704
Views
19
CrossRef citations to date
0
Altmetric
Research Article

Novel tight binding PETT, HEPT and DABO-based non-nucleoside inhibitors of HIV-1 reverse transcriptase

Review

&
Pages 329-350 | Received 02 Feb 2006, Accepted 02 Apr 2006, Published online: 04 Oct 2008

References

  • Chaisson RE. HIV becomes world's leading infectious cause of death, The Hopkins HIV report-July 1999. Available from: http://www.aegis.com/pubs/jhopkins/1999/JH990702.html
  • Worldwide HIV & AIDS epidemic statistics, World estimates of the HIV & AIDS epidemics at the end of 2005. Available from: http://www.avert.org/worldstats.htm
  • Palella FJ, Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient study investigators. N Engl J Med 1998; 338: 853–860
  • Smit C, Geskus R, Uitenbroek D, Mulder D, Van Den Hoek A, Coutinho RA, Prins M. Declining AIDS mortality in Amsterdam: Contributions of declining HIV incidence and effective therapy. Epidemiology 2004; 15: 536–542
  • Yeni P, Hammer S, Hirsch M, Saag MS, Schechter M, Carpenter CC, Fischl MA, Gatell JM, Gazzard BG, Jacobsen DM, Katzenstein DA, Montaner JS, Richman DD, Schooley RT, Thompson MA, Vella S, Volberding PA. Treatment for adult HIV infection: 2004 recommendations of the international AIDS society USA panel. JAMA 2004; 292: 251–265
  • Bogaards JA, Goudsmit J. Meeting the immense need for HAART in resource-poor settings. J Antimicrob Chemother 2003; 52: 743–746
  • Moatti JP, N'Doye I, Hammer SM, Hale P, Kazatchkine M. Antiretroviral treatment for HIV infection in developing countries: An attainable new paradigm. Nat Med 2003; 9: 1449–1452
  • Craigo JK, Patterson BK, Paranjpe S, Kulka K, Ding M, Mellors J, Montelaro RC, Gupta P. Persistent HIV type 1 infection in semen and blood compartments in patients after long-term potent antiretroviral therapy. AIDS Res Hum Retroviruses 2004; 20: 1196–1209
  • Hirsch M, Brun-Vézinet F, Clotet B, Conway B, Kuritzkes DR, D'Aquila RT, Demeter LM, Hammer SM, Johnson VA, Loveday C, Mellors JW, Jacobsen DM, Richman DD. Antiretroviral drug resistance testing in adults infected with HIV-1: 2003 recommendations of an International AIDS Society USA Panel. Clin Infect Dis 2003; 37: 113–128
  • HIV and AIDS statistics and features, end of 2002 and 2004. North America, Western and Central Europe. Available from: http://www.unaids.org/wad2004/EPIupdate2004_html_en/Epi04_12_en.htm.
  • Wensing AM, van de Vijver DA, Angarano G, Asjo B, Balotta C, Boeri E, Camacho R, Chaix ML, Costagliola D, De Luca A, Derdelinckx I, Grossman Z, Hamouda O, Hatzakis A, Hemmer R, Hoepelman A, Horban A, Korn K, Kucherer C, Leitner T, Loveday C, MacRae E, Maljkovic I, de Mendoza C, Meyer L, Nielsen C, Op de Coul EL, Ormaasen V, Paraskevis D, Perrin L, Puchhammer-Stockl E, Ruiz L, Salminen M, Schmit JC, Schneider F, Schuurman R, Soriano V, Stanczak G, Stanojevic M, Vandamme AM, Van Laethem K, Violin M, Wilbe K, Yerly S, Zazzi M, Boucher CA. SPREAD Programme. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: Implications for clinical management. J Infect Dis 2005; 192: 958–966
  • Richman DD, Morton SC, Wrin T, Hellmann N, Berry S, Shapiro MF, Bozzette SA. The prevalence of antiretroviral drug resistance in the United States. AIDS 2004; 18: 1393–1401
  • De Clercq E. Antiviral drugs in current clinical use. J Clin Virol 2004; 30: 115–133
  • Gulick RM. New antiretroviral drugs. Clin Microbiol Infect 2003; 9: 186–193
  • Seminari E, Maggiolo F, Villani P, Suter F, Pan A, Regazzi MB, Paolucci S, Baldanti F, Tinelli C, Maserati R. Efavirenz, nelfinavir, and stavudine rescue combination therapy in HIV-1-positive patients heavily pretreated with nucleoside analogues and protease inhibitors. J Acquir Immune Defic Syndr 1999; 22: 453–460
