Evaluation of anticancer activity of novel platinum(II) bis(thiosemicarbazone) complex against breast cancer.

The study aims to synthesize a novel bis(thiosemicarbazone) derivative based on platinum (thioPt) and evaluate its anticancer properties against MFC-7 and MDA-MB-231 breast cancer cells. A new platinum complex was synthesised by reacting K2PtCl4 with 2,2'-(1,2-diphenylethane-1,2-diylidene)bis(hydrazine-1-carbothioamide) in ethanol in the presence of K2CO3. In the obtained complex, the platinum atom is coordinated by a conjugated system = N-NC-S-The structures of the new compound were characterised using NMR spectroscopy, HR MS, IR, and X-ray structural analysis. The obtained results of the cytotoxicity assay indicate that compound thioPt had potent anticancer activity (MCF-7: 61.03 ± 3.57 µM, MDA-MB-231: 60.05 ± 5.40 µM) with less toxicity against normal MCF-10A breast epithelial cells, even compared to the reference compound (cisplatin). In addition, subsequent experiments found that thioPt induces apoptosis through both an extrinsic (↑caspase 8 activity) and intrinsic (↓ΔΨm) pathway, which ultimately leads to an increase in active caspase 3/7 levels. The induction of autophagy and levels of proteins involved in this process (LC3A/B and Beclin-1) were examined in MCF-7 and MDA-MB-231 breast cancer cells exposed to tested compounds (thio, thioPt, cisPt) at a concentration of 50 µM for 24 h. Based on these results, it can be concluded that thio and thioPt do not significantly affect the autophagy process. This demonstrates their superiority over cisplatin, which can stimulate cancer cell survival through its effect on stimulation of autophagy.

Biological investigation of N-methyl thiosemicarbazones as antimicrobial agents and bacterial carbonic anhydrases inhibitors.

The enormous burden of the COVID-19 pandemic in economic and healthcare terms has cast a shadow on the serious threat of antimicrobial resistance, increasing the inappropriate use of antibiotics and shifting the focus of drug discovery programmes from antibacterial and antifungal fields. Thus, there is a pressing need for new antimicrobials involving innovative modes of action (MoAs) to avoid cross-resistance rise. Thiosemicarbazones (TSCs) stand out due to their easy preparation and polypharmacological application, also in infectious diseases. Recently, we reported a small library of TSCs (1-9) that emerged for their non-cytotoxic behaviour. Inspired by their multifaceted activity, we investigated the antibacterial, antifungal, and antidermatophytal profiles of derivatives 1-9, highlighting a new promising research line. Furthermore, the ability of these compounds to inhibit selected microbial and human carbonic anhydrases (CAs) was assessed, revealing their possible involvement in the MoA and a good selectivity index for some derivatives.

Synthesis of New Triazole-Based Thiosemicarbazone Derivatives as Anti-Alzheimer's Disease Candidates: Evidence-Based In Vitro Study.

Triazole-based thiosemicarbazone derivatives (6a-u) were synthesized then characterized by spectroscopic techniques, such as 1HNMR and 13CNMR and HRMS (ESI). Newly synthesized derivatives were screened in vitro for inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All derivatives (except 6c and 6d, which were found to be completely inactive) demonstrated moderate to good inhibitory effects ranging from 0.10 ± 0.050 to 12.20 ± 0.30 µM (for AChE) and 0.20 ± 0.10 to 14.10 ± 0.40 µM (for BuChE). The analogue 6i (IC50 = 0.10 ± 0.050 for AChE and IC50 = 0.20 ± 0.050 µM for BuChE), which had di-substitutions (2-nitro, 3-hydroxy groups) at ring B and tri-substitutions (2-nitro, 4,5-dichloro groups) at ring C, and analogue 6b (IC50 = 0.20 ± 0.10 µM for AChE and IC50 = 0.30 ± 0.10 µM for BuChE), which had di-Cl at 4,5, -NO2 groups at 2-position of phenyl ring B and hydroxy group at ortho-position of phenyl ring C, emerged as the most potent inhibitors of both targeted enzymes (AChE and BuChE) among the current series. A structure-activity relationship (SAR) was developed based on nature, position, number, electron donating/withdrawing effects of substitution/s on phenyl rings. Molecular docking studies were used to describe binding interactions of the most active inhibitors with active sites of AChE and BuChE.

Dipyridyl-substituted thiosemicarbazone as a potent broad-spectrum inhibitor of metallo-ß-lactamases.

