Antifungal activity of a series of 1,2-benzisothiazol-3(2H)-one derivatives

Dou, Dengfeng; Alex, Deepu; Du, Bingfan; Tiew, Kok-Chuan; Aravapalli, Sridhar; Mandadapu, Sivakoteswara Rao; Calderone, Richard; Groutas, William C.

doi:10.1016/j.bmc.2011.08.029

Cited by 32 publications

(26 citation statements)

References 14 publications

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“…PBIT is a derivative of benzisothiazolinone, a widely used microbicide and fungicide used in many home cleaning products (32). PBIT and its analogues were previously identified as inhibitors of salicylate synthase from Mycobacterium tuberculosis (33).…”

Section: Discussionmentioning

confidence: 99%

Identification of Small Molecule Inhibitors of Jumonji AT-rich Interactive Domain 1B (JARID1B) Histone Demethylase by a Sensitive High Throughput Screen

Sayegh

Cao

Zou

et al. 2013

Journal of Biological Chemistry

120

108

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Background: JARID1B is an H3K4 histone demethylase and an attractive target for cancer therapy.Results: High throughput screen identified novel compounds that can inhibit JARID1B demethylase activity. Conclusion: Drug-like small molecules can be identified to inhibit JARID1B. Significance: The identified JARID1B inhibitors are lead compounds that can be developed into anti-cancer epigenetic drugs.

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Section: Discussionmentioning

confidence: 99%

Identification of Small Molecule Inhibitors of Jumonji AT-rich Interactive Domain 1B (JARID1B) Histone Demethylase by a Sensitive High Throughput Screen

Sayegh

Cao

Zou

et al. 2013

Journal of Biological Chemistry

120

108

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“…The novelty of our studies starts first with the structures of active compounds, heretofore not reported (18). Further, from our current data, we have established that compounds with a BZT core structure have antifungal activity against a variety of human pathogen isolates, including dermatophytic fungi (Tables 1 and 2).…”

Section: Discussionmentioning

confidence: 83%

Amino Acid-Derived 1,2-Benzisothiazolinone Derivatives as Novel Small-Molecule Antifungal Inhibitors: Identification of Potential Genetic Targets

Alex

Gay-Andrieu

May

et al. 2012

Antimicrob Agents Chemother

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We have identified four synthetic compounds (DFD-VI-15, BD-I-186, DFD-V-49, and DFD-V-66) from an amino acid-derived 1,2-benzisothiazolinone (BZT) scaffold that have reasonable MIC 50 values against a panel of fungal pathogens. These compounds have no structural similarity to existing antifungal drugs. Three of the four compounds have fungicidal activity against Candida spp., Cryptococcus neoformans, and several dermatophytes, while one is fungicidal to Aspergillus fumigatus. The kill rates of our compounds are equal to those in clinical usage. The BZT compounds remain active against azole-, polyene-, and micafungin-resistant strains of Candida spp. A genetics-based approach, along with phenotype analysis, was used to begin mode of action (MOA) studies of one of these compounds, DFD-VI-15. The genetics-based screen utilized a homozygous deletion collection of approximately 4,700 Saccharomyces cerevisiae mutants. We identified mutants that are both hypersensitive and resistant. Using FunSpec, the hypersensitive mutants and a resistant ace2 mutant clustered within a category of genes related directly or indirectly to mitochondrial functions. In Candida albicans, the functions of the Ace2p transcription factor include the regulation of glycolysis. Our model is that DFD-VI-15 targets a respiratory pathway that limits energy production. Supporting this hypothesis are phenotypic data indicating that DFD-VI-15 causes increased cell-reactive oxidants (ROS) and a decrease in mitochondrial membrane potential. Also, the same compound has activity when cells are grown in a medium containing glycerol (mitochondrial substrate) but is much less active when cells are grown anaerobically.

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“…In addition to the use of the DTP library as a source of compounds, we have screened a group of synthetic, low-molecular-weight compounds that were provided to the laboratory through an ongoing collaboration [16,31]. Scaffolds such as the amino acid-derived 1,2-benzisothiazolinone (BZT; BD-I-186) scaffold were screened against pathogens that included Candida species Cryptococcus neoformans, Aspergillus fumigatus and several dermatophytic fungi [16,31].…”

Section: Compound Librariesmentioning

confidence: 99%

Antifungal Drug Discovery: The Process and Outcomes

et al. 2014

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New data suggest that the global incidence of several types of fungal diseases have traditionally been under-documented. Of these, mortality caused by invasive fungal infections remains disturbingly high, equal to or exceeding deaths caused by drug-resistant tuberculosis and malaria. It is clear that basic research on new antifungal drugs, vaccines and diagnostic tools is needed. In this review, we focus upon antifungal drug discovery including in vitro assays, compound libraries and approaches to target identification. Genome mining has made it possible to identify fungal-specific targets; however, new compounds to these targets are apparently not in the antimicrobial pipeline. We suggest that ‘repurposing’ compounds (off patent) might be a more immediate starting point. Furthermore, we examine the dogma on antifungal discovery and suggest that a major thrust in technologies such as structural biology, homology modeling and virtual imaging is needed to drive discovery.

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Antifungal activity of a series of 1,2-benzisothiazol-3(2H)-one derivatives

Cited by 32 publications

References 14 publications

Identification of Small Molecule Inhibitors of Jumonji AT-rich Interactive Domain 1B (JARID1B) Histone Demethylase by a Sensitive High Throughput Screen

Identification of Small Molecule Inhibitors of Jumonji AT-rich Interactive Domain 1B (JARID1B) Histone Demethylase by a Sensitive High Throughput Screen

Amino Acid-Derived 1,2-Benzisothiazolinone Derivatives as Novel Small-Molecule Antifungal Inhibitors: Identification of Potential Genetic Targets

Antifungal Drug Discovery: The Process and Outcomes

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