  • Clumeck N, Goebel F, Rozenbaum W, Gerstoft J, Staszewski S, Montaner J, Johnson M, Gazzard B, Stone C, Athisegaran R, Moore S. CNA30017 study team. Simplification with abacavir-based triple nucleoside therapy versus continued protease inhibitor-based highly active antiretroviral therapy in HIV-1-infected patients with undetectable plasma HIV-1 RNA. AIDS 2001; 15: 1517–1526
  • Jordan WC, Jefferson R, Yemofio F, Tolbert L, Conlon V, Carroll H, Green DC, Green A, Green R. Nevirapine plus efavirenz plus didanosine: A simple, safe, and effective once-daily regimen for patients with HIV infection. J Natl Med Assoc 2003; 95: 1152–1157
  • Chen D, Misra A, Garg A. Clinical review 153: Lipodystrophy in human immunodeficiency virus-infected patients. J Clin Endocrinol Metab 2002; 87: 4845–4856
  • Montaner JS, Reiss P, Cooper D, Vella S, Harris M, Conway B, Wainberg MA, Smith D, Robinson P, Hall D, Myers M, Lange JM. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: The INCAS Trial, Italy, The Netherlands, Canada and Australia Study. JAMA 1998; 279: 930–937
  • van Leeuwen R, Katlama C, Murphy RL, Squires K, Gatell J, Horban A, Clotet B, Staszewski S, van Eeden A, Clumeck N, Moroni M, Pavia AT, Schmidt RE, Gonzalez-Lahoz J, Montaner J, Antunes F, Gulick R, Banhegyi D, van der Valk M, Reiss P, van Weert L, van Leth F, Johnson VA, Sommadossi JP, Lange JM. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003; 17: 987–999
  • Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD. Hepatoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 2004; 18: 2277–2284
  • Young J, Weber R, Rickenbach M, Furrer H, Bernasconi E, Hirschel B, Tarr PE, Vernazza P, Battegay M, Bucher HC. Lipid profiles for antiretroviral-naive patients starting PI- and NNRTI-based therapy in the Swiss HIV cohort study. Antivir Ther 2005; 10: 585–591
  • Tebas P, Yarasheski K, Henry K, Claxton S, Kane E, Bordenave B, Klebert M, Powderly WG. Evaluation of the virological and metabolic effects of switching protease inhibitor combination antiretroviral therapy to nevirapine-based therapy for the treatment of HIV infection. AIDS Res Hum Retroviruses 2004; 20: 589–594
  • Barreiro P, García-Benayas T, Soriano V, Gallant J. Simplification of antiretroviral treatment: How to sustain success, reduce toxicity and ensure adherence avoiding PI use. AIDS Rev 2002; 4: 233–241
  • French M, Amin J, Roth N, Carr A, Law M, Emery S, Drummond F, Cooper D. OzCombo 2 investigators. Randomized, open-label, comparative trial to evaluate the efficacy and safety of three antiretroviral drug combinations including two nucleoside analogues and nevirapine for previously untreated HIV-1 Infection: The OzCombo 2 study. HIV Clin Trials 2002; 3: 177–185
  • Lange JM. Efficacy and durability of nevirapine in antiretroviral drug naive patients. Suppl 1 2003; 34: S40–S52, (Suppl 1)
  • van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, Cahn P, Lalloo UG, van der Westhuizen IP, Malan DR, Johnson MA, Santos BR, Mulcahy F, Wood R, Levi GC, Reboredo G, Squires K, Cassetti I, Petit D, Raffi F, Katlama C, Murphy RL, Horban A, Dam JP, Hassink E, van Leeuwen R, Robinson P, Wit FW, Lange JM. 2NN Study team. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: A randomised open-label trial, the 2NN Study. Lancet 2004; 363: 1253–1263
  • Luzuriaga K, McManus M, Mofenson L, Britto P, Graham B, Sullivan JL. PACTG 356 Investigators. A trial of three antiretroviral regimens in HIV-1-infected children. N Engl J Med 2004; 350: 2471–2480
  • Pedersen OS, Pedersen EB. Non-nucleoside reverse transcriptase inhibitors: The NNRTI boom. Antivir Chem Chemother 1999; 10: 285–314
