Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel amide functionalized 2H-chromene derivatives by Ritter amidation of primary alcohol using HBF4OEt2 as a mild and versatile reagent and evaluation of their antimicrobial and anti-biofilm activities K. Ratnakar Reddy a, Y. Poornachandra c, G. Jitender Dev a, G. Mallareddy a, Jagadeesh B. Nanubolu b, C. Ganesh Kumar c, B. Narsaiah a,⇑ a
Fluoroorganic Division, (AcSIR)CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India c Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India b
a r t i c l e
i n f o
Article history: Received 7 January 2015 Revised 29 April 2015 Accepted 15 May 2015 Available online xxxx Keywords: Chromene-2-ol Amide functionalized 2H-chromene Reduction Ritter amidation HBF4OEt2 catalyst
a b s t r a c t A series of novel amide functionalized 2H-chromene derivatives 3 were prepared starting from ethyl-2hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate 1 via sodium borohydride reduction followed by Ritter amidation using HBF4OEt2 as a mild and versatile reagent. All the products 3 were screened for antimicrobial activity against various Gram-positive, Gram-negative bacteria and fungal strain. The promising derivatives such as 3f, 3g, 3k, 3l, 3m, 3n and 3o were further screened for minimum bactericidal concentration and bio-film inhibition activity and identified the potential ones. Among all the promising, compound 3g was more potent for antimicrobial, MBC and anti bio-film activities. The structure verses activity relationship of 3g revealed that the presence of two bromine atoms at sixth and R position promotes high activity. Ó 2015 Elsevier Ltd. All rights reserved.
In natural environment, bacteria are able to switch between two different life styles: the plank-tonic living forms and as biofilms. Bio-films are complex and highly structured communities of microbes of multiple species that are enclosed in a self-produced polymeric matrix which shields the embedded cells and are adherent to an inert or living surface.1,2 These bio-films are formed as a survival strategy in diverse and harsh environment and enable them to disperse and colonize new niches. The plank-tonic cells and bio-films differ significantly in their physiology, gene expression pattern and even morphology. Among the different bacterial strains, the most commonly encountered and clinically relevant bio-film forming microbes are the Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli.3–5 According to the US National Institute of Health, >80% of bacterial infections are contributed by biofilms.6 The bacteria also colonize on various biomedical implants such as stents, heart valves, vascular grafts and catheters through bacterial adhesion and bio-film formation.7 The bio-films have the ability to resist against stress, antibiotics, biocides and host-immunological defense and thus they pose a ⇑ Corresponding author. Tel.: +91 40 27193185; fax: +91 40 27160387. E-mail address: [email protected] (B. Narsaiah).
challenge.8 In the recent past, a significant attention has been generated among the scientific community towards understanding the biology of bio-films and the search for novel inhibitors for the control of bio-film formation and related cellular processes.9,10 To date, only a few molecular scaffolds have been identified that function as anti bio-film compounds and amongst them the well studied examples are the natural halogenated furanones isolated from the red alga Delisea pulchra,11,12 analogues of the homo-serine lactone signaling molecules13 and sponge-derived marine natural alkaloids oroidin and bromoageliferin.14–17 We have earlier identified novel pyrazolo[3,4-b]pyridine and pyrimidine functionalized [1,2,3-triazole] derivatives as promising antimicrobial and anti bio-film active agents.18 We proposed to explore the antimicrobial and anti bio-film activities against some of the novel molecules having the 2H-chromene framework. In the present context, 2H-chromene nucleus is present in many biologically active molecules which include antioxidant,19 polyphenols20 and natural products.21 Some of the 2H-chromene derivatives also used as substrates for the synthesis of antitumor,22,23 antimicrobial,24 fungicidal,25 insecticidal26 and anti-HIV agents.27 Recently, it was found that the fluorine28 or trifluoromethyl29 group at a strategic position of an organic molecule
http://dx.doi.org/10.1016/j.bmcl.2015.05.041 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ratnakar Reddy, K.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.05.041
2
K. Ratnakar Reddy et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx 10000
Fluorescence units
Control
3g
Erythromycin
1000
100
10
1 0.5
1
1.5
2
Concentration (µM) Figure 1. ROS studies.
