Antifungal benzo[b]thiophene 1,1-dioxide IMPDH inhibitors exhibit pan-assay interference (PAINS) profiles
| Autor: | Avril A. B. Robertson, James A. Fraser, Ulrike Kappler, Amanda Nouwens, Mark E. Cooper, Lalith Kumar Kummari, Ross D. Blundell, Alberto B. Silva, Mark S. Butler, Bostjan Kobe, Emily Furlong |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Purine Models Molecular Antifungal Agents Stereochemistry Clinical Biochemistry Pharmaceutical Science Mixed inhibition Thiophenes Biochemistry Fungal Proteins 03 medical and health sciences chemistry.chemical_compound IMP Dehydrogenase IMP dehydrogenase Drug Discovery Thiophene Humans Cytotoxicity Molecular Biology Cryptococcus neoformans chemistry.chemical_classification Oxadiazoles 030102 biochemistry & molecular biology biology Organic Chemistry Cryptococcosis Hep G2 Cells biology.organism_classification 030104 developmental biology Enzyme HEK293 Cells chemistry Molecular Medicine Cysteine |
| Zdroj: | Bioorganicmedicinal chemistry. 26(20) |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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