  • Campiani G, Ramunno A, Maga G, Nacci V, Fattorusso C, Catalanotti B, Morelli E, Novellino E. Non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors: Past, present, and future perspectives. Curr Pharm Des 2002; 8: 615–657
  • Smerdon SJ, Jager J, Wang J, Kohlstaedt LA, Chirino AJ, Friedman JM, Rice PA, Steitz TA. Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proc Natl Acad Sci USA 1994; 91: 3911–3915
  • Tantillo C, Ding J, Jacobo-Molina A, Nanni RG, Boyer PL, Hughes SH, Pauwels R, Andries K, Janssen PA, Arnold E. 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 1994; 243: 369–387
  • Ding J, Das K, Hsiou Y, Sarafianos SG, Clark AD, Jr, Jacobo-Molina A, Tantillo C, Hughes SH, Arnold E. Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor alpha-APA R 95845 at 2.8 A resolution. Structure 1995; 3: 365–379
  • Esnouf R, Ren J, Ross C, Jones Y, Stammers D, Stuart D. Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nat Struct Biol 1995; 2: 303–308
  • Merluzzi VJ, Hargrave KD, Labadia M, Grozinger K, Skoog M, Wu JC, Shih CK, Eckner K, Hattox S, Adams J, Rosenthal AS, Faanes R, Eckner RJ, Koup RA, Sullivan JL. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 1990; 250: 1411–1413
  • Romero DL, Busso M, Tan CK, Reusser F, Palmer JR, Poppe SM, Aristoff PA, Downey KM, So AG, Resnick L, Tarpley WG. Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. Proc Natl Acad Sci USA 1991; 88: 8806–8810
  • 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, Linn JH, Chen I-W, Schleif WA, Sardana VV, Long WJ, Byrnes VW. Emini EA, L-743, 726 (DMP-266): A novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1995; 39: 2602–2605
  • Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, Stryker R, Johnson P, Labriola DF, Farina D, Manion DJ, Ruiz NM. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 team. N Engl J Med 1999; 341: 1865–1873
  • van Leeuwen R, Katlama C, Murphy RL, Squires K, Gatell J, Horban A, Clotet B, Staszewski S, van Eeden A, Clumeck N, Moroni M, Pavia AT, Schmidt RE, Gonzalez-Lahoz J, Montaner J, Antunes F, Gulick R, Banhegyi D, van der Valk M, Reiss P, van Weert L, van Leth F, Johnson VA, Sommadossi JP, Lange JM. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003; 17: 987–999
  • Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, Dube MP, Fischl MA, Pollard RB, Delapenha R, Gedeon L, van der Horst C, Murphy RL, Becker MI, D'Aquila RT, Vella S, Merigan TC, Hirsch MS. AIDS clinical trials group 384 team. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003; 349: 2293–2303
  • US Department of Health and Human Services Guidelines for the use of antiretroviral agents in HIV-1-Infected adults and adolescents. October 6, 2005. Available from: http://www.aidsinfo.nih.gov/guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1.
  • Palella FJ, Jr., Deloria-Knoll M, Chmiel JS, Moorman AC, Wood KC, Greenberg AE, Holmberg SD. HIV outpatient study investigators. Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata. Ann Intern Med 2003; 138: 620–626
  • Wilkin TJ, Gulick RM. Antiretroviral therapy: When and what to start- an american perspective. Curr Infect Dis Rep 2003; 5: 339–348
  • Richman D, Shih CK, Lowy I, Rose J, Prodanovich P, Goff S, Griffin J. Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc Natl Acad Sci USA 1991; 88: 11241–11245
  • Richman DD, Havlir D, Corbeil J, Looney D, Ignacio C, Spector SA, Sullivan J, Cheeseman S, Barringer K, Pauletti D, Shih C-K, Myers M, Griffin J. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 1994; 68: 1660–1666
  • Deeks SG. Non nucleoside reverse transcriptase inhibitor resistance. J Acquir Immune Defic Syndr 2001; 26(Suppl 1)S25–S33
  • Bacheler L, Jeffrey S, Hanna G, D'Aquila R, Wallace L, Logue K, Cordova B, Hertogs K, Larder B, Buckery R, Baker D, Gallagher K, Scarnati H, Tritch R, Rizzo C. Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy. J Virol 2001; 75: 4999–5008
