Skip to main content

Advertisement

SpringerLink
Log in

Tautomerism in drug discovery

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

The influence of tautomerism on the precise structure of drugs and thus of their potential to interact with biological systems is discussed from thermodynamic and kinetic aspects. The types of tautomerism encountered in the structure of drugs in current use are surveyed together with the effect of pH, solvent polarity, and temperature.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

Notes

  1. The indistinct line between slowly inter-converting tautomers and structural isomers is generally considered to fall somewhere in between CH/CH tautomerism (ΔG≠ ≈ 25–35 kcal mol−1) and cis/trans isomers (ΔG≠ ≥ 60 kcal mol−1 since the average energy for cleavage of a π bond is 63 kcal mol−1).

References

  1. Katritzky AR, Lagowski JM (1963) Adv Heterocycl Chem (Katritzky AR (eds) Academic Press, New York, N.Y.) 1: 311–338

  2. Katritzky AR, Lagowski JM (1963a) Adv Heterocycl Chem (Katritzky AR (eds) Academic Press, New York) 1: 339–437

  3. Katritzky AR, Lagowski JM (1963b) Adv Heterocycl Chem (Katritzky AR (eds) Academic Press, New York) 2: 1–26

  4. Elguero J, Marzin C, Katritzky A, Linda P (1976) Adv Heterocycl Chem, Supplement 1: the tautomerism of heterocycles. Academic Press, New York

