2-benzoylpyridine Thiosemicarbazone Research Articles

Developing a Rhodium(III) Complex to Reprogram the Tumor Immune and Metabolic Microenvironments: Overcoming Multidrug Resistance and Metastasis in Non-Small Cell Lung Cancer.

To effectively inhibit the growth and metastasis of non-small cell lung cancer (NSCLC) and overcome its multidrug resistance (MDR), we designed and synthesized a series of rhodium (Rh, III) 2-benzoylpyridine thiosemicarbazone complexes. Through studying their structure-activity relationships, we identified the Rh(III) complex (Rh4) with excellent cytotoxicity against multidrug-resistant lung cancer cells (A549/ADR cells). Additionally, we successfully constructed an apoferritin (AFt) nanoparticle (NP) delivery system (AFt-Rh4 NPs). Importantly, AFt-Rh4 NPs not only exhibited excellent antitumor and antimetastatic capabilities against multidrug-resistant NSCLC in vivo but also demonstrated enhanced targeting ability and reduced systemic toxicity and adverse effects. Furthermore, we confirmed and elucidated the mechanisms by which Rh4/AFt-Rh4 NPs inhibit tumor metastasis and reverse MDR in NSCLC. This was achieved by reprogramming the immune and metabolic tumor microenvironments through induction of immunogenic cell death and inhibition of dual-energy metabolism.

Homo- and heterometallic coordinative compounds of Cu(II) and Bi(III) with aminopolycarboxylates and 2-benzoylpyridine thiosemicarbazones

This article deals with the synthesis and study of three homometallic coordination compounds of Cu(II) and four Cu(II) - Bi(III) heterometallic compounds with mixed polydentate ligands, thiosemicarbazone - aminopolycarboxylate (APC), with the general formulas Cu(L)2Cu(APC)·nH2O, Cu(HL){Bi(APC)}2·nH2O and Cu(L)Bi(APC)·nH2O (n = 0 - 13, APC = edta4- and cdta4-), 4-methyl- and 4-ethyl-thiosemicarbazones of 2-benzoylpyridine are in the monodeprotonated (L) or nondeprotonated (HL) forms. The antibacterial activity of heterometallic compounds Cu(HBzPyTSC-4Me){Bi(edta)} 2 (4) and Cu(HBzPyTSC-4Et){Bi(edta)}2·7H2O (6) was determined against Gram-positive strains Staphylococcus aureus (ATCC 25923) and Bacillus cereus (ATCC 11778) and two Gram-negative strains Escherihia coli (ATCC 25922) and Acinetobacter baumannii (BAA- 747). The compounds displayed high activity against Staphylococcus aureus (ATCC 25923), with the minimum inhibitory concentration MIC = 0.24 μg/mL, a value approximately 19 times higher than the activity of Furacilin (4.67 μg/mL). Both compounds have bactericidal activity against Bacillus cereus strain (ATCC 11778) with MIC = 0.97 μg/mL, which is about 4.8 times higher than the activity of Furacilin. The fungicidal activity of the compounds 4 and 6 against Candida albicans strain, expressed in MIC, was found to be 7.81 and 15.62 μg/mL, correspondingly, values of about 4 and 2 times higher than the one of Nystatin (32.0 μg/mL).

Synthesis, crystal structures, and NMR (1H, 13C) spectroscopy of PdII/HgII complexes with N, S-donor thiosemicarbazone/heterocyclic-2-thione ligands

The reaction of 2-benzoylpyridine thiosemicarbazone, {(C6H5)(py-N1)C2=N2-N3H-C1(=S)-N4H2, bzpytscH}, with palladium(II) chloride in acetonitrile yielded a heteroleptic complex, [Pd(N1,N2,S-bzpytsc)Cl] (1), in which the thio-ligand coordinated through pyridyl nitrogen (N1), azomethine nitrogen (N2) and sulfur as terdentate anion (N,N,S-bzpytsc–). In another reaction, pyrimidine-2-thione (pymtH) with mercury(II) chloride in CH3CN-DMF mixture formed a homoleptic compound, [Hg(N,S-pymt)2] (2), similar to the literature report of formation of a homoleptic compound, [Hg(κ1S-pyt)2], from HgCl2 and pytH in CH3CN-DMF. A reaction of mercury(II) bromide with pyridine-2-thione (pytH) in CH3CN-DMF mixture did not remove the bromides and rather yielded a heteroleptic complex of composition, [HgBr2(κ1S-pytH)2] (3). NMR (1H, 13C NMR) spectroscopy and infrared spectroscopy of 1–4 as well as crystal structures of 1, 3, and 4 are reported.