  • Artico M. Non-nucleoside anti-HIV-1 reverse transcriptase inhibitors (NNRTIs): A chemical survey from lead compounds to selected drugs for clinical trials. Farmaco 1996; 51: 305–331
  • Casado JL, Hertogs K, Ruiz L, Dronda F, Van Cauwenberge A, Arno A, Garcia-Arata I, Bloor S, Bonjoch A, Blazquez J, Clotet B, Larder B. Non-nucleoside reverse transcriptase inhibitor resistance among patients failing a nevirapine plus protease inhibitor-containing regimen. AIDS 2000; 14: F1–F7
  • Albrecht MA, Bosch RJ, Hammer SM, Liou SH, Kessler H, Para MF, Eron J, Valdez H, Dehlinger M, Katzenstein DA. AIDS clinical trials group 364 study team. Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. N Engl J Med 2001; 345: 398–407
  • Delaugerre C, Rohban R, Simon A, Mouroux M, Tricot C, Agher R, Huraux JM, Katlama C, Calvez V. Resistance profile and cross-resistance of HIV-1 among patients failing a non-nucleoside reverse transcriptase inhibitor-containing regimen. J Med Virol 2001; 65: 445–448
  • Clevenbergh P, Cua E, Dam E, Durant J, Schmit JC, Boulme R, Cottalorda J, Beyou A, Schapiro JM, Clavel F, Dellamonica P. Prevalence of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations and polymorphisms in NNRTI-naive HIV-infected patients. HIV Clin Trials 2002; 3: 36–44
  • Joly V, Descamps D, Peytavin G, Touati F, Mentre F, Duval X, Delarue S, Yeni P, Brun-Vezinet F. Evolution of human immunodeficiency virus type 1 (HIV-1) resistance mutations in nonnucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1-infected patients switched to antiretroviral therapy without NNRTIs. Antimicrob Agents Chemother 2004; 48: 172–175
  • Hachiya A, Gatanaga H, Kodama E, Ikeuchi M, Matsuoka M, Harada S, Mitsuya H, Kimura S, Oka S. Novel patterns of nevirapine resistance-associated mutations of human immunodeficiency virus type 1 in treatment-naive patients. Virology 2004; 327: 215–224
  • Delaguerre C, Rohban R, Simon A, Mouroux M, Tricot C, Agher R, Huraux JM, Katlama C, Calvez V. Resistance profile and cross-resistance of HIV-1 among patients failing a non-nucleoside reverse transcriptase inhibitor-containing regimen. J Med Virol 2001; 65: 445–448
  • Hanna GJ, Johnson VA, Kuritzkes DR, Richman DD, Brown AJ, Savara AV, Hazelwood JD, D'Aquila RT. Patterns of resistance mutations selected by treatment of human immunodeficiency virus type 1 infection with zidovudine, didanosine, and nevirapine. J Infect Dis 2000; 181: 904–911
  • Eshleman SH, Krogstad P, Jackson JB, Wang YG, Lee S, Wei LG, Cunningham S, Wantman M, Wiznia A, Johnson G, Nachman S, Palumbo P. Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir. J Infect Dis 2001; 183: 1732–1738
  • Bacheler LT, Anton ED, Kudish P, Baker D, Bunville J, Krakowski K, Bolling L, Aujay M, Wang XV, Ellis D, Becker MF, Lasut AL, George HJ, Spalding DR, Hollis G, Abremski K. Human immunodeficiency virus type 1 mutations selected in patients failing efavirenz combination therapy. Antimicrob Agents Chemother 2000; 44: 2475–2484
  • Demeter LM, Shafer RW, Meehan PM, Holden-Wiltse J, Fischl MA, Freimuth WW, Para MF, Reichman RC. Delavirdine susceptibilities and associated reverse transcriptase mutations in human immunodeficiency virus type 1 isolates from patients in a phase I/II trial of delavirdine monotherapy (ACTG 260). Antimicrob Agents Chemother 2000; 44: 794–797
  • Joly V, Moroni M, Concia E, Lazzarin A, Hirschel B, Jost J, Chiodo F, Bentwich Z, Love WC, Hawkins DA, Wilkins EGL, Gatell AJ, Vetter N, Greenwald C, Freimuth WW, de Cian W, and M/3331/0013B Study Group. Delavirdine in combination with zidovudine in treatment of human immunodeficiency virus type 1-infected patients: Evaluation of efficacy and emergence of viral resistance in a randomized, comparative phase III trial. Antimicrob Agents Chemother 2000; 44: 3155–3157
