Medicinal Chemistry Research

, Volume 27, Issue 6, pp 1728–1739 | Cite as

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

  • Ramalingam Peraman
  • Amit K. Tiwari
  • M. Geetha Vani
  • J. Hemanth
  • Y. Geetha Sree
  • K. Karthik
  • Charles R. AshbyJr
  • Y. Padmanabha Reddy
  • Raghuveer V. Pemmidi
Original Research


Using the Blanc reaction, new derivatives of camphor (1ag) and camphor sulfonic acid (2ag) 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 (1ag/2ag) and the parent compounds (ag) 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 (1ag) demonstrated enhanced antimicrobial and anthelmintic efficacy compared to the camphor sulfonic acid hybrids (2ag). 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.


Camphor 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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2018_2186_MOESM1_ESM.docx (8.3 mb)
Supplementary Information


  1. 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
  2. Ajani OO (2014) Present status of quinoxaline motifs: excellent pathfinders in therapeutic medicine. Eur J Med Chem 85:688–715CrossRefPubMedGoogle Scholar
  3. American Conference of Governmental Industrial Hygienists (2015) Threshold limit values for chemical substances and physical agents and biological exposure indices. ACGIH, Cincinnati, OH. Accessed 30 Dec 2015
  4. Ammerlaan HS, Harbarth H, Buiting AG, Crook DW, Fitzpatrick F (2013) Secular trends in nosocomial bloodstream infections: antibiotic-resistant bacteria increase the total burden of infection. Clin Infect Dis 56:798–805CrossRefPubMedGoogle Scholar
  5. Andrade JC, Morais Braga MFB, Guedes GMM, Tintino SR, Freitas MA, Quintans Jr LJ, Menezes IRA (2017) Coutinho,Menadione (Vitamin K) enhances the antibiotic activity of drugs by cell membrane permeabilization mechanism. Saudi J Biol Sci 24:59–64CrossRefPubMedGoogle Scholar
  6. Anne HD (2009) Outer membrane permeability and antibiotic resistance. Biochim Biophys Acta 1794:808–816CrossRefGoogle Scholar
  7. Arendrup MC (2014) Update on antifungal resistance in Aspergillus and Candida. Clin Microbiol Infect 20:42–48CrossRefPubMedGoogle Scholar
  8. Busacca CA, Campbell S, Dong Y, Grossbach D, Ridges M, Smith L, Spinelli EJ (2000) Steric control in the synthesis of phosphinous acid-coordinated mono- and binuclear platinum (ii) complexes. Org Chem 65:4753CrossRefGoogle Scholar
  9. Centre for Disease Control and Prevention (2016) Superbugs threaten hospital patients. Press release.
  10. Chen W, Vermaak I, Viljoen A (2013) Camphor: a fumigant during the Black Death and a coveted fragrant wood in ancient Egypt and Babylon—a review. Molecules 18:5434–5454CrossRefPubMedGoogle Scholar
  11. Chen Y, Jeon SJ, Walsh PJ, Nugent W (2005) A publication of reliable methods for the preparation of organic compounds. Org Synth 82:87–88CrossRefGoogle Scholar
  12. Cogo J, Kaplum V, Sangi DP, Nakamura TU, Correa AG, Nakamura CV (2015) Synthesis and biological evaluation of novel 2,3-disubstituted quinoxaline derivatives as antileishmanial and antitrypanosomal agents. Eur J Med Chem 90:107–123CrossRefPubMedGoogle Scholar
  13. Dai JP, Chen J, Bei YF, Han BX, Wang S (2009) Influence of borneol on primary mice oral fibroblasts: a penetration enhancer may be used in oral submucous fibrosi. J Oral Pathol Med 38:276–281CrossRefPubMedGoogle Scholar
  14. Dart RC (2004) Medical toxicology, 3rd edn. Lippincott Williams and Wilkins, PhiladelphiaGoogle Scholar