Developing a Multitargeted Anticancer Palladium(II) Agent Based on the His-242 Residue in the IIA Subdomain of Human Serum Albumin.

To obtain next-generation metal drugs that can overcome the deficiencies of platinum (Pt) drugs and treat cancer more effectively, we proposed to develop a multitargeted palladium (Pd) agent to the tumor microenvironment (TME) based on the specific residue(s) of human serum albumin (HSA). To this end, we optimized a series of Pd(II) 2-benzoylpyridine thiosemicarbazone compounds to obtain a Pd agent (5b) with significant cytotoxicity. The HSA-5b complex structure revealed that 5b bound to the hydrophobic cavity in the HSA IIA subdomain and then His-242 replaced a leaving group (Cl) of 5b, coordinating with the Pd center. The in vivo results showed that the 5b/HSA-5b complex had significant capacity of inhibiting tumor growth, and HSA optimized the therapeutic behavior of 5b. In addition, we confirmed that the 5b/HSA-5b complex inhibited tumor growth through multiple actions on different components of TME: killing cancer cells, inhibiting tumor angiogenesis, and activating T cells.

Synthesis, structure elucidation and dft study of a new thiazole–pyridine anchored nnn donor and it's cobalt(II) complex: In-vitro antitumor activity against U937 cancer cells, dna binding property and molecular docking study

The reaction between 4-(2-bromoacetyl)benzonitrile and 2-benzoylpyridine thiosemicarbazone produces a tridentate NNN ligand, 4-(2-(2-(phenyl(pyridine-2-yl)methylene)hydrazinyl)thiazole-4-yl)benzonitrile (ppytbH). The ligand constructs an octahedral complex with composition [Co(ppytbH)2](ClO4)2.3(H2O) (1) when reacted with cobalt(II) perchlorate salt in acetonitrile methanol (1:1) solution. The structures of ppytbH and 1 have been established by single X-ray crystallography, spectroscopic (1H NMR, IR, UV-Visible and fluorescence), thermal and electrochemical methods. The chemical reactivity and HOMO–LUMO energy of the compounds have been calculated using Density Functional Theory (DFT). The compounds ppytbH and 1 exhibit potential anticancer activity against U937 human monocytic cells and IC50 values are found 12.76 ± 0.75 and 12.83 ± 1.37 µM, respectively. The fluorescence and molecular docking study interpret the intercalative DNA binding mode with the titled molecules.

Cu(II) Benzoylpyridine Thiosemicarbazone Complexes: Inhibition of Human Topoisomerase II<i>α</i> and Activity against Breast Cancer Cells

The focus of this research is on the study of a series of copper (II) benzoylpyridine thiosemicarbazone complexes. Of the six benzoylpyridine thiosemicarbazone ligands used in this study, two are reported for the first time; 2-benzoylpyridine tert-butyl thiosemicarbazone (BZP-tBTSC), and 2-benzoylpyridine benzyl thiosemicarbazone (BZP-BzTSC). Once characterized by NMR, melting point, and MS, these mono-anionic tridentate ligands were then reacted with Cu2+ to form the new square planar metal complexes [Cu(BZP-tBTSC)Cl] and [Cu(BZP-BzTSC)Cl]. All of the copper complexes display marked inhibition of human topoisomerase IIα. The [Cu(BZP-tBTSC)Cl] complex shows marked activity against human breast cancer cell lines.

Four Cu(ii) complexes based on antitumor chelators: synthesis, structure, DNA binding/damage, HSA interaction and enhanced cytotoxicity.

Four novel copper(ii) complexes [Cu(II)(Bp4mT)(μ-Cl)]2 (), [Cu(II)(μ-Bp4mT)Br]2 (), [Cu(II)(HBpT)Cl] (), and [Cu(II)(HBpT)Br] () (Bp4mT = 2-benzoylpyridine-4-methylthiosemicarbazone, HBpT = 2-benzoylpyridine thiosemicarbazone), were synthesized and characterized using single-crystal X-ray diffraction, elemental analysis, infrared, and ultraviolet-visible spectroscopy. X-ray analysis revealed that complexes and based on the Bp4mT ligand presented dimeric structures in which the Cu(ii) ions were located in a five-coordinated distorted square-pyramidal geometry, whereas both and complexes were mononuclear with the Cu(ii) ions exhibiting a tetracoordinated square planar configuration. Their interactions with calf thymus DNA (CT-DNA) were investigated using viscosity measurements and fluorescence spectroscopy. Multispectroscopic evidence has shown interactions between these complexes and human serum albumin (HSA). All these complexes have exhibited efficient oxidative cleavage of supercoiled DNA in the presence of hydrogen peroxide, presumably via an oxidative mechanism. Furthermore, in vitro cytotoxicity studies of against human liver hepatocellular carcinoma cells (HepG-2), human large cell lung carcinoma cells (NCI-H460), and human cervical carcinoma cells (HeLa) indicated their promising antitumor activity with quite low IC50 values in the range of 0.08-1.98 μM, which are 83 times lower than those of cisplatin. The mechanistic studies revealed that four complexes, which induced early apoptosis, were involved in reactive oxygen species generation and DNA cleavage for their antitumor activities.