  • Shulman N, Zolopa AR, Passaro D, Shafer RW, Huang W, Katzenstein D, Israelski DM, Hellmann N, Petropoulos C, Whitcomb J. Phenotypic hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in treatment-experienced HIV-infected patients: Impact on virological response to efavirenz-based therapy. AIDS 2001; 15: 1125–1132
  • Whitcomb JM, Huang W, Limoli K, Paxinos E, Wrin T, Skowron G, Deeks SG, Bates M, Hellmann NS, Petropoulos CJ. Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: Clinical, phenotypic and genotypic correlates. AIDS 2002; 16: F41–F47
  • Antinori A, Zaccarelli M, Cingolani A, Forbici F, Rizzo MG, Trotta MP, Di Giambenedetto S, Narciso P, Ammassari A, Girardi E, De Luca A, Perno CF. Cross-resistance among nonnucleoside reverse transcriptase inhibitors limits recycling efavirenz after nevirapine failure. AIDS Res Hum Retrovir 2002; 18: 835–838
  • Bacheler LT. Resistance to non-nucleoside inhibitors of HIV-1 reverse transcriptase. Drug Resist Updates 1999; 2: 56–67
  • Hsiou Y, Das K, Ding J, Clark AD, Jr, Kleim JP, Rosner M, Winkler I, Riess G, Hughes SH, Arnold E. Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: Inhibitor flexibility is a useful design feature for reducing drug resistance. J Mol Biol 1998; 284: 313–323
  • Pelemans H, Esnouf R, De Clercq E, Balzarini J. Mutational analysis of trp-229 of human immunodeficiency virus type 1 reverse transcriptase (RT) identifies this amino acid residue as a prime target for the rational design of new non-nucleoside RT inhibitors. Mol Pharmacol 2000; 57: 954–960
  • Bell FW, Cantrell AS, Hogberg M, Jaskunas SR, Johansson NG, Jordan CL, Kinnick MD, Lind P, Morin JM, Jr, Noreen R, Oberg B, Palkowitz JA, Parrish CA, Pramo P, Sahlberg C, Ternansky RT, Vasileff RT, Vrang L, West SJ, Zhang H, Zhou XX. 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 1995; 38: 4929–4936
  • Cantrell AS, Engelhardt P, Hogberg M, Jaskunas SR, Johansson NG, Jordan CL, Kangasmetsa J, Kinnick MD, Lind P, Morin JM, Jr, Muesing MA, Noreen R, Oberg B, Pranc P, Sahlberg C, Ternansky RJ, Vasileff RT, Vrang L, West SJ, Zhang H. Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors 2. Synthesis and further structure–activity relationship studies of PETT analogs. J Med Chem 1996; 39: 4261–4274
  • Vig R, Mao C, Venkatachalam TK, Tuel-Ahlgren L, Sudbeck EA, Uckun FM. Rational design and synthesis of phenethyl-5-bromopyridyl thiourea derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase. Bioorg Med Chem 1998; 6: 1789–1797
  • Vig R, Mao C, Venkatachalam TK, Tuel-Ahlgren L, Sudbeck EA, Uckun FM. 5-Alkyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-ones as potent non-nucleoside reverse transcriptase inhibitors of S-DABO series. Bioorg Med Chem Lett 1998; 8: 1461–1466
  • Sudbeck EA, Mao C, Vig R, Venkatachalam TK, Tuel-Ahlgren L, Uckun FM. Structure-based design of novel dihydroalkoxybenzyloxopyrimidine derivatives as potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase. Antimicrob Agents Chemother 1998; 42: 3225–3233
  • Mao C, Vig R, Venkatachalam TK, Sudbeck EA, Uckun FM. Structure-based design of N-[2-(1-piperidinylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea as potent non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett 1998; 8: 2213–2218
  • D'Cruz OJ, Uckun FM. Novel derivatives of phenethyl-5-bromopyridylthiourea and dihydroalkoxybenzyloxopyrimidine are dual-function spermicides with potent anti-human immunodeficiency virus activity. Biol Reprod 1999; 60: 1419–1428
