New camphor hybrids: lipophilic enhancement improves antimicrobial efficacy against drug-resistant pathogenic microbes and intestinal worms
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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.
KeywordsCamphor derivatives Lipophilic enhancement Drug-resistant pathogen Antimicrobial resistance Anthelmintic activity Antimicrobial activity
The antimicrobial efficacy data for the drug-resistant pathogens were provided by the CO-ADD Community for Open Antimicrobial Drug Discovery, Institute for Molecular Bioscience, The University of Queensland, Australia (Project ID: PO319). Spectral data were supported by Laila implex Pvt. Ltd, Vijaawada (AP), India. The authors thank J. Lakshmi Narasa Reddy and K. Bala Ranga Samy for their assistance with some of the spectral assays.
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Conflict of interest
The authors declare that they have no conflict of interest.
- Aggarwal VK, Ford G, Fonquerna S, Adams H, Jones RVH, Fieldhouse RJ (1998) Catalytic asymmetric epoxidation of aldehydes: optimization, mechanism, and discovery of stereoelectronic control involving a combination of anomeric and cieplak effects in sulfurylide epoxidations with chiral 1,3-oxathianes. J Am Chem Soc 120:8328–8339CrossRefGoogle Scholar
- American Conference of Governmental Industrial Hygienists (2015) Threshold limit values for chemical substances and physical agents and biological exposure indices. ACGIH, Cincinnati, OH. http://www.chemsafetypro.com/Topics/USA/ACGIHTLVsThresholdLimitValues.html. Accessed 30 Dec 2015
- Centre for Disease Control and Prevention (2016) Superbugs threaten hospital patients. Press release. https://www.cdc.gov/media/releases/2016/p0303-superbugs.html
- Dart RC (2004) Medical toxicology, 3rd edn. Lippincott Williams and Wilkins, PhiladelphiaGoogle Scholar
- Francesco M, Alfonso C, Bruno C, Francesca M, RosaLoffredo M, Di Grazia A, Yousif Ali M, Diego B, Luciana P, Ettore N, Massimiliano G, Maria Iovene R, Maria Mangoni L, Paolo G (2017) Glycine-replaced derivatives of [Pro3,DLeu9] TL, a temporin L analogue: evaluation of antimicrobial, cytotoxic and hemolytic activities. Eur J Med Chem 139:750–761CrossRefGoogle Scholar
- Ganapaty S, Ramalingam P, BabuRao CH (2008) SAR study: impact of hydrazide hydrazones and sulfonamide side chain on in vitro antimicrobial activity of quinoxaline. Int J Pharmacol Biol 2(2):13–18Google Scholar
- Gupta G, Verma P (2014) Antimicrobial activity of quinoxaline derivatives. Chem Sci Trans 3:876–884Google Scholar
- Gustave Louis Blanc (1923) The blanc chloromethylation. Bull Soc Chim Fr 33:313–317Google Scholar
- Munita J, Arias C (2016) Mechanisms of antibiotic resistance, Microbiol Spectr 4: VMBF-0016-2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888801
- Kulhanek J, Ludwig M, Bures F (2010) One-step and solvent-free synthesis of terpene-fused pyrazines. ARKIVOC 2:315–322Google Scholar
- Mohamed Ismail A, Zoorob HH, Strekowski L (2002) Synthesis and regioselective transformations of ethoxy-substituted 5-(perfluoroalkyl) pyrimidines. ARKIVOC 10:1–14Google Scholar
- National Poisons Information Service Center (1996) United Kingdom; Poisons information monograph: Camphor. http://www.npis.org/. Accessed 7 Sept 2017
- Rahman FA, Priya V, Gayathri R, Geetha RV (2016) In vitro antibacterial activity of camphor oil against oral microbes. Int J Pharm Sci Rev Res 39:119–121Google Scholar
- Ramalingam P, Rajendran K, Sunil Kumar K, Padmanabha Reddy Y (2016) New conjugates of quinoxaline as potent antitubercular and antibacterial agents. Int J Med Chem 2016:1–8Google Scholar
- Van Asselt R, Elsevier CJ, Smeets WJJ, Spek AL, Benedix Recl R (1994) Synthesis and characterization of rigid bidentate nitrogen ligands and some examples of coordination to divalent palladium. X-ray crystal structures of bis (p-tolylimino) acenaphthene and methylchloro [bis(o,o′-diisopropylphenyl-imino) acenaphthene] palladium (II)Trav. Chim Pays-Bas 113:88–98CrossRefGoogle Scholar