  15. De Kraker MEA, Stewardson AJ, Harbarth S (2016) Will 10 million people die a year due to antimicrobial resistance by 2050? PLoS Med 13:e1002184CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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
  17. Gan FF, Yang SB, Luo YC, Yang W, FeiXu P (2010) Total synthesis of Sphingofungin F based on chiral tricyclic Iminolactone. J Org Chem 75:2737–2740CrossRefPubMedGoogle Scholar
  18. 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
  19. Gao Y, Qiang Wang G, Wei K, Hai P, Wang F, Kai Liu J (2012) Isolation and biomimetic synthesis of (±)Guajadial B, a novel menoterpenoid from Psidiumguajava. Org Lett 14:5936–5939CrossRefPubMedGoogle Scholar
  20. Groselj U, Sevsek A, Ricko S, Golobic A, Svete J, Stanovnik B (2012) Synthesis and structural elucidation of novel camphor-derived thioureas. Chirality 24:307–317CrossRefPubMedGoogle Scholar
  21. Gupta G, Verma P (2014) Antimicrobial activity of quinoxaline derivatives. Chem Sci Trans 3:876–884Google Scholar
  22. Gustave Louis Blanc (1923) The blanc chloromethylation. Bull Soc Chim Fr 33:313–317Google Scholar
  23. Harris PN, Ferguson JK (2012) Antibiotic therapy for inducible AmpC beta-lactamase-producing Gram-negative bacilli: what are the alternatives to carbapenems, quinolones and aminoglycosides? Int J Antimicrob Agents 40:297–305CrossRefPubMedGoogle Scholar
  24. Hintermann L, Dang T, Labonne TA, Kribber T, Xiao L, Naumov P (2009) The Azaryphos family of ligands for ambifunctional catalysis: syntheses and use in ruthenium- catalyzed anti-Markovnikov hydration of terminal alkynes. Chem Eur J 15:7167–7179CrossRefPubMedGoogle Scholar
  25. Jana N, Nguyen Q, Driver TG (2014) Development of a Suzuki cross-coupling reaction between 2-azidoarylboronic pinacolate esters and vinyl triflates to enable the synthesis of [2,3]-fused indole heterocycles. J Org Chem 79:2781–2791CrossRefPubMedPubMedCentralGoogle Scholar
  26. Janardhan S, Ram Vivek M, NarahariSastry G (2016) Modeling the permeability of drug-like molecules through the cell wall of Mycobacterium tuberculosis: an analogue based approach. Mol Biosyst 18:3377–3384CrossRefGoogle Scholar
  27. Jesmin M, Mohsin Ali M, Salahuddin MS, RowshanulHabib M, AraKhanam J (2008) Antimicrobial activity of some schiff bases derived from benzoin, salicylaldehyde, aminophenol and 2,4 dinitrophenyl hydrazine. Mycobiol 36:70–73CrossRefGoogle Scholar
  28. Munita J, Arias C (2016) Mechanisms of antibiotic resistance, Microbiol Spectr 4: VMBF-0016-2015.
  29. Kulhanek J, Ludwig M, Bures F (2010) One-step and solvent-free synthesis of terpene-fused pyrazines. ARKIVOC 2:315–322Google Scholar
  30. Leonid B, Yu VB, Karmanova IB (1977) New data on the chloromethylation of aromatic and heteroaromatic compounds. Russ Chem Rev 46:891–903CrossRefGoogle Scholar
  31. Lian W, Jiang B, Qian Z, Pei D (2014) Cell-permeable bicyclic peptide inhibitors against intracellular proteins. J Am Chem Soc 136:9830–9833CrossRefPubMedPubMedCentralGoogle Scholar
  32. LuLiu G, Hao B, Peng Liu S, Xue Wang G (2012) Synthesis and anthelmintic activity of ostholanalogs against Dactylogyrusintermedius in goldfish. Eur J Med Chem 54:582–590CrossRefGoogle Scholar
  33. Ramirez MS, Tolmasky ME (2006) Aminoglycoside modifying enzymes. Drug Resist Updates 13:151–171CrossRefGoogle Scholar
  34. Mangoni ML, Carotenuto A, Auriemma L, Saviello MR, Campiglia P, GomezMonterrey I, Malfi S, Marcellini L, Barra D, Novellino E, Grieco P (2011) Structure–activity relationship, conformational and biological studies of temporin l analogues. J Med Chem 54:1298–1307CrossRefPubMedGoogle Scholar