  • Sudbeck EA, Jennissen JD, Venkatachalam TK, Uckun FM. Inhibitor of HIV-1 reverse transcriptase: N′-(5-bromo-2-pyridyl)-N-[2-(2,5-dimethoxyphenyl)ethyl] thiourea. Acta Crystallogr C 1999; 55: 2122–2124
  • Uckun FM, Pendergrass S, Maher D, Zhu D, Tuel-Ahlgren L, Mao C, Venkatachalam TK. N′-[2-(2-thiophene)ethyl]-N′-[2-(5-bromopyridyl)] thiourea as a potent inhibitor of NNI-resistant and multidrug-resistant human immunodeficiency virus-1. Bioorg Med Chem Lett 1999; 9: 3411–3416
  • Mao C, Sudbeck EA, Venkatachalam TK, Uckun FM. Structure-based design of non-nucleoside reverse transcriptase inhibitors of drug-resistant human immunodeficiency virus. Antivir Chem Chemother 1999; 10: 233–240
  • Uckun FM, Mao C, Pendergrass S, Maher D, Zhu D, Tuel-Ahlgren L, Venkatachalam TK. N-[2-(1-cyclohexenyl)ethyl]-N′-[2-(5-bromopyridyl)]-thiourea and N′-[2-(1-cyclohexenyl)ethyl]-N′-[2-(5-chloropyridyl)]-thiourea as potent inhibitors of multidrug-resistant human immunodeficiency virus-1. Bioorg Med Chem Lett 1999; 9: 2721–2726
  • D'Cruz OJ, Venkatachalam TK, Uckun FM. Novel thiourea compounds as dual-function microbicides. Biol Reprod 2000; 63: 196–205
  • Mao C, Sudbeck EA, Venkatachalam TK, Uckun FM. Rational design of N-[2-(2,5-dimethoxyphenylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-236) as a potent non-nucleoside inhibitor of drug-resistant human immunodeficiency virus. Bioorg Med Chem Lett 1999; 9: 1593–1598
  • Mao C, Sudbeck EA, Venkatachalam TK, Uckun FM. Structure-based drug design of non-nucleoside inhibitors for wild-type and drug-resistant HIV reverse transcriptase. Biochem Pharmacol 2000; 60: 1251–1265
  • Venkatachalam TK, Sudbeck EA, Mao C, Uckun FM. Stereochemistry of halopyridyl and thiazolyl thiourea compounds is a major determinant of their potency as nonnucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett 2000; 10: 2071–2074
  • D'Cruz OJ, Samuel P, Uckun FM. Conceival: A novel noncontraceptive vaginal vehicle for lipophilic microbicides. AAPS Pharm Sci Tech 2005; 6: E56–E64, Available from: http://www.aapspharmscitech.org/view.asp?art=pt060111
  • Uckun FM, Mao C, Pendergrass S, Maher D, Zhu D, Tuel-Ahlgren L, Venkatachalam TK. N-[2-(4-methylphenyl)ethyl]-N′-[2-(5-bromopyridyl)]-thiourea as a potent inhibitor of NNRTI-resistant and multidrug-resistant human immunodeficiency virus type 1. Antivir Chem Chemother 2000; 11: 135–140
  • Venkatachalam TK, Sudbeck EA, Mao C, Uckun FM. Piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thiourea compounds with potent anti-HIV activity. Antivir Chem Chemother 2000; 11: 329–336
  • Venkatachalam TK, Sudbeck EA, Mao C, Uckun FM. Anti-HIV activity of aromatic and heterocyclic thiazolyl thiourea compounds. Bioorg Med Chem Lett 2001; 11: 523–528
  • D'Cruz OJ, Samuel P, Uckun FM. PHI-443: A novel noncontraceptive broad-spectrum anti-human immunodeficiency virus microbicide. Biol Reprod 2004; 71: 2037–2047
  • D'Cruz OJ, Uckun FM. Discovery of 2-5-dimethoxy-substituted 5-bromopyridyl thiourea (PHI-236) as a potent broad-spectrum anti-human immunodeficiency virus microbicide. Mol Hum Reprod 2005; 11: 767–777
  • Mulky A, Kappes JC. Analysis of human immunodeficiency virus type 1 reverse transcriptase subunit structure/function in the context of infectious virions and human target cells. Antimicrob Agents Chemother 2005; 49: 3762–3769
  • Shen L, Shen J, Luo X, Cheng F, Xu Y, Chen K, Arnold E, Ding J, Jiang H. Steered molecular dynamics simulation on the binding of NNRTI to HIV-1 RT. Biophys J 2003; 84: 3547–3563
  • Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA. Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 1992; 256: 1783–1790
  • Ren J, Esnouf R, Garman E, Somers D, Ross C, Kirby I, Keeling J, Darby G, Jones Y, Stuart D, Stammers D. High resolution structures of HIV-1 RT from four RT-inhibitor complexes. Nat Struct Biol 1995; 2: 293–302
