, Illinois State University, Normal, IL 61790-4160, United States.
⁴ Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, United States.
⁵ Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, United States; Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: ferguson@umn.edu.

PMID: 24908610
DOI: 10.1016/j.bmcl.2014.05.037

Abstract

A series of 9-alkylaminoacridines were synthesized and evaluated for activity against two strains of methicillin-resistant and one strain of methicillin-sensitive Staphylococcus aureus. Results are presented that show a clear structure activity relationship between the N-alkyl chain length and antibacterial activity with peak MIC99 values of 2-3 μM for alkyl chains ranging from 10 to 14 carbons in length. Although prior work has linked the function of acridine-based compounds to intercalation and topoisomerase inhibition, the present results show that 9-alkylaminoacridines likely function as amphiphilic membrane-active disruptors potentially in a similar manner as quaternary ammonium antimicrobials.

Keywords: Acridines; Amphiphiles; Antimicrobials; Drug design; Intercalation; MRSA; SAR; Synthesis; Topoisomerase.

MeSH terms

Aminoacridines / chemical synthesis*
Aminoacridines / chemistry
Aminoacridines / pharmacology*
Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Dose-Response Relationship, Drug
Methicillin / pharmacology
Microbial Sensitivity Tests
Molecular Structure
Staphylococcus aureus / drug effects
Structure-Activity Relationship

Substances

Aminoacridines
Anti-Bacterial Agents
Methicillin