Skip to main content
SpringerLink
Log in

Random and Rational Approaches to HIV Drug Discovery in Africa

  • Chapter
  • First Online:
Drug Discovery in Africa

  • 1205 Accesses

Abstract

The development of therapeutic agents to inhibit human immunodeficiency virus (HIV) replication began soon after the isolation and identification of the virus as the causative agent of the acquired immune deficiency syndrome (AIDS). Within a short period of time thereafter, azidothymidine (AZT) was found to inhibit viral replication and became the first FDA-approved drug for the treatment of HIV/AIDS in 1987. Since then, continual and substantial progress has been made. To date, 35 drugs have been clinically approved, and with treatment, HIV infection has been transformed from a life-threatening disease with a short survival rate into a chronic manageable condition. Furthermore, several drugs are currently under investigation in various stages of clinical and preclinical development. Despite this remarkable success, there is continued global effort directed towards the design, discovery and development of novel inhibitors that may improve treatment strategies and overcome new challenges that have arisen. This chapter focuses on the discovery phase of the HIV drug discovery and development pipeline and describes the contribution and progress made by African scientists and research laboratories. Review of the period 1990 to present day reveals considerable African research describing anti-HIV inhibitors, derived from natural sources or through synthetic means, and identified through both rational and random drug discovery approaches. Several challenges facing HIV researchers on the continent disproportionately affected by HIV/AIDS are also described.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. DiMasi J (2002) The value of improving the productivity of the drug development process: faster times and better decisions. Pharmacoeconomics 20(3):1–10

    Google Scholar 

  2. DiMasi J, Hansen R, Grabowski H (2003) The price of innovation: new estimates of drug development costs. J Health Econ 22(2):151–185

    Google Scholar 

  3. Light DW, Warburton R (2011) Demythologizing the high costs of pharmaceutical research. BioSocieties 6:34–50

    Google Scholar 

  4. Adams CP, Brantner VV (2010) Spending on new drug development. Health Econ 19(2):130–141

    Google Scholar 

  5. http://www.fda.gov/ForConsumers/byAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm118915.htm. Accessed Nov 2011

  6. UNAIDS (2008) Report on the global HIV/AIDS epidemic 2008: Annex 1, HIV and AIDS estimates and data, 2007 and 2001

    Google Scholar 

  7. World Health Organisation (2010) Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach – 2010 rev

    Google Scholar 

  8. Barnhart M, Shelton J (2011) A better state of ART improving antiviral regimens to increase global access to HIV treatment. J AIDS HIV Res 3:71–78

    Google Scholar 

  9. HIV drugs: a global strategic business report. 2010 Global Industry Analysts Inc., CA

    Google Scholar 

  10. http://www.avert.org/new-aids-drugs.htm. Accessed Nov 2011

  11. i-BASE/Treatment Action Group (Second Edition, September 2011) ‘2011 Pipeline Report’ HIV, hepatitis C virus (HCV), and tuberculosis drugs, diagnostics, vaccines, and preventive technologies in development

    Google Scholar 

  12. Comley J (2006) Tools and technology that facilitate automated screening. In: Huser J (ed) High throughput-screening in drug discovery. Wiley-VCH, Verlag GmbH & Co. KGaA, Weinheim, Germany

    Google Scholar 

  13. Downey W, Liu C, Hartigan J (2010) Compound profiling: size impact on primary screening libraries. Drug Discov World, Spring 2010

    Google Scholar 

  14. Davis AM, Teague SJ, Kleywegt GJ (2003) Application and limitations of X-ray crystallographic data in structure-based ligand and drug design. Angew Chem Int Ed 42:2718–2736

    CAS  Google Scholar 

  15. Wlodawer A (2002) Rational approach to AIDS drug design through structural biology. Annu Rev Med 53:595–614

    CAS  Google Scholar 

  16. Wang Y, Lu H, Zhu Q, Jiang S et al (2010) Structure-based design, synthesis and biological evaluation of new N-carboxyphenylpyrrole derivatives as HIV fusion inhibitors targeting gp41. Bioorg Med Chem Lett 20(1):189–192

    Google Scholar 

  17. Das K, Lewi PJ, Hughes SH et al (2005) Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. Prog Biophys Mol Biol 88(2):209–231

    CAS  Google Scholar 

  18. Chin Y-W, Balunas MJ, Chai HB et al (2006) Drug discovery from natural sources. AAPS J 8(2):E239–E253

    CAS  Google Scholar 

  19. Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477

    CAS  Google Scholar 

  20. Molinari G (2009) Natural products in drug discovery: present status and perspectives. Adv Exp Med Biol 655:13–27

    CAS  Google Scholar 

  21. Kuete V, Metuno R, Keilah PL et al (2010) Evaluation of the genus Treculia for antimycobacterial, anti-reverse transcriptase, radical scavenging and antitumor activities. S Afr J Bot 76(3):530–535

    Google Scholar 

  22. Lee JS, Oh WK, Ahn JS et al (2009) Prenylisoflavonoids from Erythrina senegalensis as novel HIV-1 protease inhibitors. Planta Med 75:268–270

    CAS  Google Scholar 

  23. Wafo P, Nyasse B, Fontaine C (1999) A 7,8-dihydro-8-hydroxypalmatine from Enantia chlorantha. Phytochemistry 50:279–281

    CAS  Google Scholar 

  24. Asres K, Bucar F, Kartnig T et al (2001) Antiviral activity against human immunodeficiency virus type 1 (HIV-1) and type 2. Phytother Res 15:62–69

    CAS  Google Scholar 

  25. Asres K, Seyoum A, Veeresham C et al (2005) Antiviral activity against human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) of ethnobotanically selected Ethiopian medicinal plants. Phytother Res 19:557–581

