Novel thiosemicarbazone derivatives containing indole fragment as potent and selective anticancer agent

He, Zhang-Xu; Qiao, Hui; Yang, Feifei; Zhou, Wenjuan; Gong, Yunpeng; Zhang, Xinhui; Wang, Haojie; Zhao, Bing; Ma, Liying; Liu, Hong‐Min; Zhao, Wen

doi:10.1016/j.ejmech.2019.111764

Cited by 43 publications

(13 citation statements)

References 39 publications

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“…Notable medicinal applications associated with the quinoline heterocycle include anticancer, anti-tubercular, antiproliferative, anti-malarial, antibacterial, anti-inflammatory, anti-protozoal, anti-fungal, anti-tumor, antioxidant, anti-HIV, anti-hypertensive, alkaline phosphatase inhibition and for the treatment of neurodegenerative disorders [19][20][21][22][23][24][25][26][27][28]. In parallel, thiosemicarbazones also display a wide plethora of biological properties ranging from anticancer, anti-bacterial, anti-tumor, anti-protozoal, anti-fungal, anti-leishmanial, and antiviral activities [29][30][31][32][33][34]. Thiosemicarbazone derivatives have also been employed as NDRG1 up-regulators, cathepsin inhibitors, and cholinesterase inhibitors for the treatment of Alzheimer's disease [35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

et al. 2021

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC50 value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC50 = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer’s disease.

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Section: Introductionmentioning

confidence: 99%

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

et al. 2021

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“…Thiosemicarbazones (TSCs) and their metal complexes are versatile molecules with a wide spectrum of antimicrobial, antitrypanosomal, antitumor, antimalarial, and antiviral activities and have been studied intensely in pharmaceutical and medicinal chemistry [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. TSCs are able to block the genetic expression of wide variety of viruses [ 11 , 13 ], including the herpes simplex virus [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization and Release Behavior of a Thiosemicarbazone from Electrospun Polyvinyl Alcohol Core-Shell Nanofibers

et al. 2020

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Mats of polyvinyl alcohol (PVA) core–shell nanofibers were produced using coaxial electrospinning in the presence of a thiosemicarbazone (TSC) N4-(S)-1-phenylethyl)-2-(pyridin-2-yl-ethylidene)hydrazine-1-carbothioamide (HapyTSCmB). Monolithic fibers with 0% or 5% TSC and core–shell fibers with 10% TSC in the spinning solution were studied to compare stability and release rates. SEM showed the formation of uniform, bead-free, cylindrical, and smooth fibers. NMR spectroscopy and thermal analysis (TG/DTA) gave proof for the chemical integrity of the TSC in the fiber mats after the electrospinning process. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy showed no TSC on the surface of the PVA/TSC-PVA fibers confirming the core–shell character. The TSC release profiles of the fibers as studied using UV-vis absorption spectroscopy showed a slower release from the PVA/TSC-PVA core–shell structure compared with the monolithic PVA/TSC fibers as well as lower cumulative release percentage (17%). Out of several release models, the Korsmeyer–Peppas model gave the best fit to the experimental data. The main release phase can be described with a Fick-type diffusion mechanism. Antibacterial properties were tested against the Gram-positive Staphylococcus aureus bacterium and gave a minimal inhibitory concentration of 12.5 μg/mL. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazoliumbromide (MTT)-based cytotoxicity experiments showed that the cell viability of fibroblast at different contents of TSC was slightly decreased from 1.5% up to 3.5% when compared to control cells.

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“…Therefore, there is an urgent need to produce newer, more adaptable newer chemotherapeutic agents. Unceasing exploration for anticancer drugs with less toxicity and high efficacy is a significant orientation in anticancer drug studies 10 , 11 .…”

Section: Introductionmentioning

confidence: 99%

“…To date, various TSC-linked drug candidates have entered clinical trials. For example, 3-AP, a metal chelating agent, is presently in a phase II clinical trial 10 . COTI-2 and DPC 10 , another TSC-containing drug, enhanced the effectiveness and selectivity against cancer cells in comparison with 3-AP 12 , 17 , 20 .…”

Section: Introductionmentioning

confidence: 99%

Enhanced anticancer potency with reduced nephrotoxicity of newly synthesized platin-based complexes compared with cisplatin

Salehi

Abyar

Ramazani

et al. 2022

Sci Rep

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As a platinum-containing anticancer drug, cisplatin is the keystone for treating many malignancies. Nephrotoxicity is the main dose-limiting toxicity, and several hydration therapies and supplementary strategies are utilized to reduce cisplatin-induced kidney damage, so the discovery and development of effective and safe antitumor drugs are still on the path of human health. Herein, a new four-coordinated Pt complex [Pt(TSC)Cl] using N(4)-phenyl-2-formylpyridine thiosemicarbazone (HTSC) was synthesized and characterized by single-crystal X-ray diffraction, 1HNMR, FT-IR, LC/MS and CHN elemental analysis. The Pt(TSC)Cl complex revealed antiproliferative activity against A549, MCF-7 and Caco-2 cell lines with a low micromolar IC50 (200–1.75 µM). Specifically, the Pt(TSC)Cl complex displayed more selectivity in Caco-2 cells (IC50 = 2.3 µM) than cisplatin (IC50 = 107 µM) after 48 h of treatment. Moreover, compared with cisplatin, a known nephrotoxic drug, the Pt(TSC)Cl complex exhibited lower nephrotoxicity against Hek293 normal cells. We also found that the Pt(TSC)Cl complex can effectively prevent cancer cell propagation in sub-G1 and S phases and induce apoptosis (more than 90%). Real time PCR and western analysis demonstrated that the expression pattern of apoptotic genes and proteins is according to the intrinsic apoptosis pathway through the Bax/Bcl-2-Casp9-Casp3/Casp7 axis. Collectively, our findings indicated that the Pt(TSC)Cl complex triggers apoptosis in Caco-2 cell lines, while low nephrotoxicity was shown and may be considered a useful anticancer drug candidate for colorectal cancers for further optimization and growth.

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Novel thiosemicarbazone derivatives containing indole fragment as potent and selective anticancer agent

Cited by 43 publications

References 39 publications

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

Characterization and Release Behavior of a Thiosemicarbazone from Electrospun Polyvinyl Alcohol Core-Shell Nanofibers

Enhanced anticancer potency with reduced nephrotoxicity of newly synthesized platin-based complexes compared with cisplatin

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