Synthesis and evaluation of coumarin derivatives as potential dual-action HIV-1 protease and reverse transcriptase inhibitors Temitope O. Olomola a , Rosalyn Klein a , Nicodemus Mautsa a , Yasien Sayed b , Perry T. Kaye a,⇑ a Department of Chemistry and Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa b Protein Structure–Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, South Africa article info Article history: Received 30 November 2012 Revised 6 January 2013 Accepted 12 January 2013 Available online xxxx Keywords: Dual-action HIV-1 PR/RT inhibitors Baylis–Hillman reaction Coumarins Azidothymidine (AZT) abstract Baylis–Hillman-derived 3-(benzylaminomethyl)coumarins have been treated, sequentially, with chloro- acetyl chloride and propargylamine to afford alkynylated coumarins as substrates for Click Chemistry reactions with azidothymidine (AZT) in the presence of a Cu(I) catalyst. The dual-action HIV-1 protease (PR) and reverse transcriptase (RT) inhibition potential of the resulting N-benzylated cycloaddition prod- ucts, and a series of non-benzylated analogues, has been explored using saturation transfer difference (STD) NMR, computer modelling and enzyme inhibition techniques. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Highly active antiretroviral therapy (HAART) has been intro- duced to address the emergence of drug-resistant viral variants. 1–3 Such therapy typically involves the simultaneous administration of nucleoside and non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors and an HIV-1 protease (PR) inhibitor. The use of Designed Multiple Ligands (DMLs) 4–6 or ‘portmanteau inhibitors’ 7 to facilitate patient compliance during multiple-drug regimens is gaining increasing interest. In our research on applications of Bay- lis–Hillman-derived scaffolds in the construction of biologically ac- tive systems, attention has been given to the synthesis of such DMLs as lead compounds for the development of novel dual-action drugs. 8 Having established effective Baylis–Hillman methodologies to access coumarin derivatives (2H-chromen-2-ones or 2H-1-benzo- pyran-2-ones), 9 we have been exploring the use of these heterocy- clic scaffolds in the construction of potential HIV-1 PR inhibitors, including a series of ritonavir analogues 1. 10,11 Both naturally occurring and synthetic coumarin derivatives are known to exhibit a variety of medicinally useful properties; 12–16 phenprocoumon 2, for example, has been identified as a lead compound for the devel- opment of non-peptidic HIV-1 PR inhibitors. 17–21 In an earlier pa- per, 8 we described the preparation of the series of DMLs 8a–e (Scheme 1) which contain a coumarin moiety coupled with the well-known HIV-1 RT inhibitor, azidothymidine 3 (AZT). 22 Inter- estingly, the HIV-1 protease inhibition potential of the 1,2,3-tria- zole moiety has also been demonstrated. 23 The clinical ethylene dipeptide HIV-1 PR inhibitors typically contain benzyl groups which are accommodated by the largely hydrophobic S 1 and S 0 1 en- zyme receptor sub-sites 24 and, in a continuation of our earlier re- search, we now report: (i) the synthesis of a series of N-benzylated amido analogues 12a–e; and (ii) the evaluation of both series of ligands (8a–e and 12a–e) as dual-action HIV-1 PR and RT inhibitors, using a combination of STD NMR, enzyme- inhibition and computer-modelling methods. 0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2013.01.025 ⇑ Corresponding author. Tel.: +27 46 6037030; fax: +27 46 6225109. E-mail address: P.Kaye@ru.ac.za (P.T. Kaye). HO N 3 O N O NH O 3 H N N H O O Ph OH O O Ph R R O O OH 1 2 Bioorganic & Medicinal Chemistry xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc Please cite this article in press as: Olomola, T. O.; et al. Bioorg. Med. Chem. (2013), http://dx.doi.org/10.1016/j.bmc.2013.01.025