    CAS  Google Scholar 

  26. Gosse B, Gnabre J, Bates RB et al (2002) Antiviral saponins from Tieghemella heckelii. J Nat Prod 65:1942–1944

    CAS  Google Scholar 

  27. Kanyara JN, Njagi ENM (2005) Anti-HIV-1 activities in extracts from some medicinal plants as assessed in an in vitro biochemical HIV-1 reverse transcriptase assay. Phytother Res 19:287–290

    CAS  Google Scholar 

  28. Daoubi M, Marquez N, Mazoir N et al (2007) Isolation of new phenylacetylingol derivatives that reactivate HIV-1 latency and a novel spirotriterpenoid from Euphorbia officinarum latex. Bioorg Med Chem 15:4577–4584

    CAS  Google Scholar 

  29. Esimone CO, Eck G, Nworu CS et al (2010) Dammarenolic acid, a secodammarane triterpenoid from Aglaia sp. shows potent anti-retroviral activity in vitro. Phytomedicine 17:540–547

    CAS  Google Scholar 

  30. Esimone CO, Grunwald T, Wildner O et al (2005) In vitro pharmacodynamic evaluation of antiviral medicinal plants using a vector-based assay technique. J Appl Microbiol 99:1346–1355

    CAS  Google Scholar 

  31. Bot YS, Mgbojikwe LO, Chika N et al (2007) Screening of the fruit pulp extract of Momordica balsamina for anti HIV property. Afr J Biotechnol 6(1):47–52

    Google Scholar 

  32. Prinsloo G, Meyer JJM, Hussein AA et al (2010) A cardiac glucoside with in vitro anti-HIV activity isolated from Elaeodendron croceum. Nat Prod Res 24(18):1743–1746

    CAS  Google Scholar 

  33. Prinsloo G, Meyer JJM, Hussein AA (2007) Anti-HIV activity of a cardiac glycoside isolated from Elaeodendron croceum. S Afr J Bot 73(2):308

    Google Scholar 

  34. Mujovo SF, Hussein AA, Meyer JJM et al (2008) Bioactive compounds from Lippia javanica and Hoslundia opposite. Nat Prod Res 22(12):1047–1054

    CAS  Google Scholar 

  35. Klos M, van de Venter M, Milne PJ et al (2009) In vitro anti-HIV activity of five selected South African medicinal plant extracts. J Ethnopharmacol 124:182–188

    CAS  Google Scholar 

  36. Harnett SM, Oosthuizen V, van de Venter M (2005) Anti-HIV activities of organic and aqueous extracts of Sutherlandia frutescens and Lobostemon trigonus. J Ethnopharmcol 96:113–119

    CAS  Google Scholar 

  37. Tshikalange TE, Meyer JJM, Lall N et al (2008) In vitro anti-HIV-1 properties of ethnobotanically selected South African plants used in the treatment of sexually transmitted diseases. J Ethnopharmacol 119:478–481

    CAS  Google Scholar 

  38. Tshikalange TE, Meyer JJM, Hattori T et al (2008) Anti-HIV screening of ethnobotanical selected SA plants. S Afr J Bot 74(2):391

    Google Scholar 

  39. Tshikalange TE, Lall N, Meyer JJM et al (2007) In vitro HIV-1 reverse transcriptase inhibitory activity of naphthoquinones and derivatives from Euclea natalensis. S Afr J Bot 73(2):308

    Google Scholar 

  40. Bessong PO, Obi CL, Andreola ML et al (2005) Evaluation of selected South African medicinal plants for inhibitory properties against human immunodeficiency virus type 1 reverse transcriptase and integrase. J Ethnopharmcol 99:83–91

    Google Scholar 

  41. Bessong PO, Rojas LB, Obi LC et al (2006) Further screening of Venda medicinal plants for activity against HIV type 1 reverse transcriptase and integrase. Afr J Biotechnol 5(6):526–528

    CAS  Google Scholar 

  42. Ndhlala AR, Finnie JF, Van Staden J (2010) In vitro antioxidant properties, HIV-1 reverse transcriptase and acetylcholinesterase inhibitory effects of traditional herbal. Preparations Sold in South Africa. Molecules 15:6888–6904

    CAS  Google Scholar 

  43. Van Wyk BE, Albrecht C (2008) A review of the taxonomy, ethnobotany, chemistry and pharmacology of Sutherlandia frutescens (Fabaceae). J Ethnopharmacol 119:620–629

    Google Scholar 

  44. Ali H, Konig GM, Khalid SA, Wright AD et al (2002) Evaluation of selected Sudanese medicinal plants for their in vitroactivity against hemoflagellates, selected bacteria, HIV-1-RT and tyrosine kinase inhibitory, and for cytotoxicity. J Ethnopharmacol 83:219–228

    CAS  Google Scholar 

  45. Hussein G, Miyashiro H, Nakamura N et al (1999) Inhibitory effects of Sudanese plant extracts on HIV-1 replication and HIV-1 protease. Phytother Res 13:31–36

    CAS  Google Scholar 

  46. Magadula JJ, Tewtrakul S (2010) Anti-HIV-1 protease activities of crude extracts of some Garcinia species growing in Tanzania. Afr J Biotechnol 9(12):1848–1852

    Google Scholar 

  47. Magadula JJ (2010) A bioactive isoprenylated xanthone and other constituents of Garcinia edulis. Fitoterapia 81:420–423

    CAS  Google Scholar 

  48. Maregesi SM, Hermans N, Dhooghe L et al (2010) Phytochemical and biological investigations of Elaeodendron schlechteranum. J Ethnopharmacol 129:319–326

    CAS  Google Scholar 

  49. Maregesi S, Van Miert S, Pannecouque C et al (2010) Screening of Tanzanian medicinal plants against Plasmodium falciparum and human immunodeficiency virus. Planta Med 76:195–201

