(Hetero)aroyl esters of 2-(N-phthalimido)ethanol and analogues: parallel synthesis, anti-HIV-1 activity and cytotoxicity

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• 作者：Sara Cesarini (1)
  Andrea Spallarossa (1)
  Angelo Ranise (1)
  Silvia Schenone (1)
  Paolo La Colla (2)
  Gabriella Collu (2)
  Giuseppina Sanna (2)
  Roberta Loddo (2)
  
• 关键词：Anti ; HIV ; 1 activity ; Cytotoxicity ; Parallel synthesis ; Esters
• 刊名：Medicinal Chemistry Research
• 出版年：2010
• 出版时间：May 2010
• 年：2010
• 卷：19
• 期：4
• 页码：311-336
• 全文大小：727KB
• 参考文献：1. Artico M, Silvestri R, Massa S, Loi AG, Corrias S, Piras G, La Colla P (1996) 2-Sulfonyl-4-chloroanilino moiety: a potent pharmacophore for the anti-human immunodeficiency virus type 1 activity of pyrrolyl aryl sulfones. J Med Chem 39:522-30. doi:10.1021/jm950568w CrossRef
  2. Balzarini J (2004) Current status of the non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1. Curr Top Med Chem 4:921-44. doi:10.2174/1568026043388420 CrossRef
  3. Barbaro G, Scozzafava A, Mastrolorenzo A, Supuran CT (2005) Highly active antiretroviral therapy: current state of the art, new agents and their pharmacological interactions useful for improving therapeutic outcome. Curr Pharm Des 11:1805-843. doi:10.2174/1381612053764869 CrossRef
  4. Bell FW, Cantrell AS, H?gberg M, Jaskunas SR, Johansson NG, Jordan CL, Kinnick MD, Lind P, Morin JM Jr, Noréen R, ?berg B, Palkowitz JA, Parrish CA, Pranc P, Sahlberg C, Ternansky RJ, Vasileff RT, Vrang L, West SJ, Zhang H, Zhou X (1995) Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs. J Med Chem 38:4929-936. doi:10.1021/jm00025a010 CrossRef
  5. Campiani G, Ramunno A, Maga G, Nacci V, Fattorusso C, Catalanotti B, Morelli E, Novellino E (2002) Non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors: past, present, and future perspectives. Curr Pharm Des 8:615-57. doi:10.2174/1381612024607207 CrossRef
  6. De Clercq E (1998) The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res 38:153-79. doi:10.1016/S0166-3542(98)00025-4 CrossRef
  7. De Clercq E (2001) New developments in anti-HIV chemotherapy. Farmaco 56:3-2. doi:10.1016/S0014-827X(01)01007-2 CrossRef
  8. De Clercq E (2004) Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present, and future. Chem Biodivers 1:44-4. doi:10.1002/cbdv.200490012 CrossRef
  9. De Clercq E (2005a) Emerging anti-HIV drugs. Expert Opin Emerg Drugs 10:241-73. doi:10.1517/14728214.10.2.241 CrossRef
  10. De Clercq E (2005b) New approaches toward anti-HIV chemotherapy. J Med Chem 48:1297-313. doi:10.1021/jm040158k CrossRef
  11. Jonckheere H, Anne J, De Clercq E (2000) The HIV-1 reverse transcription (RT) process as target for RT inhibitors. Med Res Rev 20:129-54. doi:10.1002/(SICI)1098-1128(200003)20:2<129::AID-MED2>3.0.CO;2-A CrossRef
  12. Leigh Brown AJ, Frost SD, Mathews WC, Dawson K, Hellmann NS, Daar ES, Richman DD, Little SJ (2003) Transmission fitness of drug-resistant human immunodeficiency virus and the prevalence of resistance in the antiretroviral-treated population. J Infect Dis 187:683-86. doi:10.1086/367989 CrossRef
  13. Maass G, Immendoerfer U, Koenig B, Leser U, Mueller B, Goody R, Pfaff E (1993) Viral resistance to the thiazolo-iso-indolinones, a new class of nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 37:2612-617
  14. Mizuch KG, Kasatkin NM, Gel’fer TM (1957) Reaction of acyl chlorides with some hydroxymethyl compounds. Zh Obshch Khim 27:189-95
  15. Pauwels R (2004) New non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development for the treatment of HIV infections. Curr Opin Pharmacol 4:437-46. doi:10.1016/j.coph.2004.07.005 CrossRef
  16. Pauwels R, Balzarini J, Baba M, Snoeck R, Schols D, Herdewijn P, Desmyter J, De Clercq E (1988) Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods 20:309-21. doi:10.1016/0166-0934(88)90134-6 CrossRef
  17. Pedersen OS, Pedersen EB (1999) Non-nucleoside reverse transcriptase inhibitors, the NNRTI boom. Antivir Chem Chemother 10:285-14
  18. Pedersen OS, Pedersen EB (2000) The flourishing syntheses of non-nucleoside reverse transcriptase inhibitors. Synthesis 4:479-95. doi:10.1055/s-2000-6357 CrossRef
  19. Ranise A, Spallarossa A, Cesarini S, Bondavalli F, Schenone S, Bruno O, Menozzi G, Fossa P, Mosti L, La Colla M, Sanna G, Murreddu M, Collu G, Busonera B, Marongiu ME, Pani A, La Colla P, Loddo R (2005) Structure-based design, parallel synthesis, structure-activity relationship, and molecular modeling studies of thiocarbamates, new potent non-nucleoside HIV-1 reverse transcriptase inhibitor isosteres of phenethylthiazolylthiourea derivatives. J Med Chem 48:3858-873. doi:10.1021/jm049252r CrossRef
  20. Ranise A, Spallarossa A, Schenone S, Bruno O, Bondavalli F, Vargiu L, Marceddu T, Mura M, La Colla P, Pani A (2003) Design, synthesis, SAR, and molecular modeling studies of acylthiocarbamates: a novel series of potent non-nucleoside HIV-1 reverse transcriptase inhibitors structurally related to phenethylthiazolylthiourea derivatives. J Med Chem 46:768-81. doi:10.1021/jm0209984 CrossRef
  21. Ren J, Diprose J, Warren J, Esnouf RM, Bird LE, Ikemizu S, Slater M, Milton J, Balzarini J, Stuart DI, Stammers DK (2000) Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. J Biol Chem 275:5633-639. doi:10.1074/jbc.275.8.5633 CrossRef
  22. Richman DD, Morton SC, Wrin T, Hellmann N, Berry S, Shapiro MF, Bozzette SA (2004) The prevalence of antiretroviral drug resistance in the United States. AIDS 18:1393-401. doi:10.1097/01.aids.0000131310.52526.c7 CrossRef
  23. Silverman RB (2004) The organic chemistry of drug design and drug action. Elsevier, Amsterdam, pp 17-0
  24. Sova M, Perdih A, Kotnik M, Kristan K, Ri?ner TL, Solmajer T, Gobec S (2006) Flavonoid and cinnamic acid esters as inhibitors of fungal 17β-hydroxysteroid dehydrogenase: a synthesis, QSAR and modelling study. J Biol Chem 275:5633-639
  25. Spallarossa A, Cesarini S, Ranise A, Bruno O, Schenone S, La Colla P, Collu G, Sanna G, Secci B, Loddo R (2008a) Novel modifications in the series of O-(2-phthalimidoethyl)-N-substituted thiocarbamates and their ring-opened congeners as non-nucleoside HIV-1 reverse transcriptase inhibitors. Eur J Med Chem. doi:10.1016/j.ejmech.2008.09.024
  26. Spallarossa A, Cesarini S, Ranise A, Schenone S, Bruno O, Borassi A, La Colla P, Pezzullo M, Sanna G, Collu G, Secci B, Loddo R (2008b) Parallel synthesis, molecular modelling and further structure-activity relationship studies of new acylthiocarbamates as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. Eur J Med Chem. doi:10.1016/j.ejmech.2008.10.032
  27. Tantillo C, Ding J, Jacobo-Molina A, Nanni RG, Boyer PL, Hughes SH, Pauwels R, Andries K, Janssen PA, Arnold E (1994) Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. J Mol Biol 243:369-87. doi:10.1006/jmbi.1994.1665 CrossRef
  28. Thomas G (2000) Medicinal chemistry. Wiley, New York, pp 40-2
  29. Vig R, Mao C, Venkatachalam TK, Tuel-Ahlgren L, Sudbeck EA, Uckun FM (1998) Rational synthesis of phenethyl--bromopyridyl thiourea derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase. Bioorg Med Chem 6:1789-797. doi:10.1016/S0968-0896(98)00108-4 CrossRef
  