Kinetico-mechanistic studies on methemoglobin generation by biologically active thiosemicarbazone iron(III) complexes

The oxidation of human oxyhemoglobin (HbO2) to methemoglobin (metHb) is an undesirable side effect identified in some promising thiosemicarbazone anti-cancer drugs. This is attributable to oxidation reactions driven by FeIII complexes of these drugs formed in vivo. In this work the FeIII complexes of selected 2-benzoylpyridine thiosemicarbazones (HBpT), 2-acetylpyridine thiosemicarbazones (HApT), and the clinically trialled thiosemicarbazone, Triapine® (3-amino-2-pyridinecarboxaldehyde thiosemicarbazone, H3-AP), have been studied. This was achieved by time-resolved UV–Visible absorption spectroscopy and the sequential oxidation of the α- and β-chains of HbO2 at distinctly different rates has been identified. A key structural element, namely a terminal –NH2 group on the thiosemicarbazone moiety, was found to be an important common feature of the most active HbO2 oxidising complexes that were investigated. Therefore, these studies indicate that an unsubstituted –NH2 moiety at the terminus of the thiosemicarbazone group should be avoided in the design of future compounds from this class.

Synthesis and biological evaluation of 2-benzoylpyridine thiosemicarbazones in a dimeric system: Structure–activity relationship studies on their anti-proliferative and iron chelation efficacy

Thiosemicarbazone chelators represent an exciting class of biologically active compounds that show great potential as anti-tumor agents. Our previous studies demonstrated the potent anti-tumor activity of the 2′-benzoylpyridine thiosemicarbazone series. While extensive studies have been performed on monomeric thiosemicarbazone compounds, dimeric thiosemicarbazone chelators have received comparatively less attention. Thus, it was of interest to investigate the anti-proliferative activity and iron chelation efficacy of dimeric thiosemicarbazones. Two classes of dimeric thiosemicarbazones were designed and synthesized. The first class consisted of two benzoylpyridine-based thiosemicarbazone units connected via a hexane or dodecane alkyl bridge, while the second class of dimer consisted of two thiosemicarbazones attached to a 2,6-dibenzoylpyridine core. These dimeric ligands demonstrated greater anti-proliferative activity than the clinically used iron chelator, desferrioxamine. This study highlights the importance of optimal lipophilicity as a factor influencing the cytotoxicity and iron chelation efficacy of these chelators.

Synthesis and biological evaluation of substituted 2-benzoylpyridine thiosemicarbazones: Novel structure–activity relationships underpinning their anti-proliferative and chelation efficacy

The 2-benzoylpyridine thiosemicarbazone (BpT) chelators demonstrate potent anti-proliferative effects against tumor cells. To understand their structure–activity relationships, BpT analogues incorporating electron-donating substituents on the pyridine and phenyl rings of the BpT scaffold were designed and represent the first attempts to modify the pyridine ring of these thiosemicarbazones. Eight analogues showed significantly (p <0.001) greater anti-proliferative activity than the ‘gold-standard’ chelator, desferrioxamine. Structure–activity analysis revealed that mono- or di-methoxy substitution at the phenyl ring resulted in lower anti-proliferative activity, while methoxy substitutions at the phenyl ring enhanced iron chelation efficacy. These important findings facilitate the design of thiosemicarbazones with greater anti-tumor activity.