To combat the superbug infection caused by metallo-ß-lactamases (MßLs), a dipyridyl-substituted thiosemicarbazone (DpC), was identified to be the broad-spectrum inhibitor of MßLs (NDM-1, VIM-2, IMP-1, ImiS, L1), with an IC50 value in the range of 0.021-1.08 µM. It reversibly and competitively inhibited NDM-1 with a Ki value of 10.2 nM. DpC showed broad-spectrum antibacterial effect on clinical isolate K. pneumonia, CRE, VRE, CRPA and MRSA, with MIC value ranged from 16 to 32 µg/mL, and exhibited synergistic antibacterial effect with meropenem on MßLs-producing bacteria, resulting in a 2-16-, 2-8-, and 8-fold reduction in MIC of meropenem against EC-MßLs, EC01-EC24, K. pneumonia, respectively. Moreover, mice experiments showed that DpC also had synergistic antibacterial action with meropenem. In this work, DpC was identified to be a potent scaffold for the development of broad-spectrum inhibitors of MßLs.

Synthesis and evaluation of novel thiosemicarbazone and semicarbazone analogs with both anti-proliferative and anti-metastatic activities against triple negative breast cancer.

Triple-negative breast cancer (TNBC) is one of the most aggressive cancer with high mortality and recurrence rates. Hecogenin, a steroidal sapogenin, is reported as a potential anti-tumor agent against breast cancer. However, the moderate activity limits its further application in clinical. With the aim to identify novel analogues that are especially efficacious in therapy of TNBC, a series of novel hecogenin thiosemicarbazone and semicarbazone derivatives were designed, synthesized and biologically evaluated. Screening of cytotoxicity revealed that 4c could potently inhibit the proliferation of breast cancer cells (MCF-7 and MDA-MB-231 cells), lung cancer cells (A549) and colon cancer cells (HT-29) at low µM level. Importantly, further mechanism studies indicated the ability of 4c in inducing apoptosis of MDA-MB-231 cells by arresting the cell cycle. Moreover, 4c notably suppressed the migration and invasion of MDA-MB-231 cells compared to its parent hecogenin at the equal concentration.

An efficient and concise synthesis of a selective small molecule non-peptide inhibitor of cathepsin L: KGP94.

KGP94 is a potent, selective, and competitive inhibitor of the lysosomal endopeptidase enzyme (Cathepsin L) currently in preclinical trials for the treatment of metastatic cancer, which is a leading cause of cancer-associated death. Herein, we report two new synthetic routes for synthesizing the target compound through four consecutive steps, using a Weinreb amide approach starting from a common 3-bromobenzoyl chloride. A key step in the approach is a coupling reaction of a readily available Grignard reagent with amide 4 to produce 6, a previously unreported coupling pattern. These new strategies offer an efficient and alternative approach to synthesis of target compound with an excellent overall yield.

Diaryl-substituted thiosemicarbazone: A potent scaffold for the development of New Delhi metallo-ß-lactamase-1 inhibitors.

The superbug infection caused by New Delhi metallo-ß-lactamase (NDM-1) has become an emerging public health threat. Inhibition of NDM-1 has proven challenging due to its shuttling between pathogenic bacteria. A potent scaffold, diaryl-substituted thiosemicarbazone, was constructed and assayed with metallo-ß-lactamases (MßLs). The obtained twenty-six molecules specifically inhibited NDM-1 with IC50 0.038-34.7 µM range (except 1e, 2e, and 3d), and 1c is the most potent inhibitor (IC50 = 0.038 µM). The structure-activity relationship of synthetic thiosemicarbazones revealed that the diaryl-substitutes, specifically 2-pyridine and 2-hydroxylbenzene improved inhibitory activities of the inhibitors. The thiosemicarbazones exhibited synergistic antimycobacterial actions against E. coli-NDM-1, resulted a 2-512-fold reduction in MIC of meropenem, while 1c restored 16-256-, 16-, and 2-fold activity of the antibiotic on clinical isolates ECs, K. pneumonia and P. aeruginosa harboring NDM-1, respectively. Also, mice experiments showed that 1c had a synergistic antibacterial ability with meropenem, reduced the bacterial load clinical isolate EC08 in the spleen and liver. This work provided a highly promising scaffold for the development of NDM-1 inhibitors.

