New camphor hybrids: lipophilic enhancement improves antimicrobial efficacy against drug-resistant pathogenic microbes and intestinal worms

Abstract

Using the Blanc reaction, new derivatives of camphor (1a–g) and camphor sulfonic acid (2a–g) were synthesized. Chemical structures of the new derivatives were supported by IR, 1H-NMR, 13C-NMR, and LC-MS/MS (ESI) spectrometric analyses. The new compounds (1a–g/2a–g) and the parent compounds (a–g) were tested for their antimicrobial efficacy against the following drug-resistant pathogens: methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant Klebsiella pneumonia (MDR-Kb), Escherichia coli (FDA control), Acinetobacter baumannii, Pseudomonas aeruginosa, Candida albicans (CLSI: Clinical and Laboratory Standards Institute strain) and Cryptococcus neoformans var. grubii. The linking of camphor to quinoxalin-2,3(1H, 4H)-dione (1a) enhances the antibacterial efficacy approximately 8-folds (MIC: 24 µM) against MRSA. Camphor linking with isatin (1g) increased efficacy against Acinetobacter baumannii by 8-fold (MIC: 26 µM) and by 4-fold (MIC: 51 µM) against MRSA, MDR-Kb, E. coli, P. auruginosa and C. albicans. Among the series, derivatives of benzoin (1e) and salicylic acid (1f) exhibited greater efficacy against drug-resistant Candida albicans, MDR-Kb and Acinetobacter baumannii, whereas 6, 7-biphenylquinoxalin 2-sulfonamide/sulphonyl chloride (1b/1d) selectively inhibited the growth of Gram-negative bacteria. None of these compounds were active against Cryptococcus neoformans var. grubii. Furthermore, these new derivatives were tested for anthelmintic efficacy and the results indicated that new compounds had significant anthelmintic efficacy (p < 0.05) at 2.5 mg/mL, except for the salicylic acid hybrids (1f, 2f). To conclude, camphor hybrids (1a–g) demonstrated enhanced antimicrobial and anthelmintic efficacy compared to the camphor sulfonic acid hybrids (2a–g). This improved antimicrobial efficacy may be due to the increased membrane permeability of the compounds across the cell wall, via the camphor moiety, which augmented the lipophilicity of the new compounds.