dramatically alters the properties of molecule in terms of lipid solubility, oxidative thermal stability, permeability and oral bioavailability thereby enhancement in the transport mechanism. The Ritter reaction was used in preparation of many bioactive molecules and drugs such as amantadine as an antiviral and antiParkinson drug.30 Crixivan as an anti-HIV,31 and aristotelone alkaloid as a dopamine receptor ligand.32 In earlier reports, several methodologies have been reported for Ritter reaction in which sulfuric acid was replaced by formic acid under reflux,33 P2O5/SiO2,34 2,4-dinitrobenzene disulfonic acid,35 O-benzene disulfonamide,36 HClO4-functionalized silica-coated nano particles,37 ionic liquid,38 liquid HF,39 Bi(OTf)340 and SiO2-Pr-SO3H41 (sulfonic-acid-functionalized silica as a heterogeneous solid acid catalyst). HBF4OEt242 was also used for the amidation of olefins with nitriles, however, there are no reports available on the amidation of alcohols with nitriles using HBF4OEt2. Based on the above importance, the interest is continuously growing on synthesis of fluorinated chromenes. In continuation to our efforts on synthesis of trifluoromethyl substituted 2H-chromenes,43 we have synthesized a series of novel amide functionalized 2H-chromene derivatives by Ritter amidation of primary alcohol using HBF4OEt2 as a mild and versatile reagent. All the products were screened for antimicrobial activity. Compounds which showed promising activity were further screened for minimum bactericidal concentration, bio-film inhibition activity and potential compounds have been identified. The ethyl-2-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carb oxylate 143 was reduced with sodium borohydride in THF at room temperature for ten minutes followed by reflux for 1 hour to obtain 3-(hydroxymethyl)-2-(trifluoromethyl)-2H-chromen-2-ol 2. Compound 2 was further reacted with diverse substituted acetonitriles in the presence of HBF4OEt2 under solvent-free conditions to form amide functionalized 2H-chromene derivatives 3a–o via
Figure 2. Crystal structure of compound 3l.
Ritter amidation reaction. The reaction was completed in 15– 20 min with high yields. The primary alcohol was selectively protonated in presence of HBF4 followed by amidation by nucleophilic attack on primary carbon to give products 3a–o. The product 3l was identified by spectroscopy followed by single crystal X-ray crystallography. The ORTEP diagram44,45 of compound 3l is presented in Figure 2 and deposited in data bank with a unique depository number, CCDC 1020412 (e-mail: [email protected]. uk). The possible mechanism for the synthesis of compounds 3a–o by Ritter reaction is outlined in Scheme 2. The reaction steps involved drawn in Scheme 1 and products are tabulated in Table 1. Compounds 3a–o were screened against various Gram-positive bacteria such as (Bacillus subtilis MTCC 121, Staphylococcus aureus MLS-16 MTCC 2940, Micrococcus luteus MTCC 2470) and Gramnegative bacteria (Escherichia coli MTCC 739, Klebsiella planticola MTCC 530) using ciprofloxacin as standard and also screened against fungal strain (Candida albicans MTCC 3017) using miconazole as standard. Compounds 3f, 3g, 3k, 3l, 3m, 3n, and 3o showed promising activity towards Gram-positive and Gram-negative bacteria at 125 lg/mL. e CIP: ciprofloxacin. f MIC: miconazole.
Table 3 MBC of the selected amide functionalized 2H-chromene derivatives Minimum bactericidal concentration (lM)
Compd
Bacteriaa
3f 3g 3k 3l 3m 3n 3o CIPc
Bacteriab
ML
SA
BS
EC
KP
38.3 8.3 33.6 74.2 74.2 33.6 28.6 5.7
19.1 4.0 67.2 37.1 37.1 67.2 14.3 2.7
19.1 4.0 >230 74.2 74.2 >230 28.6 5.7
38.3 16.6 >230 >230 37.1 >230 14.3 5.7
19.1 8.3 >230 >230 74.2 >230 57.3 2.7
a Gram-positive bacteria; ML, Micrococcus luteus MTCC 2470; SA, Staphylococcus aureus; MLS-16 MTCC 2940; BS, Bacillus subtilis MTCC 121. b Gram-negative bacteria; EC, Escherichia coli MTCC 739; KP, Klebsiella planticola MTCC 530. c CIP: ciprofloxacin.