    Google Scholar 

  5. Katritzky AR (1970) Chimia 24:134–146

    CAS  Google Scholar 

  6. Gronowitz S, Hoffman RA (1960) Arkiv foer Kemi 15:499–512

    CAS  Google Scholar 

  7. Hino T, Nakagawa M, Hashizume T, Yamaji N, Miwa Y, Tsuneoka K, Akaboshi S (1971) Tetrahedron 27:775–787

    Article  CAS  Google Scholar 

  8. Dickinson RP, Iddon B (1970) J Chem Soc C 14:1926–1928

    Article  Google Scholar 

  9. Woerner FP, Reimlinger H, Merenyi R (1971) Chem Ber 104:2789–2792

    Article  CAS  Google Scholar 

  10. Katritzky AR, Jozwiak A, Lue P, Yannakopoulou K, Palenik GJ, Zhang ZY (1990) Tetrahedron 46:633–640

    Article  CAS  Google Scholar 

  11. Katritzky AR, El-Gendy B-EM, Draghici B, Hall CD, Steel PJ (2010) Manuscript in preparation

  12. Cox BG (1994) Modern liquid phase kinetics. Oxford University Press, New York

    Google Scholar 

  13. Hore PJ (1995) Nuclear magnetic resonance. Oxford University Press, New York

    Google Scholar 

  14. Shanan-Atidi H, Bar-Eli KH (1970) J Phys Chem 74:961–963

    Article  CAS  Google Scholar 

  15. McKeage K, Blick SKA, Croxtall JD, Lyseng-Williamson KA, Keating GM (2008) Drugs 68:1571–1607

    Article  CAS  Google Scholar 

  16. Inoue M, Zhai H, Sakazaki H, Furuyama H, Fukuyama Y, Hirama M (2004) Bioorg Med Chem 14:663–665

    Article  CAS  Google Scholar 

  17. Cheer SM, Prakash A, Faulds D, Lamb M (2003) Drugs 63:101–132

    Article  CAS  Google Scholar 

  18. Th Moenius VR, Burtscher P, Zuger Ch (2000) J Labelled Compd Radiopharm 43:1245–1252

    Article  Google Scholar 

  19. Becker A (2008) PCT Int Appl WO 2008149155A1

  20. Alkorta I, Rozas I, Elguero J (1998) J Chem Soc Perkin Trans 2:2671–2675

    Google Scholar 

  21. Mulvany MJ, Skov K, Eiskjær H, Hansen HE, Madsen JK, Kvist S, Mulvany MJ (2007) Hypertension 50:89–95

    Article  Google Scholar 

  22. Wilson TW, Lacourciere Y, Barnes CC (1998) CMAJ 159:469–476

    CAS  Google Scholar 

  23. Bauer M, Harris RK, Rao RC, Apperley DC, Rodger CA (1998) J Chem Soc, Perkin Trans 2:475–482

    Google Scholar 

  24. Myznikov LV, Hrabalek A, Koldobskiil GI (2007) Chem Heterocycl Comp 43:1–9

    Article  CAS  Google Scholar 

  25. McCarthy KE, Wang Q, Tsai EW, Gilbert RE, Dominic P, Brooks MA (1998) J Pharm Biomed Anal 17:671–677

    Article  CAS  Google Scholar 

  26. Cagigal E, Gonzalez L, Alonso RM, Jimenez RM (2001) J Pharm Biomed Anal 26:477–486

    Article  CAS  Google Scholar 

  27. Fudemberg SJ, Batiste C, Katz LJ (2008) Expert Opin Drug Saf 7:795–799

    Article  CAS  Google Scholar 

  28. JackmanIb LM, Jen T (1975) J Am Chem Soc 97:2811–2818

    Article  Google Scholar 

  29. Varga LI, Ako-Agugua N, Colasante J, Hertweck L, Houser T, Smith J, Watty AA, Naga S, Raffa RB (2009) J Clin Pharm Ther 34:493–505

    Article  CAS  Google Scholar 

  30. Pool CR, Roman RS, Brighwell MD, Tremper AW (1994) PCT Int Appl WO9405659A1

  31. Seufert J (2006) Curr Med Res Opin 22:S39–S48

    Article  CAS  Google Scholar 

  32. Poklis JL, Ropero-Miller JD, Garside D, Winecker RE (2004) J Anal Toxicol 28:537–540

    CAS  Google Scholar 

  33. Rapoport AM, Bigal ME, Tepper SJ, Sheftell FD (2004) Expert Rev Neurotherapeutics 4:33–41

    Article  CAS  Google Scholar 

  34. Daluge SM, Good SS, Faleto MB, Miller WH, St. Clair MH, Boone LR, Tisdale M, Parry NR, Reardon JE, Dornsife RE, Averett DR, Krenitsky TA (1997) Antimicrob Agents Chemother 41:1082–1093

    CAS  Google Scholar 

  35. Daluge SM (1991) U.S. Patent US5034394A

  36. Deeks SG, Barditch-Crovo P, Lietman PS, Hwang F, Cundy KC, Rooney JF, Hellmann NS, Safrin S, Kahn JO (1998) Antimicrob Agents Chemother 42:2380–2384

    CAS  Google Scholar 

  37. Binnie CD, Boas WVE, Land W, Meijer GS, Overweg JWA, Van Wieringen A (1985) Br J Clin Pharmacol 20: 285 (abstract)

  38. Beutner KR, Geisse JK, Helman D, Fox TL, Ginkel A, Owens ML (1999) J Am Acad Dermatol 41:1002–1007

    Article  CAS  Google Scholar 

  39. Sidky YA, Borden EC, Weeks CE, Reiter MJ, Hatcher JF, Bryan GT (1992) Cancer Res 52:3528–3533

    CAS  Google Scholar 

  40. Rusch V, Baselga J, Cordon-Cardo C, Orazem J, Hoda S, Mclntosh J, Kurie J, Dmitrovsky E (1993) Cancer Res 53:2379–2385

    CAS  Google Scholar 

  41. Grandis JR, Tweardy DJ (1993) Cancer Res 53:3579–3584

    CAS  Google Scholar 

  42. Moyer JD, Barbacci EG, Iwata KK, Arnold L, Boman B, Cunningham A, Diorio C, Doty J, Morin MJ, Moyer MP, Neveu M, Pollack VA, Pustilnik LR, Reynolds MM, Sloan D, Theleman A, Miller P (1997) Cancer Res 57:4838–4848

    CAS  Google Scholar 

  43. Bartlett JB, Dredge K, Dalgleish AG (2004) Nat Rev Cancer 4:314–322

    Article  CAS  Google Scholar 

  44. Laffitte E, Revuz J (2004) Expert Opin Drug Saf 3:47–56

    Article  CAS  Google Scholar 

  45. Murphy RL, Brun S, Hicks C, Eron JJ, Gulick R, King M, White AC, Benson C, Thompson M, Kessler HA, Hammer S, Bertz R, Hsu A, Japour A, Sun E (2001) AIDS 15:F1–F9

    Article  CAS  Google Scholar 

  46. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R, Corso A, Masliak Z, Marta Olesnyckyj, Yu Z, Patin J, Zeldis JB, Knight RD (2007) N Engl J Med 357:2123–2132

    Article  CAS  Google Scholar 

  47. Weber D, Chen C, Niesvizky R, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD (2007) N Engl J Med 357:2133–2142

    Article  CAS  Google Scholar 

  48. Young SD, Britcher SF, Tran LO, Payne LS, Lumma WC, Lyle TA, Huff JR, Anderson PS, Olsen DB, Carroll SS, Pettibone DJ, O’Brien JA, Ball RG, Balani SK, Lin JH, Chen I-WU, Schleif WA, Sardana VV, Long WJ, Byrnes VW, Emini EA (1995) Antimicrob Agents Chemother 39:2602–3605