Synthesis, Crystal Structure, Biological Evaluation and in Silico Studies on Novel (E)-1-(Substituted Benzylidene)-4-(3-isopropylphenyl)thiosemicarbazone Derivatives.

A series of (E)-1-(substituted benzylidene)-4-(3-isopropylphenyl)thiosemicarbazone derivatives were synthesized and characterized by FT-IR spectrum, elemental analysis, NMR spectrum, HR-MS spectrum, and X-ray single crystal diffraction technology. The crystal structures and packing of (E)-1-(4-fluorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone and (E)-1-(3-fluorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone were maintained through the intramolecular hydrogen bond (N3-H6⋅⋅⋅N1) and intermolecular hydrogen bonds (N2-H4⋅⋅⋅S1, C14-H14⋅⋅⋅F1 and C7-H7⋅⋅⋅S1). The results obtained by employing the DPPH free radicals scavenging assay indicated that (E)-1-(4-methoxylbenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone had a more significant antioxidant activity compared with other compounds. The results measured by adopting the disc diffusion method elucidated that (E)-1-(4-trifluoromethylbenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone possessed a more prominent antifungal activity than other compounds. Molecular docking showed that (E)-1-(4-chlorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone had the highest affinity with receptor protein (1NMT). Moreover, the drug-likeness characteristic, physicochemical properties, pharmacokinetic profiles, and bioactivity scores of all the compounds were predicted through in silico studies. The results illustrated that (E)-1-(4-fluorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone had the drug-likeness characteristic and all the compounds were considered as moderately biological active molecules.

Design, Synthesis, Cytotoxic Screening and Molecular Docking Studies of Novel Hybrid Thiosemicarbazone Derivatives as Anticancer Agents.

Thiosemicarbazones have been the focus of scientists owing to their broad clinical anticancer range. Herein, A Series of new thiosemicarbazone derivatives 5-9 were synthesized and confirmed through the use of different spectroscopic techniques along with elemental analysis. The in vitro cytotoxic activity of compounds 5-9 against MCF-7 and A549 cell lines and normal breast cells were assessed. Several compounds were found to be active. The most active compound 7 caused MCF-7 cell cycle arrest at G1/ S phases; and induced apoptosis at the pre-G1 phase. The apoptosis-inducing activity of compound 7 was proofed by the elevation of caspase 3/7 activity and also by up-regulation of the expression of Bax and p53 proteins together with the down-regulation of the expression of the Bcl-2 protein. It also had a strong inhibitory effect topoisomerase IIß enzyme. Molecular Docking study revealed that the synthesized compounds had good docking scores compared to the standard drug Etoposide towards the topoisomerase IIß protein (3QX3). Overall, these findings confirmed that the new thiosemicarbazone derivatives could aid in the development of promising cancer drug candidates.

Molecular mechanisms of apoptosis induction in K562 and KG1a leukemia cells by a water-soluble copper(II) thiosemicarbazone complex.

Thiosemicarbazones (TSCs) and their metal complexes exhibit pronounced and selective cytotoxic potential against a broad span of cancers. Here, we assessed the anti-cancer activity of a water-soluble copper(II) complex of thiosemicarbazone (Cu-TSC) against two cancer cell lines of human leukemia. Our analysis revealed that Cu-TSC treatment results in a time and dose-dependent growth inhibition in K562 and KG1a cells while sparing normal human fibroblast (HFF2) cells. The IC50 values for the Cu-TSC treatment were measured to be 21.7 ± 1.5 µM and 50.25 ± 2.5 µM for K562 and KG1a cells, respectively. Cell cycle analysis indicated that Cu-TSC induces the accumulation of cells in the sub-G1 fraction as well as the reversible arrest in G0/G1 and G2/M phases in K562 and KG1a cells, respectively. Furthermore, the occurrence of apoptosis as the prime mode of cell death was verified through apoptotic body formation, phosphatidylserine externalization, and caspase-3 activation. Additionally, the real-time quantitative PCR analysis revealed that Cu-TSC triggers apoptosis in both cell lines via the upregulation of caspases-8, -9, and the changing of Bax/Bcl2 ratio. Finally, flow cytometric analysis confirmed that Cu-TSC treatment causes the enhancement of reactive oxygen species formation in both K562 and KG1a cells. Altogether, these findings suggest that Cu-TSC is a promising inducer of apoptosis in leukemia cells and carries potential as an anti-cancer compound.

