Synthesis and biological evaluation of simplified mycothiazole analogues

Mahler, Graciela; Serra, Gloria; Dematteis, Sylvia; Saldaña, Jenny; Domínguez, Laura; Manta, Eduardo

doi:10.1016/j.bmcl.2005.11.072

Cited by 24 publications

(15 citation statements)

References 14 publications

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“…Noteworthy is the route for the synthesis of racemic cysteine introduced by Degussa AG, in which the key intermediate is the 2,2-dimethyl-3-thiazoline [35]. Thiazolines are also important due to their activity against several life threatening infections or diseases, including antimicrobial [36], anti-inflammatory [37], anticancer [38], anti-oxidant [39] and antimycobacterium [40] activities.…”

Section: Introductionmentioning

confidence: 99%

Ruthenium (II) complexes containing 2-mercaptothiazolinates as ligands and evaluation of their antimicrobial activity

Appelt

Fagundes

Facchin

et al. 2015

Inorganica Chimica Acta

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Section: Introductionmentioning

confidence: 99%

Ruthenium (II) complexes containing 2-mercaptothiazolinates as ligands and evaluation of their antimicrobial activity

Appelt

Fagundes

Facchin

et al. 2015

Inorganica Chimica Acta

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“…Structural analog studies revealed that the thiazole component of MYZ was important for its bioactivity [2]. The original chemical structure of MYZ as proposed by Crews et al [1] was later found to be incorrect, and a corrected structure was subsequently published in 2006 [3].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Genome-Knockout Cells Demonstrate a Dual Mechanism of Action for the Electron Transport Complex I Inhibitor Mycothiazole

et al. 2012

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Mycothiazole, a polyketide metabolite isolated from the marine sponge Cacospongia mycofijiensis, is a potent inhibitor of metabolic activity and mitochondrial electron transport chain complex I in sensitive cells, but other cells are relatively insensitive to the drug. Sensitive cell lines (IC50 0.36–13.8 nM) include HeLa, P815, RAW 264.7, MDCK, HeLa S3, 143B, 4T1, B16, and CD4/CD8 T cells. Insensitive cell lines (IC50 12.2–26.5 μM) include HL-60, LN18, and Jurkat. Thus, there is a 34,000-fold difference in sensitivity between HeLa and HL-60 cells. Some sensitive cell lines show a biphasic response, suggesting more than one mechanism of action. Mitochondrial genome-knockout ρ0 cell lines are insensitive to mycothiazole, supporting a conditional mitochondrial site of action. Mycothiazole is cytostatic rather than cytotoxic in sensitive cells, has a long lag period of about 12 h, and unlike the complex I inhibitor, rotenone, does not cause G2/M cell cycle arrest. Mycothiazole decreases, rather than increases the levels of reactive oxygen species after 24 h. It is concluded that the cytostatic inhibitory effects of mycothiazole on mitochondrial electron transport function in sensitive cell lines may depend on a pre-activation step that is absent in insensitive cell lines with intact mitochondria, and that a second lower-affinity cytotoxic target may also be involved in the metabolic and growth inhibition of cells.

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“…Bengazole and mycothiazole analogues, such as compounds 11 and 12 , were reported by Manta et al [29,30] These derivatives were found to have in vitro Nippostrongylus brasiliensis activity similar to bengazole and mycothiazole whilst being more chemically stable than the parent analogues. …”

Section: Recent Patent Landscape: New Antiparasitic Compoundsmentioning

confidence: 93%

Anthelmintic discovery and development in the animal health industry

Woods

Lauret

Geary

2007

Expert Opinion on Drug Discovery

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Most modern anthelmintics used against human pathogens have come from the animal health (AH) industry. Historically, new molecules were discovered empirically, but recent developments in genomic and screening technologies have significantly enhanced the opportunities for target-based identification of novel therapies. However, drug discovery and development is still a complicated and costly process with high attrition. Absence of a return in investment for tropical parasitic diseases makes it difficult for large pharmaceutical companies to justify seeking antiparasitics for less developed countries in isolation. A partnership in which there is a sharing of costs and leveraging of resources is one way forward and is reflected in the new paradigm of 'integrated drug discovery', where collaborations and networks of academic institutions and industry are working together towards the discovery of new treatments for tropical parasitic diseases.

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Synthesis and biological evaluation of simplified mycothiazole analogues

Cited by 24 publications

References 14 publications

Ruthenium (II) complexes containing 2-mercaptothiazolinates as ligands and evaluation of their antimicrobial activity

Ruthenium (II) complexes containing 2-mercaptothiazolinates as ligands and evaluation of their antimicrobial activity

Mitochondrial Genome-Knockout Cells Demonstrate a Dual Mechanism of Action for the Electron Transport Complex I Inhibitor Mycothiazole

Anthelmintic discovery and development in the animal health industry

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