    CAS  Google Scholar 

  50. El Dine RS, El Halawany AM, Ma CM et al (2009) Inhibition of the dimerization and active site of HIV-1 protease by secondary metabolites from the Vietnamese mushroom Ganoderma colossum. J Nat Prod 72:2019–2023

    CAS  Google Scholar 

  51. Hooper GJ, Davies-Coleman MT (1995) Sesquiterpene hydroquinones from the South African soft coral Alcyonium fauri. Tetrahedron Lett 36(18):3265–3268

    Google Scholar 

  52. Wayengera M, Byarugaba W, Kajjumbula H (2007) Frequency and site mapping of HIV 1/SIVcpz, HIV-2/SIVsmm and other SIV gene sequence cleavage by various bacteria restriction enzymes: precursors for a novel HIV inhibitory product. Afr J Biotechnol 6(10):1225–1232

    Google Scholar 

  53. Wayengera M (2008) Why bacteria derived R-M nucleic enzymatic peptides are likely efficient therapeutic molecules for use in the design and development of novel HIV inhibitory strategies. Afr J Biotechnol 7(12):1791–1796

    Google Scholar 

  54. Wayengera M (2007) A recombinant lactobacillus strain expressing genes coding for restriction enzymes cleaving the HIV genomes for use as a live microbicide strategy against heterosexual transmission of HIV. Afr J Biotechnol 6(15):1750–1756

    Google Scholar 

  55. Gericke N, Albrecht CF, Van Wyk B et al (2001) Sutherlandia frutescens. Aust J Med Herb 13:9–15

    Google Scholar 

  56. Chaffy N, Stokes T (2002) AIDS herbal therapy. Trends Plant Sci 7:57

    Google Scholar 

  57. Mills E, Cooper C, Seely D et al (2005) African herbal medicines in the treatment of HIV: Hypoxis and Sutherlandia. An overview of evidence and pharmacology. Nutr J 4:1–6

    Google Scholar 

  58. Johnson Q, Syce J, Nell H et al (2007) A randomized, double-blind, placebo-controlled trial of Lessertia frutescens in healthy adults. PLOS Clin Trials 2(4):e16

    Google Scholar 

  59. Singh IP, Bharate SP, Bhutani KK (2005) Anti-HIV natural products. Curr Sci 89(2):269–290

    CAS  Google Scholar 

  60. Chinsembu KC, Hedimbi M (2010) Ethnomedicinal plants and other natural products with anti-HIV active compounds and their putative models of action. Int J Biotechnol Mol Biol Res 1:74–91

    Google Scholar 

  61. De Koning CB, Michael JP, van Otterlo WAL (2000) Synthesis of isochromane analogues of the michellamines and korupensamines. J Chem Soc Perkin Trans 1:799–811

    Google Scholar 

  62. Olomola TO, Klein R, Lobb KA et al (2010) Towards the synthesis of coumarin derivatives as potential dual-action HIV-1 protease and reverse transcriptase inhibitors. Tetrahedron Lett 51:6325–6328

    CAS  Google Scholar 

  63. Kaye PT, Musa MA, Nchinda AT et al (2004) Novel heterocyclic analogues of the HIV-1 protease inhibitor, ritonavir. Synth Commun 34(14):2575–2589

    CAS  Google Scholar 

  64. Familoni OB, Klaas PJ, Lobb KA et al (2006) The Baylis–Hillman approach to quinoline derivatives. Org Biomol Chem 4:3960–3965

    CAS  Google Scholar 

  65. Webb MR, Ebeler SE (2004) Comparative analysis of topoisomerase IB inhibition and DNA intercalation by flavonoids and similar compounds: structural determinates of activity. Biochem J 384:527–541

    CAS  Google Scholar 

  66. Cowan MM (1999) Plant products as antimicrobial agents. Clin Microbiol Rev 12:564–582

    CAS  Google Scholar 

  67. http://apps.who.int/tdr/svc/research/lead-discovery-drugs/management. Accessed Nov 2011

  68. Essa AH, Ibrahim M, Hameed AJ et al (2008) Theoretical investigation of 3’-subtituted-2’-3’-dideoxythymidines related to AZT. QSAR infrared and substituent electronic effect studies. ARKIVOC xiii:255–265

    Google Scholar 

  69. Sheha MM, El-Koussi NA, Farag HH (2003) Brain delivery of HIV protease inhibitors. Arch Pharm Pharm Med Chem 1:47–52

    Google Scholar 

  70. Sheha MM, Mahfouz NM, Hassan HY et al (2000) Synthesis of di- and tripeptide analogues containing a-ketoamide as a new core structure for inhibition of HIV-1 protease. Eur J Med Chem 35:887–894

    CAS  Google Scholar 

  71. Dessalew N (2009) Investigation of the structural requirement for blocking the human CCR5 chemokine receptor. An insight from quantitative structure activity relationships study. Lett Drug Des Discov 6:114–124

    CAS  Google Scholar 

  72. Dessalew N (2008) QSAR Study on piperidinecarboxamides as antiretroviral agents: an insight into the structural basis for HIV coreceptor antagonist activity. QSAR Comb Sci 27(7):901–912

    CAS  Google Scholar 

  73. Darnag R, Schmitzer A, Belmiloud Y et al (2010) Quantitative structure-activity relationship studies of TIBO derivatives using support vector machines. SAR QSAR Environ Res 21(3–4):231–246

    CAS  Google Scholar 

  74. Darnag R, Mazouz ELM, Schmitzer A et al (2010) Support vector machines: development of QSAR models for predicting anti-HIV-1 activity of TIBO derivatives. Eur J Med Chem 45:1590–1597

    CAS  Google Scholar 

  75. Darnag R, Schmitzer A, Belmiloud Y et al (2008) QSAR Studies of HEPT derivatives using support vector machines. QSAR Comb Sci 28(6–7):709–718