Table 4 Bio-film inhibition assay of the selected amide functionalized 2H-chromene derivatives Ca
IC50 values in (lM, mean ± SD, n = 3) Bacteriab
3f 3g 3k 3l 3m 3n 3o ERd a
Bacteriac
ML
SA
BS
EC
KP
8.3 ± 0.31 1.7 ± 0.11 19.1 ± 0.41 17.1 ± 0.19 18.4 ± 0.32 17.4 ± 0.26 7.7 ± 0.16 0.31 ± 0.14
3.6 ± 0.22 1.2 ± 0.22 21.9 ± 0.38 19.7 ± 0.41 9.2 ± 0.23 16.8 ± 0.36 6.2 ± 0.17 0.25 ± 0.22
5.1 ± 0.09 1.4 ± 0.08 — 43.8 ± 0.42 22.2 ± 0.36 — 8.8 ± 0.19 0.42 ± 0.18
10.5 ± 0.26 1.4 ± 0.11 — — 8.2 ± 0.22 — 5.8 ± 0.18 0.43 ± 0.17
12.7 ± 0.25 1.7 ± 0.16 — — 24.6 ± 0.18 — 14.8 ± 0.22 0.35 ± 0.16
C: compound Gram-positive bacteria; ML, Micrococcus luteus MTCC 2470; SA, Staphylococcus aureus; MLS-16 MTCC 2940; BS, Bacillus subtilis MTCC 121. c Gram-negative bacteria; EC, Escherichia coli MTCC 739; KP, Klebsiella planticola MTCC 530. d ER: erythromycin. b
Authors are thankful to the Council of Scientific & Industrial Research (CSIR), New Delhi, India for the financial support through Development of Innovative Technologies for Strategic Fluorochemicals (DITSF) under XII five year plan project code:CSC-0204. Authors (K. Ratnakar Reddy, Y. Poornachandra, G. Jitender Dev and G. Mallareddy) are also thankful to the Council of Scientific and Industrial Research (CSIR), India for providing financial assistance in the form of Research Fellowship and contingency grant. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.05. 041. References and notes 1. Costerton, J. W.; Lewandowski, Z.; Caldwell, D. E.; Korber, D. R.; Lappin-Scott, H. M. Annu. Rev. Microbiol. 1995, 49, 711. 2. Donlan, R. M.; Costerton, J. W. Clin. Microbiol. Rev. 2002, 15, 167. 3. Otto, M. Curr. Top. Microbiol. Immunol. 2008, 322, 207. 4. Mann, E. E.; Wozniak, D. J. FEMS Microbiol. Rev. 2012, 36, 893. 5. Beloin, C.; Roux, A.; Ghigo, J. C. Curr. Top. Microbiol. Immunol. 2008, 322, 249. 6. Davies, D. Nat. Rev. Drug Discov. 2003, 2, 114. 7. Saint, S.; Chenoweth, C. E. Infect. Dis. Clin. North Am. 2003, 17, 411. 8. Costerton, J. W.; Stewart, P. S.; Greenberg, E. P. Science 1999, 284, 1318. 9. Musk, D. J., Jr.; Hergenrother, P. J. Curr. Med. Chem. 2006, 13, 2163. 10. Landini, P.; Antoniani, D.; Burgess, J. G.; Nijland, R. Appl. Microbiol. Biotechnol. 2010, 86, 813. 11. Gram, L.; De Nys, R.; Maximilien, M.; Givskov, M.; Steinberg, P.; Kjelleberg, S. D. Appl. Environ. Microbiol. 1996, 62, 4284. 12. Janssens, J. C.; Steenackers, H.; Robijns, S.; Gellens, E.; Levin, J.; Zhao, H.; Hermans, K.; De Coster, D.; Verhoeven, T. L.; Marchal, K.; Vanderleyden, J.; De Vos, D. E.; De Keersmaecker, S. C. Appl. Environ. Microbiol. 2008, 74, 6639. 13. Geske, G. D.; Wezeman, R. J.; Siegel, A. P.; Blackwell, H. E. J. Am. Chem. Soc. 2005, 127, 12762. 14. Huigens, R. W.; Richards, J. J.; Parise, G.; Ballard, T. E.; Zeng, W.; Deora, R.; Melander, C. J. Am. Chem. Soc. 2007, 129, 6966. 15. Richards, J. J.; Ballard, T. E.; Melander, C. Org. Biomol. Chem 2008, 6, 1356. 16. Richards, J. J.; Ballard, T. E.; Huigens, R. W.; Melander, C. ChemBioChem 2008, 9, 1267. 17. Richards, J. J.; Reyes, S.; Stowe, S. D.; Tucker, A. T.; Ballard, T. E.; Mathies, L. D.; Cavanagh, J.; Melander, C. J. Med. Chem. 2009, 52, 4582. 18. Nagender, P. Bioorg. Med. Chem. Lett. 2014, 24, 2905. 19. Mukai, K.; Okabe, K.; Hosose, H. J. Org. Chem. 1989, 54, 557. 20. Jankun, J.; Selman, S. H.; Swierez, R. Nature 1997, 387, 561. 21. Parmar, V. S.; Jain, S. C.; Bisht, K. S., et al. Phytochemistry 1997, 46, 597. 22. Reddy, B. V. S.; Divya, B.; Swain, M.; Rao, T. P.; Yadav, J. S.; Vishnu Vardhan, M. V. P. S. Bioorg. Med. Chem. Lett. 1995, 2012, 22. 