  • Hopkins AL, Ren J, Esnouf RM, Willcox BE, Jones EY, Ross C, Miyasaka T, Walker RT, Tanaka H, Stammers DK, Stuart DI. Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors. J Med Chem 1996; 39: 1589–1600
  • Schafer W, Friebe WG, Leinert H, Mertens A, Poll T, von der Saal W, Zilch H, Nuber B, Ziegler ML. Non-nucleoside inhibitors of HIV-1 reverse transcriptase: Molecular modeling and X-ray structure investigations. J Med Chem 1993; 36: 726–732
  • Ren J, Esnouf RM, Hopkins AL, Warren J, Balzarini J, Stuart DI, Stammers DK. Crystal structures of HIV-1 reverse transcriptase in complex with carboxanilide derivatives. Biochemistry 1998; 37: 14394–14403
  • Larder BA. Interactions between drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase. J Gen Virol 1994; 75: 951–957
  • Huang H, Chopra R, Verdine GL, Harrison SC. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: Implications for drug resistance. Science 1998; 282: 1669–1675
  • Hsiou Y, Das K, Ding J, Clark AD, Jr, Kleim JP, Rosner M, Winkler I, Riess G, Hughes SH, Arnold E. Structure of tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: Inhibitor flexibility is a useful design feature for reducing drug resistance. J Mol Biol 1998; 284: 313–323
  • Abrahao-Junior O, Nascimento PG, Galembeck SE. Conformational analysis of the HIV-1 virus reverse transcriptase nonnucleoside inhibitors: TIBO and nevirapine. J Comput Chem 2001; 22: 1817–1829
  • Molecular Simulations Inc. InsightII. Molecular Simulations Inc., San Diego, CA 1996
  • Bohm HJ. The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure. J Comput Aided Mol Des 1994; 8: 243–256
  • Bohm HJ. LUDI: Rule-based automatic design of new substituents for enzyme inhibitor leads. J Comput-Aided Mol Des 1992; 6: 593–606
  • Luty BA, Wasserman ZR, Stouten PFW, Hodge CN, Zacharias M, McCammon JA. A molecular mechanics/grid method for evaluation of ligand-receptor interactions. J Comp Chem 1995; 16: 454–464
  • Brodine SK, Mascola JR, Weiss PJ, Ito SI, Porter KR, Artenstein AW, Garland FC, McCutchan FE, Burke DS. Detection of diverse HIV-1 genetic subtypes in the USA. Lancet 1995; 346: 1198–1199
  • Schinazi RF, Larder BA, Mellors JW. Mutations in retroviral genes associated with drug resistance. Int Antiviral News 1997; 5: 129–135
  • Marcelin AG, Delaugerre C, Wirden M, Viegas P, Simon A, Katlama C, Calvez V. Thymidine analogue reverse transcriptase inhibitors resistance mutations profiles and association to other nucleoside reverse transcriptase inhibitors resistance mutations observed in the context of virological failure. J Med Virol 2004; 72: 162–165
  • Rapatski BL, Suppe F, Yorke JA. HIV epidemics driven by late disease stage transmission. J Acquir Immune Defic Syndr 2005; 38: 241–253
  • D'Cruz OJ, Venkatachalam TK, Mao C, Qazi S, Uckun FM. Structural requirements for potent anti-human immunodeficiency virus (HIV) and sperm-immobilizing activities of cyclohexenyl thiourea and urea non-nucleoside inhibitors of HIV-1 reverse transcriptase. Biol Reprod 2002; 67: 1959–1974
  • Venkatachalam TK, Mao C, Uckun FM. Stereochemistry as a major determinant of the anti-HIV activity of chiral naphthyl thiourea compounds. Antivir Chem Chemother 2001; 12: 213–221
  • Venkatachalam TK, Mao C, Uckun FM. Effect of stereochemistry on the anti-HIV activity of chiral thiourea compounds. Bioorg Med Chem 2004; 12: 4275–4284
  • Venkatachalam TK, Mao C, Uckun FM. Effect of stereo and regiochemistry towards wild and multidrug resistant HIV-1 virus: Viral potency of chiral PETT derivatives. Biochem Pharmacol 2004; 67: 1933–1946