    Google Scholar 

  76. Douali L, Villemin D, Zyad A et al (2004) Artificial neural networks: non-linear QSAR studies of HEPT derivatives as HIV-1 reverse transcriptase inhibitors. Mol Divers 8:1–8

    CAS  Google Scholar 

  77. Douali L, Villemin D, Cherqaoui D (2004) Exploring QSAR of non-nucleoside reverse transcriptase inhibitors by neural networks: TIBO derivatives. Int J Mol Sci 5:48–55

    CAS  Google Scholar 

  78. Douali L, Villemin D, Cherqaoui D (2003) Neural networks: accurate nonlinear QSAR model for HEPT derivatives. J Chem Inf Comput Sci 43:1200–1207

    CAS  Google Scholar 

  79. Zahouily M, Rakik J, Lazar M et al (2007) Exploring QSAR of non-nucleoside reverse transcriptase inhibitors by artificial neural networks: HEPT derivatives. ARKIVOC xiv:245–256

    Google Scholar 

  80. Bazoui H, Zahouily M, Sebti S et al (2002) Structure-cytotoxicity relationships for a series of HEPT derivatives. J Mol Model 8:1–7

    CAS  Google Scholar 

  81. Bode ML, Gravestock D, Moleele SS et al (2011) Imidazo[1,2-a]pyridin-3-amines as potential HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg Med Chem 19:4227–4237

    CAS  Google Scholar 

  82. Makatini MM, Petzold K, Sriharsha SN et al (2011) Pentacycloundecane-based inhibitors of wild-type C-South African HIV-protease. Bioorg Med Chem Lett 21:2274–2277

    CAS  Google Scholar 

  83. Makatini MM, Petzold K, Sriharsha SN et al (2011) Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors: a hybrid 2D NMR and docking/QM/MM/MD approach. Eur J Med Chem 46(9):3976–3985

    CAS  Google Scholar 

  84. Karpoormath R, Sayed Y, Govender P et al (2012) Pentacycloundecance derived hydroxyl acid peptides: a new class of irreversible non-scissile ether bridged isoster as potential HIV-1 wild type C-SA protease inhibitors. Bioorg Chem 40(1):19–29

    CAS  Google Scholar 

  85. Mphahlele M, Papathanasopoulos M, Cinellu MA et al (2012) Modification of HIV-1 reverse transcriptase and integrase activity by gold(III) complexes in direct biochemical assays. Bioorg Med Chem 20(1):401–407

    CAS  Google Scholar 

  86. El-Sayed WA, El-Essawy FA, Ali OM et al (2010) Synthesis and antiviral evaluation of new 2,5-disubstituted 1,3,4-oxadiazole derivatives and their acyclic nucleoside analogues. Monatsh Chem 141:1021–1028

    CAS  Google Scholar 

  87. Abdel-Rahman AAH, El-Etrawy AASH, Abdel-Megied AES et al (2008) Synthesis and antiviral evaluation of novel 2,3-dihydroxypropyl nucleosides from 2- and 4-thiouracils. Nucleosides Nucleotides Nucleic Acids 27:1257–1271

    CAS  Google Scholar 

  88. Abdel-Rahman AAH (2008) Amino acid derivatives, VI [1]: synthesis, antiviral, and antimicrobial evaluation of a-amino acid esters bearing a 1,2,3-triazolo[4,5-d]pyrimidinedione side chain. Monatsh Chem 139:61–68

    CAS  Google Scholar 

  89. Abdel-Rahman AAH (2008) Amino acid derivatives, VII [1]: synthesis and antiviral evaluation of a-amino acid esters bearing an indazole side chain. Monatsh Chem 139:289–297

    CAS  Google Scholar 

  90. Abdel-Rahman AAH, Abdel-Megied AES, Goda AES et al (2003) Synthesis and anti-HBV activity of thiouracils linked via S and N-1 to the 5-position of methyl b-D-ribofuranoside. Nucleosides Nucleotides Nucleic Acids 22(11):2027–2038

    CAS  Google Scholar 

  91. Abdel-Rahman AAH (2003) Synthesis and anti-hepatitis B virus activity of glucosylated 2-O-ethyluracils. Monatsh Chem 134:929–939

    CAS  Google Scholar 

  92. Ali IAI, Al-Masoudi IA, Hassan HG et al (2007) Synthesis and anti-HIV activity of new homo acyclic nucleosides, 1-(pent-4-enyl)quinoxalin-2-ones and 2-(pent-4-enyloxy) quinoxalines. Chem Heterocycl Compd 43(8):1052

    CAS  Google Scholar 

  93. Al-Masoudi NA, Al-Soud YA, Ali IAI et al (2007) New AZT analogues having 5-alkylsulfonyl groups: synthesis and anti-HIV activity. Nucleosides Nucleotides Nucleic Acids 26:223–230

    CAS  Google Scholar 

  94. Ali IAI, Al-Masoudi IA, Aziz NM et al (2008) New acyclic quinoxaline nucleosides. Synthesis and anti-HIV activity. Nucleosides Nucleotides Nucleic Acids 27:146–156

    CAS  Google Scholar 

  95. Al-Masoudi IA, Khodair AI, Al-Soud YA et al (2003) Synthesis of N-substituted 1-amino-2,3-dihydro- 1 H-imidazole-2-thione-N-nucleosides and S-glycosylated derivatives. Nucleosides Nucleotides Nucleic Acids 22(3):299–307

    CAS  Google Scholar 

  96. Rida SM, Ashour FA, El-Hawash SAM et al (2007) Synthesis of some novel substituted purine derivatives as potential anticancer, anti-HIV-1 and antimicrobial agents. Arch Pharm Chem Life Sci 340:185–194

