Novel 4-acetamide-2-alkylthio-N-acetanilides resembling nimesulide: Synthesis, cell viability evaluation and in silico studies

Catarro, Mafalda; Serrano, João L.; Cavalheiro, Eunice; Ramos, Susana S.; Santos, Adriana O.; Silvestre, Samuel; Almeida, Paulo

doi:10.1016/j.bmc.2017.06.009

Cited by 12 publications

(11 citation statements)

References 45 publications

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“…The cell proliferation was evaluated by quantifying the extent of the reduction of 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) according to a previously described procedure [52].…”

Section: Mtt Assaymentioning

confidence: 99%

Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents

Figueiredo

Serrano

Cavalheiro

et al. 2018

European Journal of Medicinal Chemistry

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Barbituric and thiobarbituric acid derivatives have become progressively attractive to medicinal chemists due to their wide range of biological activities. Herein, different series of 1,3,5-trisubstituted barbiturates and thiobarbiturates were prepared in moderate to excellent yields and their activity as xanthine oxidase inhibitors, antioxidants, antibacterial agents and as anti-proliferative compounds was evaluated in vitro. Interesting bioactive barbiturates were found namely, 1,3-dimethyl-5-[1-(2-phenylhydrazinyl)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6c) and 1,3-dimethyl-5-[1-[2-(4-nitrophenyl)hydrazinyl]ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6e), which showed concomitant xanthine oxidase inhibitory effect (IC values of 24.3 and 27.9 μM, respectively), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (IC values of 18.8 and 23.8 μM, respectively). In addition, 5-[1-(2-phenylhydrazinyl)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6d) also revealed DPPH radical scavenger effect, with an IC value of 20.4 μM. Moreover, relevant cytotoxicity against MCF-7 cells (IC = 13.3 μM) was observed with 5-[[(2-chloro-4-nitrophenyl)amino]methylene]-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (7d). Finally, different 5-hydrazinylethylidenepyrimidines revealed antibacterial activity against Acinetobacter baumannii (MIC values between 12.5 and 25.0 μM) which paves the way for developing new treatments for infections caused by this Gram-negative coccobacillus bacterium, known to be an opportunistic pathogen in humans with high relevance in multidrug-resistant nosocomial infections. The most promising bioactive barbiturates were studied in silico with emphasis on compliance with the Lipinski's rule of five as well as several pharmacokinetics and toxicity parameters.

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Section: Mtt Assaymentioning

confidence: 99%

Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents

Figueiredo

Serrano

Cavalheiro

et al. 2018

European Journal of Medicinal Chemistry

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“…Similar to CoMFA study, molecular interactions fields (MIFs) regarding van‐der‐Waals and electrostatic field interactions for Open3DQSAR analysis, were calculated by using a grid box around the aligned structures with a 0.5 Å step size and a 5.0 Å margin . These MIF descriptors were pretreated with max/min cut‐off (level=± 30), zeroing (level=0.05), standard deviation cut‐off (level=0.1), N‐level variable elimination and block unscaled weighting (BUW).…”

Section: Resultsmentioning

confidence: 99%

Understanding Chemico‐Biological Interactions of Glutamate MMP‐2 Inhibitors through Rigorous Alignment‐Dependent 3D‐QSAR Analyses

et al. 2017

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The current study involves different alignment techniques (pharmacophore‐based, docking‐based and Open3DALIGN‐based) extensively at the first time to build three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models on some potential glutamate‐based in house MMP‐2 inhibitors. The docking‐based alignment method yields the best 3D‐QSAR models though other alignment‐based methods also provide statistically significant and validated models. 3D‐QSAR models are correlated with molecular docking study and pharmacophore mapping. Biphenyl moiety of glutamines enters into the S1′ pocket and involves π‐π interactions with Tyr142 and His120, while none of the phenylacetyl/naphthylacetyl isoglutamines interacts with Tyr142. 3D‐QSAR models also suggest the importance of hydrophobicity and steric features of biphenyl function required for higher MMP‐2 inhibition. The sulfonyl oxygen may form potential hydrogen bonding interaction with Leu83 and Ala84 of S1' pocket. This study clearly points out that biphenylsulfonyl glutamines are favorable than phenylacetyl/naphthylacetyl isoglutamines for imparting higher MMP‐2 inhibition.

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“…In the last years, nimesulide was reported as an antitumor agent, besides its roles as an anti-inflammatory, pain killer, and antipyretic action. [27][28] Thus, numerous works were achieved on the nimesulide skeleton to obtain selective cyclooxygenase-2 inhibitors with potential antitumor action. [27][28] Further studies are required to address this assumption.…”

Section: Introductionmentioning

confidence: 99%

“…[27][28] Thus, numerous works were achieved on the nimesulide skeleton to obtain selective cyclooxygenase-2 inhibitors with potential antitumor action. [27][28] Further studies are required to address this assumption. Therefore, the current work aimed to develop novel, and potential…”

Section: Introductionmentioning

confidence: 99%

Development of Nimesulide Analogues as Dual Tubulin and HSP27 Inhibitor for Treating Female Cancers

Alhadad¹,

Alanazi²,

Harisa³

2020

Preprint

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Tubulin and heat shock protein 27 (HSP27) are up-regulated in cancer cells, and play a critical role in cell division, and proliferation. Therefore, they are targets for discovery of anticancer therapy. The objective of this study is to design, characterize, and biologically evaluate the nimesulide analogues to combat female cancer such as ovarian cancer, and breast cancer. Herein, the nimesulide analogues are designed to target both tubulin and HSP27 functions. Ovarian cancer (SKOV3) and breast cancer (SKBR3) cell lines were used as surrogate models to test the nimesulide analogs biological activities using MTT assay. In the present study, four nimesulide analogues were designed, synthesized and the chemical structures were with the biological evaluation were studied. The synthesized agents were characterized by 1H-NMR, 13C-NMR, the molecular weight was confirmed using GC-MS technique, and melting point. Besides, the agent L4 structure was confirmed using X-ray crystallographic analysis. The present data revealed that nimesulide analogs have potent anticancer activity against SKOV3and SKBR3 cell lines. The IC50 values for both SKOV3 and SKBR3 cell lines treated with the agents showed a potent cell growth inhibition range of 0.23-2.02 µM and 0.50-3.73 µM respectively. In conclusion, the designed nimesulide analogues can target both tubulins, and HSP27 concurrently, and they are promising agents as future chemotherapy female cancers.

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Novel 4-acetamide-2-alkylthio-N-acetanilides resembling nimesulide: Synthesis, cell viability evaluation and in silico studies

Cited by 12 publications

References 45 publications

Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents

Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents

Understanding Chemico‐Biological Interactions of Glutamate MMP‐2 Inhibitors through Rigorous Alignment‐Dependent 3D‐QSAR Analyses

Development of Nimesulide Analogues as Dual Tubulin and HSP27 Inhibitor for Treating Female Cancers

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