  • Venkatachalam TK, Sudbeck E, Uckun FM. Structural influence on the anisotropic intermolecular hydrogen bonding in solid state of substituted thioureas: Evidence by X-ray crystal structure. J Mol Struct 2004; 687: 45–56
  • Venkatachalam TK, Sudbeck E, Uckun FM. Structural influence on the solid state intermolecular hydrogen bonding of substituted thioureas. J Mol Struct 2004; 751: 45–58
  • Venkatachalam TK, Uckun FM. Synthesis of β-fluorophenethyl halopyridyl thiourea compounds as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Synth Commun 2004; 34: 2462–2472
  • Venkatachalam TK, Sudbeck EA, Mao C, Uckun FM. Stereochemistry of halopyridyl and thiazolyl thiourea compounds is a major determinant of their potency as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett 2000; 10: 2071–2074
  • Venkatachalam TK, Uckun FM. Regiospecific synthesis of 5-halo-substituted thiophene pyridyl thiourea compounds as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Synth Commun 2004; 34: 1–11
  • Chen CL, Uckun FM. Evaluation of the pharmacokinetic features and tissue distribution of the potent nonnucleoside inhibitor of HIV-1 reverse transcriptase, N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240) with an analytical HPLC method. Pharm Res 1999; 16: 1226–1232
  • Chen CL, Venkatachalam TK, Waurzyniak B, Chelstrom L, Uckun FM. In vivo toxicity, pharmacokinetic features and tissue distribution of N-[2-(2,5-dimethoxyphenylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-236), a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase. Arzneimittelforschung 2001; 51: 574–581
  • D'Cruz OJ, Waurzyniak B, Uckun FM. A 13-week subchronic intravaginal toxicity study of the novel broad-spectrum anti-HIV and spermicidal agent, N-[2-(1-cyclohexenyl)ethyl]-N′-[2-(5-bromopyridyl)]-thiourea (PHI-346) in mice. Toxicol Pathol 2002; 30: 687–695
  • Zussman A, Lara L, Lara HH, Bentwich Z, Borkow G. Blocking of cell-free and cell-associated HIV-1 transmission through human cervix organ culture with UC781. AIDS 2003; 17: 653–661
  • Van Herrewege Y, Penne L, Vereecken C, Fransen K, van der Groen G, Kestens L, Balzarini J, Vanham G. Activity of reverse transcriptase inhibitors in monocyte-derived dendritic cells: A possible in vitro model for postexposure prophylaxis of sexual HIV transmission. AIDS Res Hum Retrovir 2002; 18: 1091–1102
  • Di Fabio S, Van Roey J, Giannini G, van den Mooter G, Spada M, Binelli A, Pirillo MF, Germinario E, Belardelli F, de Bethune MP, Vella S. Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulation. AIDS 2003; 17: 1597–1604
  • Van Herrewege Y, Michiels J, Van Roey J, Fransen K, Kestens L, Balzarini J, Lewi P, Vanham G, Janssen P. In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides. Antimicrob Agents Chemother 2004; 48: 337–339
  • Njai HF, Lewi PJ, Janssen CG, Garcia S, Fransen K, Kestens L, Vanham G, Janssen PA. Pre-incubation of cell-free HIV-1 group M isolates with non-nucleoside reverse transcriptase inhibitors blocks subsequent viral replication in co-cultures of dendritic cells and T cells. Antivir Ther 2005; 10: 255–262
  • Fletcher P, Kiselyeva Y, Wallace G, Romano J, Griffin G, Margolis L, Shattock R. The nonnucleoside reverse transcriptase inhibitor UC-781 inhibits human immunodeficiency virus type 1 infection of human cervical tissue and dissemination by migratory cells. J Virol 2005; 79: 11179–11186
  • D'Cruz OJ, Uckun FM. Dawn of non-nucleoside inhibitor-based anti-HIV microbicides. J Antimicrob Chemother 2006; 57: 411–423
  • Biosyn, Inc. 2003., Initiates Phase I Clinical Testing of UC-781, a Novel HIV Microbicide. September 4, 2003. http://www.aegis.org/news/pr/2003/PR030908.html.
  • Alliance for Microbicide Development., http://www.microbicide.org.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.