    CAS  Google Scholar 

  97. Attia AM, Sallam MA, Almehdi AA et al (1999) Synthesis and biological activity of modified thiopyrimidine nucleosides. Nucleosides Nucleotides 18:2307–2315

    CAS  Google Scholar 

  98. Attia AM, Elgemeie GH, Alnaimi IS (1998) Synthesis of 1-(β-D-glycopyranosyl)-3-deazapyrimidines from 2-hydroxy and 2-mercaptopyridines. Nucleosides Nucleotides 17(8):1355–1363

    CAS  Google Scholar 

  99. EIgemeie GEH, Attia AME, Hussain BAW (1998) A synthetic strategy to a new class of cycloalkane ring-fused pyridine nucleosides as potential anti HIV agents. Nucleosides Nucleotides 17(5):855–868

    Google Scholar 

  100. El-Emam AA, Nasr MNA, Pedersen EB et al (2001) Synthesis of certain 6-(arylthio)uracils as potential antiviral agents. Phosphorus Sulfur Silicon Relat Elem 174:25–35

    CAS  Google Scholar 

  101. Elshehry MF, Balzarini J, Meier C (2009) Synthesis of new cyclic and acyclic 5-halouridine derivatives as potential antiviral agents new 5-halouridine derivatives as potential antiviral agents. Synthesis 5:841–847

    Google Scholar 

  102. Elgemeie GEH, Mansour OA, Metwally NH (1999) Synthesis and anti-HIV activity of different novel nonclassical nucleosides. Nucleosides Nucleotides 18(1):113–123

    CAS  Google Scholar 

  103. Hafez HN, Hussein HAR, El-Gazzar ARBA (2010) Synthesis of substituted thieno[2,3-d]pyrimidine-2,4-dithiones and their S-glycoside analogues as potential antiviral and antibacterial agents. Eur J Med Chem 45:4026–4034

    CAS  Google Scholar 

  104. Galal SA, Abd El-All ASA, Hegab KH et al (2010) Novel antiviral benzofuran-transition metal complexes. Eur J Med Chem 45:3035–3046

    CAS  Google Scholar 

  105. Galal SA, Abd El-All ASA, Abdallah MM et al (2009) Synthesis of potent antitumor and antiviral benzofuran derivatives. Bioorg Med Chem Lett 19:2420–2428

    CAS  Google Scholar 

  106. Prestat G, Dubreui D, Adjou A et al (2000) Synthesis of 3′-O2-(azaheterocycle)- thymidines nucleosides. Nucleosides Nucleotides Nucleic Acids 19(4):735–748

    CAS  Google Scholar 

  107. Ané A, Prestat G, Manh GT et al (2001) Synthesis of nucleoside analogs and new Tat protein inhibitors. Pure Appl Chem 73(7):1189–1196

    Google Scholar 

  108. Al-Masoudi NA, Al-Soud YA, Al-Masoudi WA (2004) Thiosugar nucleosides. Synthesis and biological activity of 1,3,4-thiadiazole, thiazoline and thiourea derivatives of 5-thio-d-glucose. Nucleosides Nucleotides Nucleic Acids 23(11):1739–1749

    CAS  Google Scholar 

  109. Len C, Selouane A, Weiling A et al (2003) Asymmetric synthesis of (3S) 3-benzoyloxymethylisobenzofuranone and its 3R enantiomer as analogues of α, β-butenolides. Tetrahedron Lett 44:663–666

    CAS  Google Scholar 

  110. Selouane A, Vaccher C, Villa P et al (2002) Enantiomeric d4T analogues and their structural determination. Tetrahedron Asymmetry 13:407–413

    CAS  Google Scholar 

  111. Chaouni-Benabdallah A, Galtier C, Allouchi H et al (2001) A 3-benzamido, ureido and thioureidoimidazo[1,2-a]pyridine derivatives as potential antiviral agents. Chem Pharm Bull 49(12):1631–1635

    CAS  Google Scholar 

  112. Chaouni-Benabdallah A, Galtier C, Allouchi H et al (2001) Synthesis of 3-nitrosoimidazo[1,2-a]pyridine derivatives as potential antiretroviral agents. Arch Pharm Pharm Med Chem 334:224–228

    CAS  Google Scholar 

  113. Lazrek HB, Vasseur JJ, Secrist J et al (2007) A glutaric acid ester as carrier system for sustained delivery of lamuvidine (3tc) dimers. Nucleosides Nucleotides Nucleic Acids 26:1103–1106

    CAS  Google Scholar 

  114. Taourirte M, Lazrek HB, Rochdi A et al (2005) Homo and heterodimers of ddi, d4t and azt: influence of (5′-5′) thiolcabonate-carbamate linkage on anti-HIV activity. Nucleosides Nucleotides Nucleic Acids 24(5–7):523–525

    CAS  Google Scholar 

  115. Tourirte M, Oulih T, Lazrek HB et al (2003) Synthesis of 3O-deoxy-3O-[4-(pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]thymidine via 1,3-dipolar cycloaddition. Nucleosides Nucleotides Nucleic Acids 22(11):1985–1993

    CAS  Google Scholar 

  116. Ait Mohamed L, Taourirte M, Rochdi A et al (2003) Synthesis of new homo and heterodimers of 2O,3O-dideoxyinosine (ddI) using ester linkages. Nucleosides Nucleotides Nucleic Acids 22(5–8):829–831

    CAS  Google Scholar 

  117. Moukha-chafiq O, Taha ML, Lazrek HB et al (2002) Synthesis and biological evaluation of some acyclic a-(1H-pyrazolo- [3,4-d]pyrimidin-4-yl)thioalkylamide nucleosides. Nucleosides Nucleotides Nucleic Acids 21(2):165–176