    CAS  Google Scholar 

  49. Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, Ali MW (2002) J Clin Psychiatry 63:763–771

    CAS  Google Scholar 

  50. Thomas LN, Douglas RC, Lazier CB, Too CKL, Rittmaster RS, Tindall DJ (2008) Eur Urol 53:244–252

    Article  CAS  Google Scholar 

  51. Miller J, Tarter TH (2009) Clin Interv Aging 4:251–258

    CAS  Google Scholar 

  52. Gormley GJ, Stoner E, Rittmaster RS, Gregg H, Thompson DL, Lasseter KC, Vlasses PH, Steven EA (1990) J Clin Endocrinol Metab 70:1136–1141

    Article  CAS  Google Scholar 

  53. Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ (1995) Antimicrob Agents Chemother 39:1546–1553

    CAS  Google Scholar 

  54. DeJesus E, Wald A, Warren T, Schacker TW, Trottier S, Shahmanesh M, Hill JL, Brennan CA (2003) J Infect Dis 188:1009–1016

    Article  CAS  Google Scholar 

  55. Elion GB, Furman PA, Fyfe JA, de Miranda P, Beauchamp L, Schaeffer HJ (1977) Proc Natl Acad Sci USA 74:5716–5720

    Article  CAS  Google Scholar 

  56. Schaeffer HJ, Beauchamp L, de Miranda P, Elion GB, Bauer DJ, Collins P (1978) Nature 272:583–585

    Article  CAS  Google Scholar 

  57. McGavin JK, Goa KL (2001) Drugs 61:1153–1183

    Article  CAS  Google Scholar 

  58. Singh N (2000) Clin Liver Dis 4:657–673

    Article  CAS  Google Scholar 

  59. Van der Bij W, Speich R (2001) Clin Infect Dis 33(Suppl 1):S32–S37

    Google Scholar 

  60. Schinazi RF, McMillan A, Cannon D, Mathis R, Lloyd RM, Peck A, Sommadoss JP, St Clair M, Wilson J, Furman PA, Painter GR, Choi WB, Liotta DC (1992) Antimicrob Agents Chemother 36:2423–2431

    CAS  Google Scholar 

  61. Furman PA, Davis M, Liotta DC, Paff M, Frick LW, Nelson DJ, Dornsife RE, Wurster JA, Wilson LJ, Fyfe JA, Tuttle JV, Miller WH, Condreay L, Averett DR, Schinazi RF, Painter GR (1992) Antimicrob Agents Chemother 36:2686–2692

    CAS  Google Scholar 

  62. Tisdale M, Kemp SD, Parry NR, Larder BA (1993) Proc Natl Acad Sci USA 90:5653–5656

    Article  CAS  Google Scholar 

  63. Lai CL, Chien RN, Leung NWY, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Debt JC, Barber J, Stephenson SL, Gray DF (1998) N Engl J Med 339:61–68

    Article  CAS  Google Scholar 

  64. Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HWL, Goodman Z, Crowther L, Condreay LD, Woessner M, Rubin M, Brown NA (1999) N Engl J Med 341:1256–1263

    Article  CAS  Google Scholar 

  65. Tassopoulos NC, Volpes R, Pastore G, Heathcote J, Buti M, Goldin R, Hawley S, Gray DF et al (1998) Hepatology 28(Suppl):43

    Google Scholar 

  66. Ishitsuka H, Miwa M, Ishikawa T, Ura M, Sawada N, Nishida M, Fukase Y, Yamamoto T, Mori K, Arasaki M, Umeda I, Shimma N (1995) Proc Am Assoc Cancer Res 36:407

    Google Scholar 

  67. Terrett NK, Bell AS, Brown D, Ellis P (1996) Bioorg Med Chem Lett 6:1819–1824

    Article  Google Scholar 

  68. Turker L (2000) ACH-Models Chem 137:767–774

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL, 32611-7200, USA

    Alan R. Katritzky, C. Dennis Hall, Bahaa El-Dien M. El-Gendy & Bogdan Draghici

  2. Department of Chemistry, Faculty of Science, Benha University, Benha, Egypt

    Bahaa El-Dien M. El-Gendy

Authors
  1. Alan R. Katritzky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Dennis Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bahaa El-Dien M. El-Gendy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bogdan Draghici
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan R. Katritzky.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Katritzky, A.R., Hall, C.D., El-Gendy, B.ED.M. et al. Tautomerism in drug discovery. J Comput Aided Mol Des 24, 475–484 (2010). https://doi.org/10.1007/s10822-010-9359-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-010-9359-z

Keywords

Search

Navigation