  35. Meleddu R, Distinto S, Corona A, Tramontano E, Bianco G, Melis C, Cottiglia EF (2017) Maccioni, Isatinthiazoline hybrids as dual inhibitors of HIV-1 reverse transcriptase. J Enzym Inhib Med Chem 32:130–136CrossRefGoogle Scholar
  36. Mohamed Ismail A, Zoorob HH, Strekowski L (2002) Synthesis and regioselective transformations of ethoxy-substituted 5-(perfluoroalkyl) pyrimidines. ARKIVOC 10:1–14Google Scholar
  37. National Poisons Information Service Center (1996) United Kingdom; Poisons information monograph: Camphor. Accessed 7 Sept 2017
  38. Perlin DS, Shor E, Zhao Y (2015) Update on antifungal drug resistance. Curr Clin Microbiol Rep 2:84–95CrossRefPubMedPubMedCentralGoogle Scholar
  39. Prasad B, Rojubally A, Plettner E (2011) Identification of camphor oxidation and reduction products in Pseudomonas putida: New activity of the cytochrome P450 cam system. J Chem Ecol 37:657–667CrossRefPubMedGoogle Scholar
  40. 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
  41. 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
  42. Ramalingam P, Varma RV, Reddy YP (2015) Re-engineering nalidixic acid’s chemical scaffold: a step towards the development of novel anti-tubercular and anti-bacterial leads for resistant pathogens. Bioorg Med Chem Lett 25:4314–4319CrossRefGoogle Scholar
  43. Rubenstein E, Keynan Y (2013) Vancomycin-resistant enterococci. Crit Care Clin 29:841–852CrossRefGoogle Scholar
  44. Susana G, Alexander T (2014) Mechanisms of vancomycin resistance in Staphylococcus aureus. J Clin Invest 124:2836–2840CrossRefGoogle Scholar
  45. Thomas CM, Nielsen KM (2005) Mechanisms of and barriers to horizontal gene transfer between bacteria. Nat Rev Microbiol 3:711–721CrossRefPubMedGoogle Scholar
  46. 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
  47. White JD, Wardrop DJ, Sundermann K (2002) (2s) (−) -3-exo (morpholino) isoborneol [(−)-mib] [[1r-(exo,exo)]-1,7,7-trimethyl-3-morpholin-4-yl-bicyclo[2.2.1] heptan-2-ol]. Org Synth 79:130–138CrossRefGoogle Scholar
  48. Wilkinson HS, Grover PT, Vandenbossche CP, Bakale RP, Bhongle NN, Wald SA, Senanayake CH (2002) Tandem carbon–carbon bond constructions via catalyzedcyanation/brook rearrangement/c-acylation reactions of acylsilanes. Org Lett 4:2957–2960CrossRefGoogle Scholar
  49. Wilson DN (2014) Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat Rev Microbiol 12:35–48CrossRefPubMedGoogle Scholar
  50. Xu P, Li S, Lu T, Wu C, Fan B, Golfis G (2006) Asymmetric synthesis of α,α-disubstituted α-amino acids by diastereoselective alkylation of camphor-based tricyclic Iminolactone. J Org Chem 71:4364–4373CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ramalingam Peraman
    • 1
  • Amit K. Tiwari
    • 2
  • M. Geetha Vani
    • 1
  • J. Hemanth
    • 1
  • Y. Geetha Sree
    • 1
  • K. Karthik
    • 1
  • Charles R. AshbyJr
    • 3
  • Y. Padmanabha Reddy
    • 1
  • Raghuveer V. Pemmidi
    • 1
  1. 1.Medicinal Chemistry DivisionRaghavendra Institute of Pharmaceutical Education and Research (RIPER)-AutonomousAnantapurIndia
  2. 2.Department of Pharmacology & Experimental Therapeutics, College of Pharmacy & Pharmaceutical SciencesThe University of ToledoToledoUSA
  3. 3.Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health ProfessionsSt. John’s UniversityJamaicaUSA

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