2. Academic Validation
  3. Antifungal benzo[b]thiophene 1,1-dioxide IMPDH inhibitors exhibit pan-assay interference (PAINS) profiles

Antifungal benzo[b]thiophene 1,1-dioxide IMPDH inhibitors exhibit pan-assay interference (PAINS) profiles

  • Bioorg Med Chem. 2018 Nov 1;26(20):5408-5419. doi: 10.1016/j.bmc.2018.09.004.
Lalith K Kummari 1,  Mark S Butler 2,  Emily Furlong 2,  Ross Blundell 3,  Amanda Nouwens 4,  Alberto B Silva 5,  Ulrike Kappler 6,  James A Fraser 3,  Bostjan Kobe 7,  Matthew A Cooper 2,  Avril A B Robertson 8
Affiliations

Affiliations

  • 1 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia; Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 2 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 3 Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 4 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 5 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia; AC Immune SA, EPFL Innovation Park, CH-1015 Lausanne, Switzerland.
  • 6 Centre for Metals in Biology, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 7 Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 8 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address: a.robertson3@uq.edu.au.
PMID: 30322754 DOI: 10.1016/j.bmc.2018.09.004
Abstract

Fungi cause serious life-threatening infections in immunocompromised individuals and current treatments are now complicated by toxicity issues and the emergence of drug resistant strains. Consequently, there is a need for development of new Antifungal drugs. Inosine monophosphate dehydrogenase (IMPDH), a key component of the de novo purine biosynthetic pathway, is essential for growth and virulence of fungi and is a potential drug target. In this study, a high-throughput screen of 114,000 drug-like compounds against Cryptococcus neoformans IMPDH was performed. We identified three 3-((5-substituted)-1,3,4-oxadiazol-2-yl)thio benzo[b]thiophene 1,1-dioxides that inhibited Cryptococcus IMPDH and also possessed whole cell Antifungal activity. Analogs were synthesized to explore the SAR of these hits. Modification of the fifth substituent on the 1,3,4-oxadiazole ring yielded compounds with nanomolar in vitro activity, but with associated cytotoxicity. In contrast, two analogs generated by substituting the 1,3,4-oxadiazole ring with imidazole and 1,2,4-triazole gave reduced IMPDH inhibition in vitro, but were not cytotoxic. During Enzyme kinetic studies in the presence of DTT, nucleophilic attack of a free thiol occurred with the benzo[b]thiophene 1,1-dioxide. Two representative compounds with substitution at the 5 position of the 1,3,4-oxadiazole ring, showed mixed inhibition in the absence of DTT. Incubation of these compounds with Cryptococcus IMPDH followed by mass spectrometry analysis showed non-specific and covalent binding with IMPDH at multiple cysteine residues. These results support recent reports that the benzo[b]thiophene 1,1-dioxides moiety as PAINS (pan-assay interference compounds) contributor.

Keywords

Antifungal; Cryptococcus neoformans; High-throughput screening; IMPDH inhibitor; Mass spectrometry; PAINS.

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