•A series of 26 lactones and lactams inhibited biofilm formation (>60 %) of S. oralis.•A set of lactams act as inhibitors of single-species biofilms of oral pathogenic bacteria.•Single-species biofilms of oral commensal bacteria can be inhibited by rubrolides analogues.•The use of lactones and lactams can be an alternative approach to control bacterial single-species biofilms.•Non-cytotoxic lactones can control single-biofilm of several oral bacteria. In this study, a series of 26 lactones and lactams have been investigated for their effect against 14 single-species biofilm of oral commensal and pathogenic species (Streptococcus oralis, S. mitis, S. sanguinis, S. gordonii, Actinomyces naeslundii, A. viscosus, Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, Streptococcus mutans, S. sobrinus, S. salivarius, Veillonella parvula). At the dose of 128 mg/mL, all substances inhibited biofilm formation of S. oralis by more than 60 %, and 19 caused >60 % reduction in the biofilm production by S. sanguinis and A. naeslundi. In addition, 16 compounds showed better results against P. intermedia and F. nucleatum, inhibiting biofilm formation by > 50 %, while 8 compounds caused >40 % reduction in the biofilm formation of A. actinomycetemcomitans. Compounds 5b, 5c, 5d, 5f, and 7 g were the only ones active against S. mutans, and 6d was the only one active against S. sobrinus biofilm formation. Amongst all compounds tested, 24 maintained cell viability above 50 % after 24 h of exposure. In summary, a set of lactones and lactams capable of inhibiting single-species biofilms of oral commensal and pathogenic bacteria without showing significant cytotoxicity against oral epithelial cells were identified. These results highlight the potential of using such antibiofilm compounds as an alternative approach to control oral biofilms. Display omitted