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Disubstituted 4-Chloro-3-nitrophenylthiourea Derivatives: Antimicrobial and Cytotoxic Studies.

ABSTRACT: 4-Chloro-3-nitrophenylthioureas 1?30 were synthesized and tested for their antimicrobial and cytotoxic activities. Compounds exhibited high to moderate antistaphylococcal activity against both standard and clinical strains (MIC values 2?64 ?g/mL). Among them derivatives with electron-donating alkyl substituents at the phenyl ring were the most promising. Moreover, compounds 1?6 and 8?19 were cytotoxic against MT-4 cells and various other cell lines derived from human hematological tumors (CC₅₀ ? 10 ?M). The influence of derivatives 11, 13 and 25 on viability, mortality and the growth rate of immortalized human keratinocytes (HaCaT) was observed.

SUBMITTER: Bielenica A

PROVIDER: S-EPMC6222614 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Disubstituted 4-Chloro-3-nitrophenylthiourea Derivatives: Antimicrobial and Cytotoxic Studies.

Bielenica Anna A Sanna Giuseppina G Madeddu Silvia S Giliberti Gabriele G Stefańska Joanna J Kozioł Anna E AE Savchenko Oleksandra O Strzyga-Łach Paulina P Chrzanowska Alicja A Kubiak-Tomaszewska Grażyna G Struga Marta M

Molecules (Basel, Switzerland) 20180921 10

4-Chloro-3-nitrophenylthioureas 1⁻30 were synthesized and tested for their antimicrobial and cytotoxic activities. Compounds exhibited high to moderate antistaphylococcal activity against both standard and clinical strains (MIC values 2⁻64 μg/mL). Among them derivatives with electron-donating alkyl substituents at the phenyl ring were the most promising. Moreover, compounds 1⁻6 and 8⁻19 were cytotoxic against MT-4 cells and various other cell lines deriv ...[more]

PMID: 30248936

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Project description:Overactivation of Wnt/β-catenin signaling by accumulated β-catenin in the nucleus has been shown to play a crucial role in the etiology of cancer. Interaction of β-catenin with Transcription factor 4 (TCF4) is a key step for the activation of Wnt genes in response to upstream signals of the Wnt/β-catenin pathway. Hence, down regulation of Wnt/β-catenin signaling or targeting downstream events by selective β-catenin/TCF4 protein-protein interaction inhibitors could be a potential therapeutic strategy against such cancers. In this study structure-based drug design approach was followed to design novel 4,7-disubstituted 8-methoxyquinazoline-based derivatives which could act as potential cytotoxic agents inhibiting the β-catenin/TCF4 protein-protein interactions. Fifteen compounds possessing 4,7-disubstituted 8-methoxyquinazoline scaffold were synthesized. Cytotoxic potential of the synthesised derivatives were determined against constitutively activated β-catenin/TCF4 signaling pathway cancer cells (HCT116 and HepG2) using the sulforhodamine B assay. The most potent compound (18B) was selected for detailed biological evaluation. Cell morphology, Hoechst 33342 and Annexin V/PI staining were used to detect apoptosis, while inhibition of cell migration was assessed by in vitro wound healing assay against HCT116 and HepG2 cells. Effect on β-catenin/TCF mediated transcriptional activity was assessed by TOPFlash/FOPFlash assay, TCF4 and β-catenin protein expression by immunocytofluorescence, and Wnt target genes (like c-MYC and Cyclin D1) mRNA levels by RT-PCR against HCT116 cells. Cytotoxic potency of the most potential compound (18B) against primary human gallbladder cancer cells was also evaluated. The derivatives showed interactions with active site residues of β-catenin and were capable of hindering the TCF4 binding, thereby disrupting β-catenin/TCF4 interactions. Cytotoxic potencies (IC50) of these derivatives ranged from 5.64 ± 0.68 to 23.18 ± 0.45 μM against HCT116 and HepG2 cells respectively. Compound (18B), the most potent compound among the series, induced apoptosis and inhibited cell migration against HCT116 and HepG2 cells. Mechanistic studies indicated that compound (18B) downregulated β-catenin/TCF4 signaling pathway, β-catenin and TCF4 protein expression, and mRNA levels of c-MYC andCyclin D1 in HCT116 cells and showed cytotoxicity against primary human gallbladder cancer cells with IC50 value of 8.50 ± 1.44 μM. Thus, novel 4,7-disubstituted 8-methoxyquinazoline derivatives were identified as potential cytotoxic agents with potencies comparable to that of imatinib mesylate. Compound (18B) represents a promising lead molecule as anticancer agent against colon, hepatocellular and gallbladder cancers targeting β-catenin/TCF4 signaling pathway.

Dataset Information

Disubstituted 4-Chloro-3-nitrophenylthiourea Derivatives: Antimicrobial and Cytotoxic Studies.

Publications

Disubstituted 4-Chloro-3-nitrophenylthiourea Derivatives: Antimicrobial and Cytotoxic Studies.

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