23. Elomri, A.; Mitaku, S.; Michel, S.; Skaltsounis, A. L.; Illequin, F. T.; Koch, M.; Pierre, A.; Guilbaud, N.; Leonce, S.; Kraus-Berthier, L.; Rolland, Y.; Atassi, G. J. Med. Chem. 1996, 39, 4762. 24. a) Kidwai, M.; Saxena, S.; Khan, M. K. R.; Thukral, S. S. J. Org. Chem. 2010, 75, 3781. 25. Lago, J. H. G.; Ramos, C. S.; Casanova, D. C. C.; Morandim, A. A.; Bergamo, D. C. B.; Cavalheiro, A. J.; Bolzani, V. S.; Furlani, M.; Guilharaes, E. F.; Young, M. C. M.; Kato, M. J. J. Nat. Prod. 2004, 67, 1783. 26. Bernard, C. B.; Krishnamurty, H. G.; Chauret, D.; Durst, T.; Philogene, B. J. R.; Vindas, P. S.; Hasbun, C.; Poveda, L. J. Chem. Ecol. 1995, 21, 801. 27. (a) Engler, T. A.; La Tessa, K. O.; Iyengar, R.; Chai, W.; Agrios, K. Bioorg. Med. Chem. 1996, 4, 1755; (b) Kashiwada, Y.; Yamazaki, K.; Ikeshiro, Y.; Yamagishi, T.; Fujioka, T.; Mihashi, K.; Mizuki, K.; Cosentino, L. M.; Fowke, K.; MorrisNatschke, S.; Lee, K. H. Tetrahedron 2001, 57, 1559. 28. Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. J. Org. Chem. 1988, 53, 2406. 29. Chae, J.; Konno, T.; Ishihara, T.; Yamanaka, H. Chem. Lett. 2004, 33, 314. 30. Clayden, J.; Greeves, N.; Warren, S.; Worthers, P. Organic Chemistry; Oxford University Press: New York, 2001. 31. Kürti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis: Background and Detailed Mechanisms; Academic: Burlington, 2005. 32. Grieken, R. V.; Melero, J. A.; Morales, G. J. Mol. Catal. A: Chem. 2006, 256, 29. 33. Gullickson, G. C.; Lewis, D. E. Synthesis 2003, 5, 681. 34. Tamaddon, F.; Khoobi, M.; Keshavarz, E. Tetrahedron Lett. 2007, 48, 3643. 35. Sanz, R.; Martinez, A.; Guilarte, V.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Eur. J. Org. Chem. 2007, 28, 4642. 36. Barbero, M.; Bazzi, S.; Cadamuro, S.; Dughera, S. Eur. J. Org. Chem. 2009, 3, 430. 37. Ma’mani, L.; Heydari, A.; Sheykhan, M. Appl. Catal. A Gen. 2010, 384, 122. 38. Kalkhambkar, R. G.; Waters, S. N.; Laali, K. K. Tetrahedron Lett. 2011, 52, 867.
Please cite this article in press as: Ratnakar Reddy, K.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.05.041
K. Ratnakar Reddy et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx 39. Norell, J. R. J. Org. Chem. 1970, 35, 1611. 40. Vardanyan, R.; Hruby, V. J. Synthesis of Essential Drugs, 1st ed.; Elsevier: Amsterdam, 2006. p. 137. 41. Ziarani, G. M.; Badiei, A.; Dashtianeh, Z.; Gholamzadeh, P.; Mohtasham, N. H. Res. Chem. Intermed. 2013, 39, 3157. 42. Subba Reddy, B. V.; Sivasankar Reddy, N.; Madan, C.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 4827. 43. Li, H.; Cai, L.; Li, J.; Hu, Y.; Zhou, P.; Zhang, J. Dyes Pigm. 2011, 91, 309. 44. SMART & SAINT Software Reference Manuals. Versions 6.28a & 5.625; Bruker Analytical X-ray Systems Inc.: Madison, Wisconsin, USA, 2001. 45. Sheldrick, G. M. SHELXS97 and SHELXL97, Programs for Crystal Structure Solution and Refinement; University of Gottingen: Germany, 1997.
5
46. Amsterdam, D. Susceptibility testing of antimicrobials in liquid media. In Antibiotics in Laboratory Medicine; Loman, V., Ed., 4th ed.; Williams and Wilkins: Baltimore, MD, USA, 1996; p 52. 47. National Committee for Clinical Laboratory Standards Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, 5th ed.; NCCLS: Wayne, PA, 2000. 48. Furlani, R. E.; Yeagley, A. A.; Melander, C. A. Eur. J. Med. Chem. 2013, 62, 59. 49. Ratnakar Reddy, K.; Sambasiva Rao, P.; Jitender Dev, G.; Poornachandra, Y.; Kumar, C. G.; Rao, P. S.; Narsaiah, B. Bioorg. Med. Chem. Lett. 2014, 24, 1661. 50. Madeo, F.; Fröhlich, E.; Ligr, M.; Grey, M.; Sigrist, S. J.; Wolf, D. H.; Fröhlich, K. U. J. Cell Biol. 1999, 145, 757. 51. Kumar, C. G.; Poornachandra, Y. Colloids Surf. B: Biointerfaces 2015, 125, 110.
