Synthesis and evaluation of cyclohexane carboxylic acid head group containing isoxazole and thiazole analogs as DGAT1 inhibitors

Kandre, Shivaji; Bhagat, Pundlik Rambhau; Reddy, M. Mahesh Kumar; Dalal, Roda; Dixit, Amol; Deshmukh, Nitin; Anthony, Jessy; Bose, Julie; Raghuram, Anupindi; Sharma, Rajiv; Gupte, Akshaya

doi:10.1016/j.ejmech.2014.03.077

Cited by 8 publications

(3 citation statements)

References 14 publications

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“…For the synthesis of thiazole ester (14), 2-bromoacetophenone (12) was treated with ethyl thiooxamate (13) by intermolecular cyclization to obtain thiazole ester (14). For the synthesis of thiazole ester (17), the oxygen atom of the benzamide (15) was substituted with sulfur using Lawesson's reagent in toluene to obtain the corresponding thiobenzamid (16), which was subsequently coupled with ethyl bromopyruvate in ethanol under reflux to yield thiazole ester (17). For the synthesis of isoxazole ester (20), benzaldehyde was treated with hydroxylamine to yield the corresponding oxime (18), followed by the addition of N- S33 of the Supporting Information, and the crystal data of compound 4af was presented in Table S1 of the Supporting Information.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Compound 19a was synthesized using a modified procedure derived from the previously described method . A solution comprising compound 19a (10 mmol), ethyl propiolate (20 mmol), and Et 3 N in 100 mL of CH 2 Cl 2 was refluxed for 6 h. The resulting residue was isolated and further purified by silica gel column chromatography (EA/PE = 1:5) to yield intermediate 20a …”

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis, and Antifungal Evaluation of Diverse Heterocyclic Hydrazide Derivatives as Potential Succinate Dehydrogenase Inhibitors

Chen,

Liu,

Wang

et al. 2024

J. Agric. Food Chem.

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Plant pathogenic fungi pose a significant threat to agricultural production, necessitating the development of new and more effective fungicides. The ring replacement strategy has emerged as a highly successful approach in molecular design. In this study, we employed the ring replacement strategy to successfully design and synthesize 32 novel hydrazide derivatives containing diverse heterocycles, such as thiazole, isoxazole, pyrazole, thiadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, thiophene, pyridine, and pyrazine. Their antifungal activities were evaluated in vitro and in vivo. Bioassay results revealed that most of the title compounds displayed remarkable antifungal activities in vitro against four tested phytopathogenic fungi, including Fusarium graminearum, Botrytis cinerea, Sclerotinia sclerotiorum, and Rhizoctonia solani. Especially, compound 5aa displayed a broad spectrum of antifungal activity against F. graminearum, B. cinerea, S. sclerotiorum, and R. solani, with the corresponding EC50 values of 0.12, 4.48, 0.33, and 0.15 μg/mL, respectively. In the antifungal growth assay, compound 5aa displayed a protection efficacy of 75.5% against Fusarium head blight (FHB) at a concentration of 200 μg/mL. In another in vivo antifungal activity evaluation, compound 5aa exhibited a noteworthy protective efficacy of 92.0% against rape Sclerotinia rot (RSR) at a concentration of 100 μg/mL, which was comparable to the positive control tebuconazole (97.5%). The existing results suggest that compound 5aa has a broad-spectrum antifungal activity. Electron microscopy observations showed that compound 5aa might cause mycelial abnormalities and organelle damage in F. graminearum. Moreover, in the in vitro enzyme assay, we found that the target compounds 5aa, 5ab, and 5ca displayed significant inhibitory effects toward succinate dehydrogenase, with the corresponding IC50 values of 1.62, 1.74, and 1.96 μM, respectively, which were superior to that of boscalid (IC50 = 2.38 μM). Additionally, molecular docking and molecular dynamics simulation results revealed that compounds 5aa, 5ab, and 5ca have the capacity to bind in the active pocket of succinate dehydrogenase (SDH), establishing hydrogen-bonding interactions with neighboring amino acid residues.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Antifungal Evaluation of Diverse Heterocyclic Hydrazide Derivatives as Potential Succinate Dehydrogenase Inhibitors

Chen,

Liu,

Wang

et al. 2024

J. Agric. Food Chem.

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“…The compound is believed to have the potential to treat both the dyslipidemia and elevated glycemia in type 2 diabetes. DGAT-1 (Acyl CoA:DGAT-1) programs have been in existence at a number of pharmaceutical companies and it remains an attractive target since DGAT-1 knockout mice are resistant to dietinduced obesity [7,8]. In a recent abstract, it was reported that P-7435 was selective for human DGAT-1 with an IC 50 of 22.7 nM (> 10,000-fold selectivity over hDGAT2).…”

Section: Discontinued Drugsmentioning

confidence: 98%

Discontinued drug therapies to treat diabetes in 2014

Colca¹

2015

Expert Opinion on Investigational Drugs

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In general, the specific reasons for the discontinuation of these programs have not been clearly disclosed. In some cases, business considerations are given, whereas in others, there are specific safety issues that emerged which were not expected from nonclinical experience. In the final analysis, it is clear that all of these programs have been discontinued because the evidence does not favor the type of efficacy and risk:benefit ratio that justifies additional expenditures. There remains a clear need for precise addressable mechanisms to affect the root causes of diabetes.

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Synthesis and Diacylglycerol Acyltransferase‐1 Inhibition of Azabicyclo[3.1.0]hexane Derivatives

Han

Lee

Kwak

et al. 2015

Bulletin Korean Chem Soc

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Synthesis and evaluation of cyclohexane carboxylic acid head group containing isoxazole and thiazole analogs as DGAT1 inhibitors

Cited by 8 publications

References 14 publications

Design, Synthesis, and Antifungal Evaluation of Diverse Heterocyclic Hydrazide Derivatives as Potential Succinate Dehydrogenase Inhibitors

Design, Synthesis, and Antifungal Evaluation of Diverse Heterocyclic Hydrazide Derivatives as Potential Succinate Dehydrogenase Inhibitors

Discontinued drug therapies to treat diabetes in 2014

Synthesis and Diacylglycerol Acyltransferase‐1 Inhibition of Azabicyclo[3.1.0]hexane Derivatives

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