[1,2,5]Oxadiazolo[3,4-<i>b</i>]pyrazine-5,6-diamine Derivatives as Mitochondrial Uncouplers for the Potential Treatment of Nonalcoholic Steatohepatitis

Childress, Elizabeth S.; Salamoun, Joseph M.; Hargett, Stefan R.; Alexopoulos, Stephanie J.; Chen, Sing-Young; Shah, Divya P.; Santiago-Rivera, José; Garcia, Christopher J.; Dai, Yumin; Tucker, Simon P.; Hoehn, Kyle L.

doi:10.1021/acs.jmedchem.9b01440

Cited by 29 publications

(33 citation statements)

References 76 publications

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“…Uncouplers of oxidative phosphorylation in mitochondria are capable of breaking the coupling between the electron transport chain and phosphorylation reactions and thus inhibiting ATP synthesis. As a result, energy is lost, but respiration rate and oxygen consumption increase (Vitoratos, 2014;Childress et al, 2020). In addition, the MMP decreases due to the proton potential through the inner membrane of mitochondria that is disturbed by uncouplers, which inhibit the reflux of protons through ATP synthase without affecting electron transport (Ding et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Metabolic Fingerprinting for Identifying the Mode of Action of the Fungicide SYP-14288 on Rhizoctonia solani

et al. 2020

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The fungicide SYP-14288 has a high efficiency, low toxicity, and broad spectrum in inhibiting both fungi and oomycetes, but its mode of action (MoA) remains unclear on inhibiting fungi. In this study, the MoA was determined by analyzing the metabolism and respiratory activities of Rhizoctonia solani treated by SYP-14288. Wild-type strains and SYP-14288-resistant mutants of R. solani were incubated on potato dextrose agar amended with either SYP-14288 or one of select fungicides acting on fungal respiration, including complex I, II, and III inhibitors; uncouplers; and ATP synthase inhibitors. Mycelial growth was measured under fungicides treatments. ATP content was determined using an ATP assay kit, membrane potential of mitochondria was detected with the JC-1 kit, and respiratory rate was calculated based on the measurement of oxygen consumption of R. solani. A model of metabolic fingerprinting cluster was established to separate oxidation inhibitors and phosphorylation inhibitors. All the results together displayed a clear discrimination between oxidation inhibitors and phosphorylation inhibitors, and the latter inhibited ATP synthase production having or uncoupling activities. Based on the model, SYP-14288 was placed in phosphorylation inhibitor group, because it significantly reduced ATP content and membrane potential of mitochondria while increasing respiratory rate in R. solani. Therefore, the MoA of SYP-14288 on R. solani was confirmed to involve phosphorylation inhibition and possibly uncoupling activity.

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Section: Discussionmentioning

confidence: 99%

Metabolic Fingerprinting for Identifying the Mode of Action of the Fungicide SYP-14288 on Rhizoctonia solani

et al. 2020

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“…Interestingly, a subtle change to 8 such as regioisomers of the fluoroaniline provided the unsymmetrical analog 9 that was efficacious in a streptozotocin (STZ)-induced mouse model of NASH. Compound 9 lowered liver triglyceride levels and reduced inflammation and fibrosis scores …”

Section: Introductionmentioning

confidence: 99%

6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Derivatives as Efficacious Mitochondrial Uncouplers in STAM Mouse Model of Nonalcoholic Steatohepatitis

et al. 2020

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Small molecule mitochondrial uncouplers have recently garnered great interest for their potential in treating nonalcoholic steatohepatitis (NASH). In this study, we report the structure−activity relationship profiling of a 6-amino[1,2,5]oxadiazolo [3,4-b]pyrazin-5-ol core, which utilizes the hydroxy moiety as the proton transporter across the mitochondrial inner membrane. We demonstrate that a wide array of substituents is tolerated with this novel scaffold that increased cellular metabolic rates in vitro using changes in oxygen consumption rate as a readout. In particular, compound SHS4121705 (12i) displayed an EC 50 of 4.3 μM in L6 myoblast cells and excellent oral bioavailability and liver exposure in mice. In the STAM mouse model of NASH, administration of 12i at 25 mg kg −1 day −1 lowered liver triglyceride levels and improved liver markers such as alanine aminotransferase, NAFLD activity score, and fibrosis. Importantly, no changes in body temperature or food intake were observed. As potential treatment of NASH, mitochondrial uncouplers show promise for future development.

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“…Next, we resynthesized compound 1 by following Santos’ procedure. 33 Compound 1 was obtained by treating meta -toluidine with excess dichloride 2 ( Scheme 1 ) in the presence of triethylamine. To our surprise, the purified compound 1 was unable to potentiate colistin in AR-0493 at up to 64 μg/mL, the highest concentration tested.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we synthesized and purified these two compounds using their, respectively, optimized procedures. 33 , 34 …”

Section: Resultsmentioning

confidence: 99%

Serendipitous Discovery of a Highly Active and Selective Resistance-Modifying Agent for Colistin-Resistant Gram-Negative Bacteria

2022

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Antibiotic resistance is a growing global health concern. Colistin is one of the last-resort antibiotics that treats multidrug-resistant (MDR) Gram-negative bacterial infection. However, bacteria resistant to colistin have become increasingly prevalent. Using a bacterial whole-cell screen of a fragment-based library, one compound was discovered to resensitize MDR Escherichia coli AR-0493 to colistin with low mammalian toxicity. Interestingly, postscreening validation studies identified a highly related yet distinct compound as the actual substance responsible for the activity. Further studies showed that this novel resistance-modifying agent is not only very potent but also highly selective to potentiate the activity of polymyxin family antibiotics in a wide range of MDR Gram-negative bacteria. Thus, it may be further developed as a combination therapy to prolong the life span of colistin in the clinic.

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[1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diamine Derivatives as Mitochondrial Uncouplers for the Potential Treatment of Nonalcoholic Steatohepatitis

Cited by 29 publications

References 76 publications

Metabolic Fingerprinting for Identifying the Mode of Action of the Fungicide SYP-14288 on Rhizoctonia solani

Metabolic Fingerprinting for Identifying the Mode of Action of the Fungicide SYP-14288 on Rhizoctonia solani

6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Derivatives as Efficacious Mitochondrial Uncouplers in STAM Mouse Model of Nonalcoholic Steatohepatitis

Serendipitous Discovery of a Highly Active and Selective Resistance-Modifying Agent for Colistin-Resistant Gram-Negative Bacteria

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