Please cite this article in press as: Ratnakar Reddy, K.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.05.041
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel amide functionalized 2H-chromene derivatives by Ritter amidation of primary alcohol using HBF4OEt2 as a mild and versatile reagent and evaluation of their antimicrobial and anti-biofilm activities K. Ratnakar Reddy a, Y. Poornachandra c, G. Jitender Dev a, G. Mallareddy a, Jagadeesh B. Nanubolu b, C. Ganesh Kumar c, B. Narsaiah a,⇑ a
Fluoroorganic Division, (AcSIR)CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India c Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India b
a r t i c l e
i n f o
Article history: Received 7 January 2015 Revised 29 April 2015 Accepted 15 May 2015 Available online xxxx Keywords: Chromene-2-ol Amide functionalized 2H-chromene Reduction Ritter amidation HBF4OEt2 catalyst
a b s t r a c t A series of novel amide functionalized 2H-chromene derivatives 3 were prepared starting from ethyl-2hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate 1 via sodium borohydride reduction followed by Ritter amidation using HBF4OEt2 as a mild and versatile reagent. All the products 3 were screened for antimicrobial activity against various Gram-positive, Gram-negative bacteria and fungal strain. The promising derivatives such as 3f, 3g, 3k, 3l, 3m, 3n and 3o were further screened for minimum bactericidal concentration and bio-film inhibition activity and identified the potential ones. Among all the promising, compound 3g was more potent for antimicrobial, MBC and anti bio-film activities. The structure verses activity relationship of 3g revealed that the presence of two bromine atoms at sixth and R position promotes high activity. Ó 2015 Elsevier Ltd. All rights reserved.
In natural environment, bacteria are able to switch between two different life styles: the plank-tonic living forms and as biofilms. Bio-films are complex and highly structured communities of microbes of multiple species that are enclosed in a self-produced polymeric matrix which shields the embedded cells and are adherent to an inert or living surface.1,2 These bio-films are formed as a survival strategy in diverse and harsh environment and enable them to disperse and colonize new niches. The plank-tonic cells and bio-films differ significantly in their physiology, gene expression pattern and even morphology. Among the different bacterial strains, the most commonly encountered and clinically relevant bio-film forming microbes are the Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli.3–5 According to the US National Institute of Health, >80% of bacterial infections are contributed by biofilms.6 The bacteria also colonize on various biomedical implants such as stents, heart valves, vascular grafts and catheters through bacterial adhesion and bio-film formation.7 The bio-films have the ability to resist against stress, antibiotics, biocides and host-immunological defense and thus they pose a ⇑ Corresponding author. Tel.: +91 40 27193185; fax: +91 40 27160387. E-mail address: [email protected] (B. Narsaiah).
challenge.8 In the recent past, a significant attention has been generated among the scientific community towards understanding the biology of bio-films and the search for novel inhibitors for the control of bio-film formation and related cellular processes.9,10 To date, only a few molecular scaffolds have been identified that function as anti bio-film compounds and amongst them the well studied examples are the natural halogenated furanones isolated from the red alga Delisea pulchra,11,12 analogues of the homo-serine lactone signaling molecules13 and sponge-derived marine natural alkaloids oroidin and bromoageliferin.14–17 We have earlier identified novel pyrazolo[3,4-b]pyridine and pyrimidine functionalized [1,2,3-triazole] derivatives as promising antimicrobial and anti bio-film active agents.18 We proposed to explore the antimicrobial and anti bio-film activities against some of the novel molecules having the 2H-chromene framework. In the present context, 2H-chromene nucleus is present in many biologically active molecules which include antioxidant,19 polyphenols20 and natural products.21 Some of the 2H-chromene derivatives also used as substrates for the synthesis of antitumor,22,23 antimicrobial,24 fungicidal,25 insecticidal26 and anti-HIV agents.27 Recently, it was found that the fluorine28 or trifluoromethyl29 group at a strategic position of an organic molecule
http://dx.doi.org/10.1016/j.bmcl.2015.05.041 0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ratnakar Reddy, K.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.05.041
2
K. Ratnakar Reddy et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx 10000
Fluorescence units
Control
3g
Erythromycin
1000
100
10
1 0.5
1
1.5
2
Concentration (µM) Figure 1. ROS studies.
