Evaluation of novel benzo-annelated 1,4-dihydropyridines as potential inhibitors of antibacterial efflux pumps in S. aureus and MRSA strains

Abstract

Multidrug (MDR) resistances against various classes of antibiotics used in S. aureus and MRSA infections have emerged. With limited options for novel antibacterial compounds, there is a strong focus on finding agents against MDR phenomenon, namely causative efflux pumps. We synthesised novel benzo-annelated 1,4-dihydropyridines with various substitution patterns both at the 4- and N-alkyl substituents and, additionally, at the annelated aromatic residues. MDR efflux pump-inhibiting activity was evaluated in S. aureus strains including MRSA and was measured in a fluorescent assay system using ethidium bromide as the overall substrate of S. aureus efflux pumps. Favourable substituents for inhibiting efflux pump activity in S. aureus have been 4-methoxy and 4- and 3-chloro at the 4-phenyl position of the 1,4-dihydropyridine ring combined with an N-benzyl residue. The most favourable substituents for the activity inMRSA strains have been those 4-phenyl chloro substituents combined with additional pyrido residues attached to the benzo substituent at the 1,4-dihydropyridine core. Benzo-annelated 1,4-dihydropyridines are a novel class of inhibitors of MDR relevant efflux pumps in S. aureus strains including MRSA.