Synthesis, characterization and bioactivities of a new covalent copper(II) compound derived from {P2Mo5O23}6- and thiosemicarbazones.

In this article, a new compound H2[{Cu(HL)(H2O)}2(P2Mo5O23)]·5H2O (1) (HL = 2-acetylpyrazine thiosemicarbazone) has been synthesized and structurally characterized by single-crystal X-ray diffraction of and other detection techniques. Interestingly, the structure of 1 is different from many reported copper-based complexes, in which the [P2Mo5O23]6-, two Cu2+ ions and two HL were directly connected by covalent bands. Biological studies demonstrated that 1 indicated moderate antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), and a better cytotoxicity against human hepatic cancer line (SMMC-7721) than Mitoxantrone (Mito), the current clinical anticancer drug. Besides, the antibacterial mechanisms of 1 have been studied by the membrane integrity disruption, the destructive reactive oxygen species generation (ROS), the glutathione (GSH) depletion and the depressed enzymatic activity of respiratory chain dehydrogenases (RCD). These results revealed that the combination of HL, Cu2+, [P2Mo5O23]6- shows a higher antibacterial and cytotoxic activity.

Synthesis and biological screening of thiosemicarbazones of substituted 3-acetylcoumarins having d-glucose moiety.

Thiosemicarbazones 5a-j were synthesized with yields of 45-68% by condensation of 3-acetylcoumarins 3a-j and tetra-O-acetyl-ß-d-thiosemicarbazide 4. All obtained thiosemicarbazones were screened for anti-microorganic activities against bacteria (B. subtilis, S. aureus, S. epidermidis, E. coli, P. aeruginosa, K. pneumoniae, S. typhimurium) and fungi (A. niger, C. albicans, S. cerevisiae, and A. flavus). Some compounds had significant inhibitory activity with MICs of 0.78-3.125 µM in comparison with 5a, including 5e,h,i for S. aureus, and 5c,f,i for S. epidermidis (Gram-(+) bacteria), 5c,f,g for E.coli, 5f for K. pneumoniae, 5b,c,g for P. aeruginosa, and 5i for S. typhimurium (Gram-(-) bacteria), 5d,h,i for A. niger, 5i for A. flavus, 5b,d,e,h for C. albicans, and 5i for S. cerevisiae. Compounds exhibited excellent activity against tested microorganism with MIC = 0.78 µM, including 5h,i (against S. aureus), 5h (against C. albicans), and 5i (against S. cerevisiae).

Synthesis, Characterization, and Biological Activity of Hybrid Thiosemicarbazone-Alkylthiocarbamate Metal Complexes.

A series of hybrid ligands (H2L1-H2L3) derived from 4-methyl-3-thiosemicarbazide and hydrazinecarbothioic acid O-alkyl esters were synthesized and characterized by NMR. The ligands were chelated with copper (4-6), nickel (7-9), and zinc (10-12) and characterized by spectroscopy, electrochemistry, and single crystal X-ray crystallography. The chelated metals displayed substantial anodic shifts in the CuII/I reduction potential of ∼160 mV relative to their bis(thiosemicarbazone) analogues. The metal chelates 4-12 were evaluated for potential anticancer activity by MTT assays, and selected results were confirmed by clonogenic and trypan blue assays. The copper derivatives 4 and 6 were found to have potent and cancer-selective antiproliferative effects, with GI50 values less than 100 nM in A549 lung adenocarcinoma cells compared with at least 20-fold less activity in IMR90 nonmalignant lung fibroblasts. In comparison, the nickel complexes were much less active and had little cancer-selectivity. Varying by ligand, the zinc complexes were less potent or had comparable activity compared to that of the corresponding copper complex. UV-visible spectroscopy indicated that zinc complex 10 was transmetalated in the presence of equimolar copper, whereas nickel complex 7 was not. Copper complexes 4 and 6 were also assessed in the NCI60 screen and were found to have cytotoxic activity against most solid tumor cell lines. In MTT assays, 4 and 6 were substantially more active against A549 cancer cells than Cu(ATSM) and were more cancer-selective (for A549 compared to IMR-90) than Cu(GTSM). Our results suggest that hybrid thiosemicarbazone-alkylthiocarbamate copper complexes have potential for development as new anticancer agents.

Synthesis of Palladium(II) Complexes via Michael Addition: Antiproliferative Effects through ROS-Mediated Mitochondrial Apoptosis and Docking with SARS-CoV-2.