dramatically alters the properties of molecule in terms of lipid solubility, oxidative thermal stability, permeability and oral bioavailability thereby enhancement in the transport mechanism. The Ritter reaction was used in preparation of many bioactive molecules and drugs such as amantadine as an antiviral and antiParkinson drug.30 Crixivan as an anti-HIV,31 and aristotelone alkaloid as a dopamine receptor ligand.32 In earlier reports, several methodologies have been reported for Ritter reaction in which sulfuric acid was replaced by formic acid under reflux,33 P2O5/SiO2,34 2,4-dinitrobenzene disulfonic acid,35 O-benzene disulfonamide,36 HClO4-functionalized silica-coated nano particles,37 ionic liquid,38 liquid HF,39 Bi(OTf)340 and SiO2-Pr-SO3H41 (sulfonic-acid-functionalized silica as a heterogeneous solid acid catalyst). HBF4OEt242 was also used for the amidation of olefins with nitriles, however, there are no reports available on the amidation of alcohols with nitriles using HBF4OEt2. Based on the above importance, the interest is continuously growing on synthesis of fluorinated chromenes. In continuation to our efforts on synthesis of trifluoromethyl substituted 2H-chromenes,43 we have synthesized a series of novel amide functionalized 2H-chromene derivatives by Ritter amidation of primary alcohol using HBF4OEt2 as a mild and versatile reagent. All the products were screened for antimicrobial activity. Compounds which showed promising activity were further screened for minimum bactericidal concentration, bio-film inhibition activity and potential compounds have been identified. The ethyl-2-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carb oxylate 143 was reduced with sodium borohydride in THF at room temperature for ten minutes followed by reflux for 1 hour to obtain 3-(hydroxymethyl)-2-(trifluoromethyl)-2H-chromen-2-ol 2. Compound 2 was further reacted with diverse substituted acetonitriles in the presence of HBF4OEt2 under solvent-free conditions to form amide functionalized 2H-chromene derivatives 3a–o via
Figure 2. Crystal structure of compound 3l.
Ritter amidation reaction. The reaction was completed in 15– 20 min with high yields. The primary alcohol was selectively protonated in presence of HBF4 followed by amidation by nucleophilic attack on primary carbon to give products 3a–o. The product 3l was identified by spectroscopy followed by single crystal X-ray crystallography. The ORTEP diagram44,45 of compound 3l is presented in Figure 2 and deposited in data bank with a unique depository number, CCDC 1020412 (e-mail: [email protected]. uk). The possible mechanism for the synthesis of compounds 3a–o by Ritter reaction is outlined in Scheme 2. The reaction steps involved drawn in Scheme 1 and products are tabulated in Table 1. Compounds 3a–o were screened against various Gram-positive bacteria such as (Bacillus subtilis MTCC 121, Staphylococcus aureus MLS-16 MTCC 2940, Micrococcus luteus MTCC 2470) and Gramnegative bacteria (Escherichia coli MTCC 739, Klebsiella planticola MTCC 530) using ciprofloxacin as standard and also screened against fungal strain (Candida albicans MTCC 3017) using miconazole as standard. Compounds 3f, 3g, 3k, 3l, 3m, 3n, and 3o showed promising activity towards Gram-positive and Gram-negative bacteria at 125 lg/mL. e CIP: ciprofloxacin. f MIC: miconazole.
Table 3 MBC of the selected amide functionalized 2H-chromene derivatives Minimum bactericidal concentration (lM)
Compd
Bacteriaa
3f 3g 3k 3l 3m 3n 3o CIPc
Bacteriab
ML
SA
BS
EC
KP
38.3 8.3 33.6 74.2 74.2 33.6 28.6 5.7
19.1 4.0 67.2 37.1 37.1 67.2 14.3 2.7
19.1 4.0 >230 74.2 74.2 >230 28.6 5.7
38.3 16.6 >230 >230 37.1 >230 14.3 5.7
19.1 8.3 >230 >230 74.2 >230 57.3 2.7
a Gram-positive bacteria; ML, Micrococcus luteus MTCC 2470; SA, Staphylococcus aureus; MLS-16 MTCC 2940; BS, Bacillus subtilis MTCC 121. b Gram-negative bacteria; EC, Escherichia coli MTCC 739; KP, Klebsiella planticola MTCC 530. c CIP: ciprofloxacin.