    CAS  Google Scholar 

  118. Lazrek HB, Taourirte M, Oulih T et al (2001) Synthesis and anti-HIV activity of new modified 1,2,3-triazole acyclonucleosides. Nucleosides Nucleotides Nucleic Acids 20(12):1949–1960

    CAS  Google Scholar 

  119. Moukha-chafiq O, Taha ML, Lazrek HB et al (2001) Synthesis and biological activity of 4-substituted 1-[1-(2-hydroxyethoxy)- methyl-1,2,3-triazol-(4 & 5)-ylmethyl]-1h-pyrazolo[ 3,4-d]pyrimidines. Nucleosides Nucleotides Nucleic Acids 20(10–11):1797–1810

    CAS  Google Scholar 

  120. Moukha-chafiq O, Taha ML, Lazrek HB et al (2001) Synthesis and biological evaluation of some 4-substituted 1-[1-(4-hydroxybutyl)-1,2,3-triazol- (4 & 5)-ylmethyl]-1h-pyrazolo- [3,4-d]pyrimidines. Nucleosides Nucleotides Nucleic Acids 20(10–11):1811–1821

    CAS  Google Scholar 

  121. Taourirte M, Lazrek HB, Vasseur JJ et al (2001) Synthesis of new homo and heterodinucleosides containing the 2′,3′-dideoxynucleosides AZT and D4T. Nucleosides Nucleotides Nucleic Acids 20(4–7):959–962

    CAS  Google Scholar 

  122. Lazrek HB, Engels JW, Pfleidere W (1998) Synthesis of novel branched nucleoside dimers containing a 1,2,3-triazolyl linkage. Nucleosides Nucleotides 17(9–11):1851–1856

    CAS  Google Scholar 

  123. Lazrek HB, Rochdi A, Khaider H et al (1998) Synthesis of (Z) and (E) alpha – alkenyl phosphonic acid derivatives of purines and pyrimidines. Tetrahedron 54:3807–3816

    CAS  Google Scholar 

  124. Stieger N, Caira MR, Liebenberg W et al (2010) Influence of the composition of water/ethanol mixtures on the solubility and recrystallization of nevirapine. Cryst Growth Des 10:9

    Google Scholar 

  125. Stieger N, Liebenberg W, Wessels JC et al (2010) Channel inclusion of primary alcohols in isostructural solvates of the antiretroviral nevirapine: an X-ray and thermal analysis study. Struct Chem 21:771–777

    CAS  Google Scholar 

  126. Caira MR, Stieger N, Liebenberg W et al (2008) Solvent inclusion by the anti-HIV drug nevirapine: X-ray structures and thermal decomposition of representative solvates. Cryst Growth Des 8:1

    Google Scholar 

  127. Fonteh PN, Keter FK, Meyer D et al (2009) Tetra-chloro-(bis-(3,5-dimethylpyrazolyl)methane)gold(III) chloride: an HIV-1 reverse transcriptase and protease inhibitor. J Inorg Biochem 103:190–194

    CAS  Google Scholar 

  128. Fonteh PN, Keter FK, Meyer D (2010) HIV therapeutic possibilities of gold compounds. Biometals 23:185–196

    CAS  Google Scholar 

  129. Younis Y, Hunter R, Muhanji CI et al (2010) [d4U]-Spacer-[HI-236] double-drug inhibitors of HIV-1 reverse-transcriptase. Bioorg Med Chem 18:4661–4673

    CAS  Google Scholar 

  130. Hunter R, Younis Y, Muhanji CI et al (2008) C-2-Aryl O-substituted HI-236 derivatives as non-nucleoside HIV-1 reverse-transcriptase inhibitors. Bioorg Med Chem 16:10270–10280

    CAS  Google Scholar 

  131. Hunter R, Muhanji CI, Hale I et al (2007) [d4U]-butyne-[HI-236] as a non-cleavable, bifunctional NRTI/NNRTI HIV-1 reverse-transcriptase inhibitor. Bioorg Med Chem Lett 17:2614–2617

    CAS  Google Scholar 

  132. Arnott G, Hunter R, Mbeki L et al (2005) New methodology for 2-alkylation of 3-furoic acids: application to the synthesis of tethered UC-781/d4T bifunctional HIV reverse-transcriptase inhibitors. Tetrahedron Lett 46:4023–4026

    CAS  Google Scholar 

  133. Muhanji CI, Hunter R (2007) Current developments in the synthesis and biological activity of HIV-1 double-drug inhibitors. Curr Med Chem 14:1207–1220

    CAS  Google Scholar 

  134. N’Da DD, Breytenbach JC, Legoabe LJ et al (2009) Synthesis and in vitro transdermal penetration of methoxypoly(ethylene glycol) carbonate derivatives of stavudine. Med Chem 5:497–506

    Google Scholar 

  135. Serradji N, Martin M, Bensaid O et al (2004) Structure-activity relationships in platelet-activating factor. 12. Synthesis and biological evaluation of platelet-activating factor antagonists with anti-HIV-1 activity. J Med Chem 47:6410–6419

    CAS  Google Scholar 

  136. Serradji N, Bensaid O, Martin M et al (2006) Structure–activity relationships in platelet-activating factor. Part 13: synthesis and biological evaluation of piperazine derivatives with dual anti-PAF and anti-HIV-1 or pure antiretroviral activity. Bioorg Med Chem 14:8109–8125

    CAS  Google Scholar 

  137. Bendjeddou A, Djebbar H, Berredjem M et al (2006) Cyclosulfamides as constraint dipeptides: the synthesis and structure of Chiral substituted 1,2,5-thiadiazolidine 1,1-dioxides: evaluation of the toxicity. Phosphorus Sulfur Silicon Relat Elem 181:1351–1362

    CAS  Google Scholar 

  138. Bendjeddou A, Djeribi R, Regainia Z et al (2005) N, N′-substituted 1,2,5 thiadiazolidine 1,1-dioxides: synthesis, selected chemical and spectral proprieties and antimicrobial evaluation. Molecules 10:1387–1398

