1. ChemMedChem. 2020 Apr 20;15(8):716-725. doi: 10.1002/cmdc.201900688. Epub 2020 
Mar 18.

Synthesis and Evaluation of 2-Aminothiophene Derivatives as Staphylococcus 
aureus Efflux Pump Inhibitors.

da Cruz RMD(1)(2)(3)(4), Zelli R(3), Benshain S(4), da Cruz RMD(2), 
Siqueira-Júnior JP(5), Décout JL(3), Mingeot-Leclercq MP(4), Mendonça-Junior 
FJB(1)(2).

Author information:
(1)Department of Biological Sciences, State University of Paraiba, Laboratory of 
Synthesis and Drug Delivery, João Pessoa, PB, Brazil.
(2)Department of Pharmaceutical Sciences, Federal University of Paraiba, 
Post-Graduation Program in Natural and Synthetic Bioactive Products, João 
Pessoa, PB, Brazil.
(3)Département de Pharmacochimie Moléculaire, University Grenoble Alpes, CNRS, 
Grenoble, France.
(4)Department of Pharmacologie Cellulaire et Moléculaire, Université Catholique 
de Louvain, Louvain Drug Research Institute, Brussels, Belgium.
(5)Department of Molecular Biology, Federal University of Paraiba, Laboratory of 
Microorganism Genetics, João Pessoa/PB, Brazil.

2-aminothiophene derivatives (2AT) in which the thiophene ring is fused with a 
cycloalkyl or a N-acylated piperidine ring by positions 5 and 6 and carrying a 
3-carbethoxy group were synthesized and their bacterial growth and enzyme 
inhibitory effects against efflux proteins of Staphylococcus aureus leading to 
resistance to fluoroquinolones and erythromycin (ERY) were investigated. 
Compounds that most effectively decreases the minimum inhibitory concentrations 
(MICs) of ciprofloxacin (CIP) were assayed for their dose and time effects on 
the accumulation and efflux of ethidium bromide (EtBr) in the SA-1 strain. None 
of the compounds displayed antibacterial activity however, three derivatives 
carrying 2-amino, 2-aminoacetyl and 2-aminotrifluoroacetyl group enhanced the 
activity of CIP and ERY by 8- and 16-fold, respectively, and were able to 
restore the sensitivity of resistant strains, acting as typical efflux pump 
inhibitors (EPIs). The 2-aminoacetyl and 2-aminotrifluoroacetyl derivatives and 
two other piperidinyl 2-aminotrifluoroacetyl derivatives increased EtBr 
accumulation in a dose- and time-dependent manner, and one of them was also able 
to inhibit the EtBr efflux. Taken together, these results represent an important 
advance in the development of new EPIs, and demonstrate that 2AT represent a 
good scaffold for developing new antibiotic adjuvants.

© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOI: 10.1002/cmdc.201900688
PMID: 32073756