Table 4 Bio-film inhibition assay of the selected amide functionalized 2H-chromene derivatives Ca
IC50 values in (lM, mean ± SD, n = 3) Bacteriab
3f 3g 3k 3l 3m 3n 3o ERd a
Bacteriac
ML
SA
BS
EC
KP
8.3 ± 0.31 1.7 ± 0.11 19.1 ± 0.41 17.1 ± 0.19 18.4 ± 0.32 17.4 ± 0.26 7.7 ± 0.16 0.31 ± 0.14
3.6 ± 0.22 1.2 ± 0.22 21.9 ± 0.38 19.7 ± 0.41 9.2 ± 0.23 16.8 ± 0.36 6.2 ± 0.17 0.25 ± 0.22
5.1 ± 0.09 1.4 ± 0.08 — 43.8 ± 0.42 22.2 ± 0.36 — 8.8 ± 0.19 0.42 ± 0.18
10.5 ± 0.26 1.4 ± 0.11 — — 8.2 ± 0.22 — 5.8 ± 0.18 0.43 ± 0.17
12.7 ± 0.25 1.7 ± 0.16 — — 24.6 ± 0.18 — 14.8 ± 0.22 0.35 ± 0.16
C: compound Gram-positive bacteria; ML, Micrococcus luteus MTCC 2470; SA, Staphylococcus aureus; MLS-16 MTCC 2940; BS, Bacillus subtilis MTCC 121. c Gram-negative bacteria; EC, Escherichia coli MTCC 739; KP, Klebsiella planticola MTCC 530. d ER: erythromycin. b
Authors are thankful to the Council of Scientific & Industrial Research (CSIR), New Delhi, India for the financial support through Development of Innovative Technologies for Strategic Fluorochemicals (DITSF) under XII five year plan project code:CSC-0204. Authors (K. Ratnakar Reddy, Y. Poornachandra, G. Jitender Dev and G. Mallareddy) are also thankful to the Council of Scientific and Industrial Research (CSIR), India for providing financial assistance in the form of Research Fellowship and contingency grant. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.05. 041. References and notes 1. Costerton, J. W.; Lewandowski, Z.; Caldwell, D. E.; Korber, D. R.; Lappin-Scott, H. M. Annu. Rev. Microbiol. 1995, 49, 711. 2. Donlan, R. M.; Costerton, J. W. Clin. Microbiol. Rev. 2002, 15, 167. 3. Otto, M. Curr. Top. Microbiol. Immunol. 2008, 322, 207. 4. Mann, E. E.; Wozniak, D. J. FEMS Microbiol. Rev. 2012, 36, 893. 5. Beloin, C.; Roux, A.; Ghigo, J. C. Curr. Top. Microbiol. Immunol. 2008, 322, 249. 6. Davies, D. Nat. Rev. Drug Discov. 2003, 2, 114. 7. Saint, S.; Chenoweth, C. E. Infect. Dis. Clin. North Am. 2003, 17, 411. 8. Costerton, J. W.; Stewart, P. S.; Greenberg, E. P. Science 1999, 284, 1318. 9. Musk, D. J., Jr.; Hergenrother, P. J. Curr. Med. Chem. 2006, 13, 2163. 10. Landini, P.; Antoniani, D.; Burgess, J. G.; Nijland, R. Appl. Microbiol. Biotechnol. 2010, 86, 813. 11. Gram, L.; De Nys, R.; Maximilien, M.; Givskov, M.; Steinberg, P.; Kjelleberg, S. D. Appl. Environ. Microbiol. 1996, 62, 4284. 12. Janssens, J. C.; Steenackers, H.; Robijns, S.; Gellens, E.; Levin, J.; Zhao, H.; Hermans, K.; De Coster, D.; Verhoeven, T. L.; Marchal, K.; Vanderleyden, J.; De Vos, D. E.; De Keersmaecker, S. C. Appl. Environ. Microbiol. 2008, 74, 6639. 13. Geske, G. D.; Wezeman, R. J.; Siegel, A. P.; Blackwell, H. E. J. Am. Chem. Soc. 2005, 127, 12762. 14. Huigens, R. W.; Richards, J. J.; Parise, G.; Ballard, T. E.; Zeng, W.; Deora, R.; Melander, C. J. Am. Chem. Soc. 2007, 129, 6966. 15. Richards, J. J.; Ballard, T. E.; Melander, C. Org. Biomol. Chem 2008, 6, 1356. 16. Richards, J. J.; Ballard, T. E.; Huigens, R. W.; Melander, C. ChemBioChem 2008, 9, 1267. 17. Richards, J. J.; Reyes, S.; Stowe, S. D.; Tucker, A. T.; Ballard, T. E.; Mathies, L. D.; Cavanagh, J.; Melander, C. J. Med. Chem. 2009, 52, 4582. 18. Nagender, P. Bioorg. Med. Chem. Lett. 2014, 24, 2905. 19. Mukai, K.; Okabe, K.; Hosose, H. J. Org. Chem. 1989, 54, 557. 20. Jankun, J.; Selman, S. H.; Swierez, R. Nature 1997, 387, 561. 21. Parmar, V. S.; Jain, S. C.; Bisht, K. S., et al. Phytochemistry 1997, 46, 597. 22. Reddy, B. V. S.; Divya, B.; Swain, M.; Rao, T. P.; Yadav, J. S.; Vishnu Vardhan, M. V. P. S. Bioorg. Med. Chem. Lett. 1995, 2012, 22. 23. Elomri, A.; Mitaku, S.; Michel, S.; Skaltsounis, A. L.; Illequin, F. T.; Koch, M.; Pierre, A.; Guilbaud, N.; Leonce, S.; Kraus-Berthier, L.; Rolland, Y.; Atassi, G. J. Med. Chem. 1996, 39, 4762. 