    CAS  Google Scholar 

  139. Regaınia Z, Winum JY, Smaine FZ et al (2003) General synthesis of n-membered cyclic sulfamides. Tetrahedron 59:6051–6056

    Google Scholar 

  140. Badawey EAM, Kappe T (1997) Synthesis and in vitro anti-HIV activity of certain 2-(1H-benzimidazol-2-ylamino)pyrimidin-4(3H)-ones and related derivatives. Arch Pharm Pharm Med Chem 330:59

    Google Scholar 

  141. Badawey E, Kappe T (1995) Benzimidazole condensed ring system. IX. Potential antineoplastics. New synthesis of some pyrido[l,2-a]benzimidazoles and related derivatives. Eur J Med Chem 30:327–332

    CAS  Google Scholar 

  142. Habib NS, Rida SM, Badawey EAM et al (1996) Condensed thiazoles, i: synthesis of 5,7-disubstituted thiazolo [4,5-d]pyrimidines as possible anti-HIV, anticancer, and antimicrobial agents. Monatsh Chem 127:1203–1207

    CAS  Google Scholar 

  143. Habib NS, Rida SM, Badawey EAM et al (1996) Condensed thiazoles, ii: synthesis of 7-substituted thiazolo[4,5-d]pyrimidines as possible anti-HIV, anticancer, and antimicrobial agents. Monatsh Chem 127:1209–1214

    CAS  Google Scholar 

  144. Rida SM, Habib NS, Badawey EAM et al (1995) Synthesis and biological investigations of some new thiazolylbenzimidazoles and benzirnidazolylthiazo10[3,2-a]pyridines. Arch Pharm 328:325–328

    CAS  Google Scholar 

  145. El-Barbary AA, Abou El-Ezz AZA, Sharaf AM (2007) Studies on 2,4-dithioxo and 2-thioxoimidazolidene derivatives. Phosphorus Sulfur Silicon Relat Elem 182:1621–1632

    CAS  Google Scholar 

  146. El-Barbary AA, Abou El-Ezz AZA, Sharaf AM et al (2006) The synthesis of some new quinazolone derivatives of potential biological activity. Phosphorus Sulfur Silicon Relat Elem 181:1895–1912

    CAS  Google Scholar 

  147. El-Barbary AA, Abou-El-Ezz AZA, Abdel-Kader AA et al (2004) Synthesis of some new 4-amino-1,2,4-triazole derivatives as potential anti-HIV and anti-HBV. Phosphorus Sulfur Silicon Relat Elem 179:1497–1508

    CAS  Google Scholar 

  148. Loksha YM, Pedersen EB, Loddo R et al (2009) Synthesis and anti-HIV-1 activity of 1-substituted 6-(3-cyanobenzoyl) and [(3-cyanophenyl)fluoromethyl]-5-ethyluracils. Arch Pharm Chem Life Sci 342:501–506

    CAS  Google Scholar 

  149. Loksha YM, El-Barbary AA, El-Badawi MA et al (2005) Synthesis of 2-(aminocarbonylmethylthio)-1 H-imidazoles as novel Capravirine analogues. Bioorg Med Chem 13:4209–4220

    CAS  Google Scholar 

  150. Loksha YM, El-Badawi MA, El-Barbary AA et al (2003) Synthesis of 2-methylsulfanyl-1 h-imidazoles as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs). Arch Pharm Pharm Med Chem 336:175–180

    CAS  Google Scholar 

  151. Al-Masoudi NA, Al-Masoudi IA, Ali IAI et al (2005) Amino acid derivatives, part 3: new peptide and glycopeptide derivatives conjugated naphthalene. synthesis, antitumor, anti-HIV, and BVDV evaluation. Heteroatom Chem 16(7):576

    CAS  Google Scholar 

  152. Ali IAI, Al-Masoudi IA, Saeed B et al (2005) Amino acid derivatives, part 2: synthesis, antiviral, and antitumor activity of simple protected amino acids functionalized at n-terminus with naphthalene side chain. Heteroatom Chem 16(2):148

    CAS  Google Scholar 

  153. Rida SM, Ashour FA, El-Hawash SAM et al (2005) Synthesis of some novel benzoxazole derivatives as anticancer, anti-HIV-1 and antimicrobial agents. Eur J Med Chem 40:949–959

    CAS  Google Scholar 

  154. Rida SM, Ashour FA, El-Hawash SAM et al (2006) Synthesis of novel benzofuran and related benzimidazole derivatives for evaluation of in vitro anti-HIV-1, anticancer and antimicrobial activities. Arch Pharm Res 29(10):826–833

    CAS  Google Scholar 

  155. El-Hamid A, Ismail AA, Attia AME (2003) Synthesis of some new quinazoline derivatives analogues to MKC-442 and TNK 561. Phosphorus Sulfur Silicon Relat Elem 178:1231–1240

    CAS  Google Scholar 

  156. Diallo K, Loemb H, Oliveir M et al (2000) Inhibition of human immunodeficiency virus type-1 (HIV-1) replication by immunor (Im28), a new analog of dehydroepiandrosterone. Nucleosides Nucleotides Nucleic Acids 19(10–12):2019–2024

    CAS  Google Scholar 

  157. Mavoungou D, Poaty-Mavoungou V, Akoume MY et al (2005) Inhibition of human immunodeficiency virus type-1 (HIV-1) glycoprotein-mediated cell-cell fusion by immunor (IM28). Virol J 2:9

    Google Scholar 

  158. Montembault M, Vo-Thanh G, Deyine A et al (2004) A possible improvement for structure-based drug design illustrated by the discovery of a Tat HIV-1 inhibitor. Bioorg Med Chem Lett 14:1543–1546