Metal complexes have numerous applications in the current era, particularly in the field of pharmaceutical chemistry and catalysis. A novel synthetic approach for the same is always a beneficial addition to the literature. Henceforth, for the first time, we report the formation of three new Pd(II) complexes through the Michael addition pathway. Three chromone-based thiosemicarbazone ligands (SVSL1-SVSL3) and Pd(II) complexes (1-3) were synthesized and characterized by analytical and spectroscopic tools. The Michael addition pathway for the formation of complexes was confirmed by spectroscopic studies. Distorted square planar structure of complex 2 was confirmed by single-crystal X-ray diffraction. Complexes 1-3 were subjected to DNA- and BSA-binding studies. The complex with cyclohexyl substituent on the terminal N of thiosemicarbazone (3) showed the highest binding efficacy toward these biomolecules, which was further understood through molecular docking studies. The anticancer potential of these complexes was studied preliminarily by using MTT assay in cancer and normal cell lines along with the benchmark drugs (cisplatin, carboplatin, and gemcitabine). It was found that complex 3 was highly toxic toward MDA-MB-231 and AsPC-1 cancer cells with IC50 values of 0.5 and 0.9 µM, respectively, and was more efficient than the standard drugs. The programmed cell death mechanism of the complexes in MDA-MB-231 cancer cells was confirmed. Furthermore, the complexes induced apoptosis via ROS-mediated mitochondrial signaling pathway. Conveniently, all the complexes showed less toxicity (≥50 µM) against MCF-10a normal cell line. Molecular docking studies were performed with VEGFR2, EGFR, and SARS-CoV-2 main protease to illustrate the binding efficiency of the complexes with these receptors. To our surprise, binding potential of the complexes with SARS-CoV-2 main protease was higher than that with chloroquine and hydroxychloroquine.

Synthesis, cytotoxicity, and in vivo antitumor activity study of parthenolide semicarbazones and thiosemicarbazones.

Parthenolide is an important sesquiterpene lactone with potent anticancer activities. In order to further improve its biological activity, a series of parthenolide semicarbazone or thiosemicarbazone derivatives was synthesized and evaluated for their anticancer activity. Derivatives were tested in vitro against 5 human tumor cell lines, and many of these showed higher cytotoxicity than parthenolide. Five compounds were further studied for their antitumor activity in mice. The in vivo result indicated that compound 4d showed both promising antitumor activity against mice colon tumor and small side effects on immune systems. The cell apoptosis and cell cycle distribution of compound 4d were also studied. Molecular docking studies revealed multiple interactions between 4d and NF-κB. Our findings demonstrate the potential of semicarbazones as a promising type of compounds with anticancer activity.

Synthesis, structural, cytotoxic and pharmacokinetic evaluation of some thiosemicarbazone derivatives.

Iron(III) and nickel(II) complexes bearing a thiosemicarbazone framework were synthesized by a one-pot synthesis method. The structures were characterized by elemental analysis, IR, 1 H NMR, APCI Mass, conductivity, magnetic moment measurements. Molecular and crystal structures of the iron(III) complex were obtained from single-crystal X-ray diffraction. The findings showed that the metal atom adopts a slightly distorted square-pyramidal coordination, with the four donor atoms of the thiosemicarbazone ligand defining the basal plane and a chloride atom occupying the apical position. In the crystal lattice, the structure is stabilized by intermolecular O─H···O and C─H···O interactions. The cytotoxic activity was studied by MTT assay, the expression levels of cytochrome P450 (CYP) enzymes by Western blot, and the lipophilicity (LogP) by using the shake-flask method, another pharmacokinetic parameter. The findings showed that the IC50 values decreased with the decrease of the LogP values of the substances. Cytochrome P450 expression levels were found specific for each compound and each cell line. As a result, the pharmacokinetic properties of the newly synthesized thiosemicarbazone compounds are crucial for oral administration and provide us with clues for prospective in vivo studies.

Design, synthesis and antimycobacterial activity of thiazolidine-2,4-dione-based thiosemicarbazone derivatives.

