Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists

Ivachtchenko, Alexandre V.; Ivanenkov, Yan A.; Mitkin, Oleg D.; Vorobiev, Anton A.; Кузнецова, И. В.; Shevkun, Natalia A.; Koryakova, Angela G.; Karapetian, Ruben N.; Trifelenkov, Andrey S.; Kravchenko, Dmitry V.; Veselov, Mark S.; Chufarova, Nina V.

doi:10.1016/j.ejmech.2015.05.039

Cited by 22 publications

(10 citation statements)

References 32 publications

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“…For example, Ivachtchenko et al developed novel thiohydantoin-based AR antagonists with sub-nanomolar activity, claiming that the introduction of stereospecific spiromoiety with cyclic oxygen and fluorine at the p-position of the phenyl ring is the key reason for this higher activity. [29] We synthesised various tetrahydrofuran-cyclic urea-based derivatives as an AR antagonist in a previous report; among the derivatives, the compound with cyclic oxygen at the terminal position of the phenyl ring exhibits excellent activity. [30] Recently, Yang et al developed an AR antagonist with nearly identical structural features to enzalutamide, in which the 'F' and amide substituents of the left side aromatic ring are replaced by caprolactone, and it exhibits nearly similar activity to enzalutamide.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Easily Synthesizable 4, 4‐Dimethylimidazolidin‐2‐ones as Potent Androgen Receptor Antagonists for Prostate Cancer

Yaragani

Yadlapalli²,

Raghavan

et al. 2021

ChemistrySelect

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Androgen deprivation therapy (ADT), also known as suppression of androgen activity, is a first-line treatment option for patients with prostate cancer (PC). ADT became ineffective after several years of treatment due to the development of castration-resistant prostate cancer (CRPC), which resulted in more deaths in PC patients, but it is still androgen receptor (AR) dependent. Under these conditions, the U.S. Food and Drug Administration (FDA) approved enzalutamide for the treatment of patients with metastatic CRPC (mCRPC) and, more recently, nonmetastatic CRPC (nmCRPC). Despite the fact that this drug has extended overall and progression-free survival in a wide range of CRPC patients, more research is needed to better understand the mechanisms of resistance challenges and analogues chemical lead structures as next generation AR antagonists. In this regard, we discovered simple and easily synthesizable new pharmacophore, 4,4-dimethylimidazolidin-2one, based derivatives MDV1-MDV8 for potent AR antagonists; here, the thiohydantoin pharmacophore in enzalutamide is replaced by 4,4-dimethylimidazolidin-2-one. The antiproliferative activities of these molecules have been assessed against androgen dependent PC cell line (LNCaP). The structure-activity relationship of these molecules, as well as their relationship with enzalutamide, is investigated. Among the reported molecules, MDV4 showed significantly improved in vitro activity with the IC 50 value of 780.85 nM.

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Section: Resultsmentioning

confidence: 99%

Discovery of Easily Synthesizable 4, 4‐Dimethylimidazolidin‐2‐ones as Potent Androgen Receptor Antagonists for Prostate Cancer

Yaragani

Yadlapalli²,

Raghavan

et al. 2021

ChemistrySelect

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“…N-[(4E)-5-(Dichloromethylidene)-3-methyl-2-oxoimidazolidin-4-ylidene]morpholine-4-sulfonamide (7) was synthesized by alkylation of sulfonamide VI that was previously obtained. [23] Data of synthesized novel sulfonamide derivatives 1-7 (yield, melting point, 1 H-NMR, 13 C-NMR, chromato-mass spectra and elemental analysis) are presented in the Experimental Section.…”

Section: Chemistrymentioning

confidence: 99%

“…[2] Imidazolidine derivatives are widely used to obtain compounds with different biological activities [3] including antimicrobial, [4,5] anti-inflammatory, [6,7] anticancer and anticoagulant, [8] antihypertensive, [9] and antidiabetic agents. [10,11] Compounds of 4-oxoimidazolidin-2thione and spiro-4-(5-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile derivatives showed high activity against breast [12] and prostate cancer [13] with IC 50 range of 12.5 -13.0 μg/mL and 60-80 nM, respectively. The halogenated trimethoxy and benzylidene imidazolidine derivatives demonstrated in vitro antischistosomiasis activity.…”

Section: Introductionmentioning

confidence: 99%

New 2‐Oxoimidazolidine Derivatives: Design, Synthesis and Evaluation of Anti‐BK Virus Activities in Vitro

Kornii

Chumachenko

Шаблыкин

et al. 2019

Chemistry & Biodiversity

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A series of novel 2‐oxoimidazolidine derivatives were synthesized and their antiviral activities against BK human polyomavirus type 1 (BKPyV) were evaluated in vitro. Bioassays showed that the synthesized compounds 1‐{[(4E)‐5‐(dichloromethylidene)‐2‐oxoimidazolidin‐4‐ylidene]sulfamoyl}piperidine‐4‐carboxylic acid (5) and N‐Cyclobutyl‐N′‐[(4E)‐5‐(dichloromethylidene)‐2‐oxoimidazolidin‐4‐ylidene]sulfuric diamide (4) exhibited moderate activities against BKPyV (EC50=5.4 and 5.5 μm, respectively) that are comparable to the standard drug Cidofovir. Compound 5 exhibited the same cytotoxicity in HFF cells and selectivity index (SI50) as Cidofovir. The selectivity index of compound 4 is three times less than that of Cidofovir due to the higher toxicity of this compound. Hence, these compounds may be taken as lead compound for further development of novel ant‐BKPyV agents.

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“…The reaction of 4-amino-2-fluoro-N-methylbenzamide 72 with different ketones and trimethylsilyl cyanide gave product 73 which then treated with 4-amino-2-(trifluoromethyl)benzonitrile 74 and thiophosgene and gave 2-thiohydantoins 75 (Scheme 15) (16).…”

Section: From Aminesmentioning

confidence: 99%

Synthesis, Reactions, and Applications of Hydantoin and 2-Thiohydantoin Derivatives

Elhady¹,

Desoky²,

Al-Shareef³

et al. 2019

Acta Poloniae Pharmaceutica - Drug Research

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Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists

Cited by 22 publications

References 32 publications

Discovery of Easily Synthesizable 4, 4‐Dimethylimidazolidin‐2‐ones as Potent Androgen Receptor Antagonists for Prostate Cancer

Discovery of Easily Synthesizable 4, 4‐Dimethylimidazolidin‐2‐ones as Potent Androgen Receptor Antagonists for Prostate Cancer

New 2‐Oxoimidazolidine Derivatives: Design, Synthesis and Evaluation of Anti‐BK Virus Activities in Vitro

Synthesis, Reactions, and Applications of Hydantoin and 2-Thiohydantoin Derivatives

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