    CAS  Google Scholar 

  159. Ané A, Prestat G, Manh GT et al (2001) Synthesis of nucleoside analogs and new Tat protein inhibitors. Pure Appl Chem 73(7):1189–1196

    Google Scholar 

  160. Bhowon MG, Laulloo BSJ (2004) Synthesis and anti-HIV activity of metal complexes of SRR-SB3. Indian J Chem 43(5):1131–1133

    Google Scholar 

  161. Bhowon MG (2000) Synthesis, catalytic and biological activity of ruthenium(II) complexes. Indian J Chem 39(11):1207–1209

    Google Scholar 

  162. Jhaumeer-Laulloo BS (2000) Synthesis and anti-HIV activity of novel macrocyclic disulphide compounds with thioureylene group. Asian J Chem 12(3):775–780

    CAS  Google Scholar 

  163. Jhaumeer-Laulloo S, Witvrouw M (2000) Synthesis and anti-HIV activity of novel macrocyclic benzamides with a disulphide bridge. Indian J Chem 39(11):842–846

    Google Scholar 

  164. Jhaumeer-Laulloo BS, Ramadas SR (1999) Synthesis and anti-HIV activity of macrocyclic dilactams containing disulphide bridge. Indian J Heterocycl Chem 9(1):1–6

    CAS  Google Scholar 

  165. Meskini I, Toupet L, Daoudi M et al (2010) Structure of 2-[(phenyl)-(3,5-dimethyl-pyrazol-1-yl)-methyl]- malonic acid diethyl ester. J Chem Crystallogr 40:812–815

    CAS  Google Scholar 

  166. Meskini I, Daoudi M, Daran JC et al (2010) Poly[[bis{l3-2-[(3,5-dimethyl-1H-pyrazol- 1-yl)(phenyl)methyl]propanedioato} tetrasodium(I)] 7.5-hydrate]. Acta Crystallogr Sect E Struct Rep Online E66:m1009–m1010

    CAS  Google Scholar 

  167. Meskini I, Daoudi M, Daran JC et al (2010) Diethyl 2-[(3,5-dimethyl-1 H-pyrazol-1- yl)(4-methoxyphenyl)methyl]propanedioate. Acta Crystallogr Sect E Struct Rep Online 66:o1965

    Google Scholar 

  168. Meskini I, Toupet L, Daoudi M et al (2010) An efficient protocol for accessing b-amino dicarbonyl compounds through aza-Michael reaction. J Braz Chem Soc 21(6):1129–1135

    CAS  Google Scholar 

  169. Meskini I, Daoudi M, Daran JC et al (2010) Diethyl 2-[phenyl(pyrazol-1-yl)methyl]- propanedioate. Acta Crystallogr Sect E Struct Rep Online 66:o1014

    Google Scholar 

  170. Meskini I, Daoudi M, Daran JC et al (2010) Diethyl 2-[(N-benzyl-N-methylamino)- (phenyl)methyl]propanedioate. Acta Crystallogr Sect E Struct Rep Online 66:o746

    Google Scholar 

  171. Meskini I, Daoudi M, Daran JC et al (2010) Diethyl 2-{(dibenzylamino)[4-(trifluoromethyl) phenyl]methyl}malonate. Acta Crystallogr Sect E Struct Rep Online E66:o961–o962

    CAS  Google Scholar 

  172. Meskini I, Toupet L, Akkurt M et al (2010) Crystal structure of diethyl[(4chlorophenyl) (dibenzylamino)methyl]propanedioate. J Chem Crystallogr 40:391–395

    CAS  Google Scholar 

  173. Bennani B, Kerbal A, Daoudi M et al (2007) Combined drug design of potential Mycobacterium tuberculosis and HIV-1 inhibitors: 3′,4′-di-substituted -4′H-spiro [isothiochromene-3,5′-isoxazol]-4(1H)-one. ARKIVOC xvi:19–40

    Google Scholar 

  174. Ibrahimi S, Sauvé G, Yelle J et al (2005) Synthèse racémique et énantiosélective d’énol-lactones et leur évaluation comme inhibiteurs de la protéase du VIH-1. C R Chim 8:75–83

    CAS  Google Scholar 

  175. Onajole OK, Makatini MM, Govender P et al (2010) Synthesis and NMR assignment of pentacycloundecane precursors of potential pharmaceutical agents. Magn Reson Chem 48:249–255

    CAS  Google Scholar 

  176. Touati R, Hassine BB (2008) Asymmetric synthesis of beta-aminosulfones via the enantioselective hydrogenation of the corresponding beta-ketosulfones. Lett Org Chem 5:240–243

    CAS  Google Scholar 

  177. Samarat A, Amria H, Landaisb Y (2004) Enantioselective synthesis of functionalized g-butyrolactones. Tetrahedron 60:8949–8956

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Advanced Materials Division, Mintek, X3015, Randburg, 2125, Biomed, Johannesburg, South Africa

    R. Hewer, F. H. Kriel & J. Coates

Authors
  1. R. Hewer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. H. Kriel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Coates
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Hewer .

Editor information

Editors and Affiliations

  1. , Dept. of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa

    Kelly Chibale

  2. , Department of Chemistry, Rhodes University, Grahamstown, 6140, South Africa

    Mike Davies-Coleman

  3. and Technology, African Institute of Biomedical Science, Harare, 2294, Zimbabwe

    Collen Masimirembwa

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Berlin Heidelberg

About this chapter

Cite this chapter

Hewer, R., Kriel, F.H., Coates, J. (2012). Random and Rational Approaches to HIV Drug Discovery in Africa. In: Chibale, K., Davies-Coleman, M., Masimirembwa, C. (eds) Drug Discovery in Africa. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28175-4_14

Download citation

Publish with us

Policies and ethics

Search

Navigation