• 作者单位：Sara Cesarini (1)
  Andrea Spallarossa (1)
  Angelo Ranise (1)
  Silvia Schenone (1)
  Paolo La Colla (2)
  Gabriella Collu (2)
  Giuseppina Sanna (2)
  Roberta Loddo (2)
  
  1. Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, 16132, Genova, Italy
  2. Dipartimento di Scienze e Tecnologie Biomediche, Università di Cagliari, Cittadella Universitaria, S.S. 554, Km 4,500, 09042, Monserrato (Cagliari), Italy
  

文摘

The structural simplification of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) O-(2-phthalimidoethyl)-N-(hetero)aroyl-N-arylthiocarbamates led us to design (hetero)aroyl esters of 2-(N-phthalimido)ethanol as a potential new class of anti-HIV-1 agents. The setup of a solution-phase parallel synthesis method allowed the rapid preparation of a high number of analogues. In cell-based assays, 20 of 34 esters showed anti-HIV-1 activity ranging from nanomolar to micromolar concentrations. The most potent esters had only a minor effect or were ineffective in enzyme assay against HIV-1 reverse transcriptase. Variations on the O-(2-phthalimidoethyl) moiety led to compounds devoid of antiretroviral activity, but cytotoxic, in particular those bearing the 4-chloro-3-nitrobenzoyl moiety. The most cytotoxic compound displayed a CC50 value of 1.6?μM.