The two series of thiosemicarbazone derivatives with thiazolidine-2,4-dione (TZD) core were designed and synthesized. The antimycobacterial activity of the target compounds was tested against Mycobacterium tuberculosis H37Ra by broth microdilution method with resazurin as an indicator of the metabolic activity of mycobacteria. Conducted studies revealed antimycobacterial activity in the concentration range of 0.031-64 µg/ml for 31 synthesized derivatives with TZD core. The highest antimycobacterial activity (MIC = 0.031-0.125 µg/ml) was demonstrated for the new group of compounds: TZD-based hybrids with 4-unsubstituted thiosemicarbazone substituent. Furthermore, all the tested compounds within this group were characterized by low cytotoxicity. Among tested compounds, two compounds are the most promising potential antimycobacterial agents since they not only show very low MIC values, but also non-toxicity against Vero cells at tested concentration range. High effectiveness and safety of these synthesized compounds makes them promising candidates as antimycobacterial agents.

Synthesis, bioactivity and binding energy calculations of novel 3-ethoxysalicylaldehyde based thiosemicarbazone derivatives.

In recent decade, the entrance of α-N-heterocyclic thiosemicarbazones derivates (Triapne, COTI-2 and DpC) in clinical trials for cancer and HIV-1 has vastly increased the interests of medicinal chemists towards this class of organic compounds. In the given study, a series of eighteen new (3a-r) 3-ethoxy salicylaldehyde-based thiosemicarbazones (TSC), bearing aryl and cycloalkyl substituents, were synthesized and assayed for their pharmacological potential against carbonic anhydrases (hCA I and hCA II), cholinesterases (AChE and BChE) and α-glycosidase. The hCA I isoform was inhibited by these novel 3-ethoxysalicylaldehyde thiosemicarbazone derivatives (3a-r) in low nanomolar levels, the Ki of which differed between 144.18 ± 26.74 and 454.92 ± 48.32 nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Kis varying from 110.54 ± 14.05 to 444.12 ± 36.08 nM. Also, these novel derivatives (3a-r) effectively inhibited AChE, with Ki values in the range of 385.38 ± 45.03 to 983.04 ± 104.64 nM. For BChE was obtained with Ki values in the range of 400.21 ± 35.68 to 1003.02 ± 154.27 nM. For α-glycosidase the most effective Ki values of 3l, 3n, and 3q were with Ki values of 12.85 ± 1.05, 16.03 ± 2.84, and 19.16 ± 2.66 nM, respectively. Moreover, the synthesized TCSs were simulated using force field methods whereas the binding energies of the selected compounds were estimated using MM-GBSA method. The findings indicate the present novel 3-ethoxy salicylaldehyde-based thiosemicarbazones to be excellent hits for pharmaceutical applications.

A novel 8-nitro quinoline-thiosemicarbazone analogues induces G1/S & G2/M phase cell cycle arrest and apoptosis through ROS mediated mitochondrial pathway.

A series of novel 8-nitro quinoline-based thiosemicarbazone analogues were synthesized and characterized by various spectroscopic and single crystal X-ray analyses. The potent antitumor effects of synthesized compounds towards the cancer cells were evaluated by MTT assay. Amongst, the compound 3a exhibited the highest inhibitory activity and the compounds 3f and 3b were also showed significant activity. The molecular mechanistic studies of cell death have demonstrated that the treated potent compound 3a induced G1/S & G2/M phase cell cycle arrest and induced apoptosis via mitochondrial dysfunction and increased the production of cytotoxic ROS levels. The RT-PCR gene expression analysis revealed that the cell death induced by activation of caspase-3 dependent intrinsic apoptotic signaling pathway. Further, the molecular binding affinity of compounds with estrogen receptor alpha was calculated by molecular docking studies. Thus, novel 8-nitro quinoline-thiosemicarbazone analogues provide a unique tool for breast cancer therapeutic tactics.

Synthesis and in vitro anti-Toxoplasma gondii activity of a new series of aryloxyacetophenone thiosemicarbazones.

A new series of aryloxyacetophenone thiosemicarbazones 4a-q have been synthesized as anti-Toxoplasma gondii agents. All compounds showed significant inhibitory activity against T. gondii-infected cells (IC50 values 1.09-25.19 µg/mL). The 4-fluorophenoxy derivative (4l) was the most potent compound with the highest selectivity toward host cells (SI = 19), being better than standard drug pyrimethamine. SAR study indicated that the concurrence of proper substituents on both aryl ring of phenoxyacetophenone is important for potency and safety profile. Further in vitro experiments with the representative compounds 4l and 4p revealed that these compounds at the concentration of 5 µg/mL can significantly reduce the viability of T. gondii tachyzoites, as well as their infectivity rate and intracellular proliferation, comparable to those of pyrimethamine.