Novel Second-Generation Di-2-Pyridylketone Thiosemicarbazones Show Synergism with Standard Chemotherapeutics and Demonstrate Potent Activity against Lung Cancer Xenografts after Oral and Intravenous Administration in Vivo

We developed a series of second-generation di-2-pyridyl ketone thiosemicarbazone (DpT) and 2-benzoylpyridine thiosemicarbazone (BpT) ligands to improve the efficacy and safety profile of these potential antitumor agents. Two novel DpT analogues, Dp4e4mT and DpC, exhibited pronounced and selective activity against human lung cancer xenografts in vivo via the intravenous and oral routes. Importantly, these analogues did not induce the cardiotoxicity observed at high nonoptimal doses of the first-generation DpT analogue, Dp44mT. The Cu(II) complexes of these ligands exhibited potent antiproliferative activity having redox potentials in a range accessible to biological reductants. The activity of the copper complexes of Dp4e4mT and DpC against lung cancer cells was synergistic in combination with gemcitabine or cisplatin. It was demonstrated by EPR spectroscopy that dimeric copper compounds of the type [CuLCl](2), identified crystallographically, dissociate in solution to give monomeric 1:1 Cu:ligand complexes. These monomers represent the biologically active form of the complex.

LC-MS/MS identification of the principal in vitro and in vivo phase I metabolites of the novel thiosemicarbazone anti-cancer drug, Bp4eT

The iron chelator, 2-benzoylpyridine-4-ethyl-3-thiosemicarbazone (Bp4eT), was identified as a lead compound of the 2-benzoylpyridine thiosemicarbazone series, which were designed as potential anti-cancer agents. This ligand has been shown to possess potent anti-proliferative activity with a highly selective mechanism of action. However, further progress in the development of this compound requires data regarding its metabolism in mammals. The aim of this study was to identify the main in vitro and in vivo phase I metabolites of Bp4eT using liquid chromatography tandem mass spectrometry (LC-MS/MS). Two metabolites were detected after incubation of this drug with rat and human liver microsomal fractions. Based on LC-MS(n) analysis, the metabolites were demonstrated to be 2-benzoylpyridine-4-ethyl-3-semicarbazone and N (3)-ethyl-N (1)-[phenyl(pyridin-2-yl)methylene]formamidrazone, with both resulting from the oxidation of the thiocarbonyl group. The identity of these metabolites was further shown by LC-MS/MS analysis of these latter compounds which were prepared by oxidation of Bp4eT with hydrogen peroxide and their structures confirmed by nuclear magnetic resonance and infrared spectra. Both the semicarbazone and the amidrazone metabolites were detected in plasma, urine, and feces after i.v. administration of Bp4eT to rats. In addition, another metabolite that could correspond to hydroxylated amidrazone was found in vivo. Thus, oxidative pathways play a major role in the phase I metabolism of this promising anti-tumor agent. The outcomes of this study will be further utilized for: (1) the development and validation of the analytical method for the quantification of Bp4eT and its metabolites in biological materials; (2) to design pharmacokinetic experiments; and to (3) evaluate the potential contribution of the individual metabolites to the pharmacodynamics/toxico-dynamics of this novel anti-proliferative agent.

2-Benzoylpyridine thiosemicarbazone as a novel reagent for the single pot synthesis of dinuclear CuI–CuII complexes: formation of stable copper(ii)–iodide bonds

2-Benzoylpyridine thiosemicarbazone {R(1)R(2)C(2)=N(2)·N(3)H-C(1)(=S)-N(4)H(2), R(1) = py-N(1), R(2) = Ph; Hbpytsc} with copper(I) iodide in acetonitrile-dichloromethane mixture has formed stable Cu(II)-I bonds in a dark green Cu(II) iodo-bridged dimer, [Cu(2)(II)(μ-I)(2)(η(3)-N(1),N(2),S-bpytsc)(2)] 1. Copper(I) bromide also formed similar Cu(II)-Br bonds in a dark green Cu(II) bromo-bridged dimer, [Cu(2)(II)(μ-Br)(2)(η(3)-N(1),N(2),S-bpytsc)(2)] 3. The formation of dimers 1 and 3 appears to be due to a proton coupled electron transfer (PCET) process wherein copper(I) loses an electron to form copper(II), and this is accompanied by a loss of -N(3)H proton of Hbpytsc ligand resulting in the formation of anionic bpytsc(-). When copper(I) iodide was reacted with triphenylphosphine (PPh(3)) in acetonitrile followed by the addition of 2-benzoylpyridine thiosemicarbazone in dichloromethane (Cu : PPh(3) : Hbpytsc in the molar ratio 1:1:1), both Cu(II) dimer 1 and an orange Cu(I) sulfur-bridged dimer, [Cu(2)(I)I(2)(μ-S-Hbpytsc)(2)(PPh(3))(2)] 2 were formed. Copper(I) bromide with PPh(3) and Hbpytsc also formed Cu(II) dimer 3 and an orange Cu(I) sulfur-bridged dimer, [Cu(2)(I)Br(2)(μ-S-Hbpytsc)(2)(PPh(3))(2)] 4. While complexes 2 and 4 exist as sulfur-bridged Cu(I) dimers, 1 and 3 are halogen-bridged. The central Cu(2)S(2) cores of 2 and 4 as well as Cu(2)X(2) of 1 (X = I) and 3 (X = Br) are parallelograms. One set of Cu(II)-I and Cu(II)-Br bonds are short, while the second set is very long {1, Cu-I, 2.565(1), 3.313(1) Å; 3, Cu-Br, 2.391(1), 3.111(1) Å}. The Cu···Cu separations are long in all four complexes {1, 4.126(1); 2, 3.857(1); 3, 3.227(1); 4, 3.285(1) Å}, more than twice the van der Waals radius of a Cu atom, 2.80 Å. The pyridyl group appears to be necessary for stabilizing the Cu(II)-I bond, as this group can accept π-electrons from the metal.

