2. Academic Validation
  3. Optimization of 5-substituted thiazolyl ureas and 6-substituted imidazopyridines as potential HIV-1 latency reversing agents

Optimization of 5-substituted thiazolyl ureas and 6-substituted imidazopyridines as potential HIV-1 latency reversing agents

  • Eur J Med Chem. 2020 Jun 1;195:112254. doi: 10.1016/j.ejmech.2020.112254.
William Nguyen 1,  Jonathan Jacobson 2,  Kate E Jarman 1,  Timothy R Blackmore 1,  Helene Jousset Sabroux 1,  Sharon R Lewin 3,  Damian F Purcell 2,  Brad E Sleebs 4
Affiliations

Affiliations

  • 1 The Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3052, Australia.
  • 2 Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute of Infection and Immunity, University of Melbourne, Parkville, Victoria, 3000, Australia.
  • 3 Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute of Infection and Immunity, University of Melbourne, Parkville, Victoria, 3000, Australia; The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Parkville, Victoria, 3000, Australia; Department of Infectious Diseases, Alfred Health and Monash University, Melbourne, Victoria, 3004, Australia.
  • 4 The Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3052, Australia. Electronic address: sleebs@wehi.edu.au.
PMID: 32251744 DOI: 10.1016/j.ejmech.2020.112254
Abstract

A persistent latent reservoir of virus in CD4+ T cells is a major barrier to cure HIV. Activating viral transcription in latently infected cells using small molecules is one strategy being explored to eliminate latency. We previously described the use of a FlpIn.FM HEK293 cellular assay to identify and then optimize the 2-acylaminothiazole class to exhibit modest activation of HIV gene expression. Here, we implement two strategies to further improve the activation of viral gene expression and physicochemical properties of this class. Firstly, we explored rigidification of the central oxy-carbon linker with a variety of saturated heterocycles, and secondly, investigated bioisosteric replacement of the 2-acylaminothiazole moiety. The optimization process afforded lead compounds (74 and 91) from the 2-piperazinyl thiazolyl urea and the imidazopyridine class. The lead compounds from each class demonstrate potent activation of HIV gene expression in the FlpIn.FM HEK293 cellular assay (both with LTR EC50s of 80 nM) and in the Jurkat Latency 10.6 cell model (LTR EC50 220 and 320 nM respectively), but consequently activate gene expression non-specifically in the FlpIn.FM HEK293 cellular assay (CMV EC50 70 and 270 nM respectively) manifesting in cellular cytotoxicity. The lead compounds have potential for further development as novel latency reversing agents.

Keywords

AIDS; HIV-1; Imidazopyridine; Latency; Thiazole; Transcription.

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