24. a) Kidwai, M.; Saxena, S.; Khan, M. K. R.; Thukral, S. S. J. Org. Chem. 2010, 75, 3781. 25. Lago, J. H. G.; Ramos, C. S.; Casanova, D. C. C.; Morandim, A. A.; Bergamo, D. C. B.; Cavalheiro, A. J.; Bolzani, V. S.; Furlani, M.; Guilharaes, E. F.; Young, M. C. M.; Kato, M. J. J. Nat. Prod. 2004, 67, 1783. 26. Bernard, C. B.; Krishnamurty, H. G.; Chauret, D.; Durst, T.; Philogene, B. J. R.; Vindas, P. S.; Hasbun, C.; Poveda, L. J. Chem. Ecol. 1995, 21, 801. 27. (a) Engler, T. A.; La Tessa, K. O.; Iyengar, R.; Chai, W.; Agrios, K. Bioorg. Med. Chem. 1996, 4, 1755; (b) Kashiwada, Y.; Yamazaki, K.; Ikeshiro, Y.; Yamagishi, T.; Fujioka, T.; Mihashi, K.; Mizuki, K.; Cosentino, L. M.; Fowke, K.; MorrisNatschke, S.; Lee, K. H. Tetrahedron 2001, 57, 1559. 28. Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. J. Org. Chem. 1988, 53, 2406. 29. Chae, J.; Konno, T.; Ishihara, T.; Yamanaka, H. Chem. Lett. 2004, 33, 314. 30. Clayden, J.; Greeves, N.; Warren, S.; Worthers, P. Organic Chemistry; Oxford University Press: New York, 2001. 31. Kürti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis: Background and Detailed Mechanisms; Academic: Burlington, 2005. 32. Grieken, R. V.; Melero, J. A.; Morales, G. J. Mol. Catal. A: Chem. 2006, 256, 29. 33. Gullickson, G. C.; Lewis, D. E. Synthesis 2003, 5, 681. 34. Tamaddon, F.; Khoobi, M.; Keshavarz, E. Tetrahedron Lett. 2007, 48, 3643. 35. Sanz, R.; Martinez, A.; Guilarte, V.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Eur. J. Org. Chem. 2007, 28, 4642. 36. Barbero, M.; Bazzi, S.; Cadamuro, S.; Dughera, S. Eur. J. Org. Chem. 2009, 3, 430. 37. Ma’mani, L.; Heydari, A.; Sheykhan, M. Appl. Catal. A Gen. 2010, 384, 122. 38. Kalkhambkar, R. G.; Waters, S. N.; Laali, K. K. Tetrahedron Lett. 2011, 52, 867.
Please cite this article in press as: Ratnakar Reddy, K.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.05.041
K. Ratnakar Reddy et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx 39. Norell, J. R. J. Org. Chem. 1970, 35, 1611. 40. Vardanyan, R.; Hruby, V. J. Synthesis of Essential Drugs, 1st ed.; Elsevier: Amsterdam, 2006. p. 137. 41. Ziarani, G. M.; Badiei, A.; Dashtianeh, Z.; Gholamzadeh, P.; Mohtasham, N. H. Res. Chem. Intermed. 2013, 39, 3157. 42. Subba Reddy, B. V.; Sivasankar Reddy, N.; Madan, C.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 4827. 43. Li, H.; Cai, L.; Li, J.; Hu, Y.; Zhou, P.; Zhang, J. Dyes Pigm. 2011, 91, 309. 44. SMART & SAINT Software Reference Manuals. Versions 6.28a & 5.625; Bruker Analytical X-ray Systems Inc.: Madison, Wisconsin, USA, 2001. 45. Sheldrick, G. M. SHELXS97 and SHELXL97, Programs for Crystal Structure Solution and Refinement; University of Gottingen: Germany, 1997.
5
46. Amsterdam, D. Susceptibility testing of antimicrobials in liquid media. In Antibiotics in Laboratory Medicine; Loman, V., Ed., 4th ed.; Williams and Wilkins: Baltimore, MD, USA, 1996; p 52. 47. National Committee for Clinical Laboratory Standards Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, 5th ed.; NCCLS: Wayne, PA, 2000. 48. Furlani, R. E.; Yeagley, A. A.; Melander, C. A. Eur. J. Med. Chem. 2013, 62, 59. 49. Ratnakar Reddy, K.; Sambasiva Rao, P.; Jitender Dev, G.; Poornachandra, Y.; Kumar, C. G.; Rao, P. S.; Narsaiah, B. Bioorg. Med. Chem. Lett. 2014, 24, 1661. 50. Madeo, F.; Fröhlich, E.; Ligr, M.; Grey, M.; Sigrist, S. J.; Wolf, D. H.; Fröhlich, K. U. J. Cell Biol. 1999, 145, 757. 51. Kumar, C. G.; Poornachandra, Y. Colloids Surf. B: Biointerfaces 2015, 125, 110.
Please cite this article in press as: Ratnakar Reddy, K.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.05.041