Bp44mT: an orally active iron chelator of the thiosemicarbazone class with potent anti‐tumour efficacy

Our previous studies demonstrated that a thiosemicarbazone iron chelator (di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; Dp44mT) possesses potent and selective anti-cancer activity but led to cardiotoxicity at non-optimal doses. In this study, we examined the in vivo anti-tumour efficacy and tolerability of a new-generation 2-benzoylpyridine thiosemicarbazone iron chelator (2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone; Bp44mT) administered via the oral or i.v. routes. BpT chelators were tested in vitro against human lung cancer cells (DMS-53) and in vivo in DMS-53 tumour xenografts in mice. The toxicity of Bp44mT in vivo and its effects on the expression of iron-regulated molecules involved in growth and cell cycle control were investigated. Administration of Bp44mT by either route resulted in marked dose-dependent inhibition of tumour growth. When administered at 50 mg·kg(-1) via oral gavage three times per week for 23 days, the net xenograft growth was inhibited by 75%, compared with vehicle-treated mice. Toxicological examination showed reversible alterations including slight reduction of RBC count, with a decrease of liver and splenic iron levels, which confirmed iron chelation in vivo. Importantly, in contrast to Dp44mT, the chelator-treated mice did not show cardiac histological abnormalities. There was also no significant weight loss in mice, suggesting oral administration of Bp44mT was well tolerated. This is the first study to show that Bp44mT can be given orally with potent anti-tumour efficacy. Oral administration of a novel and effective chemotherapeutic agent provides the benefits of convenience for chronic dosing regimens.

Correction to “Iron Chelators of the Di-2-pyridylketone Thiosemicarbazone and 2-Benzoylpyridine Thiosemicarbazone Series Inhibit HIV-1 Transcription: Identification of Novel Cellular Targets—Iron, Cyclin-Dependent Kinase (CDK) 2, and CDK9”

Correction to “Iron Chelators of the Di-2-pyridylketone Thiosemicarbazone and 2-Benzoylpyridine Thiosemicarbazone Series Inhibit HIV-1 Transcription: Identification of Novel Cellular Targets—Iron, Cyclin-Dependent Kinase (CDK) 2, and CDK9”

Gold(I) complexes with thiosemicarbazones: Cytotoxicity against human tumor cell lines and inhibition of thioredoxin reductase activity

Complexes [Au(H2Ac4DH)Cl]∙MeOH ( 1) [Au(H 22Ac4Me)Cl]Cl ( 2) [Au(H 22Ac4Ph)Cl]Cl∙2H 2O ( 3) and [Au(H 22Bz4Ph)Cl]Cl ( 4) were obtained with 2-acetylpyridine thiosemicarbazone (H2Ac4DH), its N(4)-methyl (H2Ac4Me) and N(4)-phenyl (H2Ac4Ph) derivatives, as well as with N(4)-phenyl 2-benzoylpyridine thiosemicarbazone (H2Bz4Ph). The compounds were cytotoxic to Jurkat (immortalized line of T lymphocyte), HL-60 (acute myeloid leukemia), MCF-7 (human breast adenocarcinoma) and HCT-116 (colorectal carcinoma) tumor cell lines. Jurkat and HL-60 cells were more sensitive than MCF-7 and HCT-116 cells. Upon coordinating to the gold(I) metal centers in complexes ( 2) and ( 4), the cytotoxic activity of the H2Ac4Me and H2Bz4Ph ligands increased against the HL-60 and Jurkat tumor cell lines. 2 was more active than auranofin against both leukemia cells. Most of the studied compounds were less toxic than auranofin to peripheral blood mononuclear cells (PBMC). All compounds induced DNA fragmentation in HL-60 and Jurkat cells indicating their pro-apoptotic potential. Complex ( 2) strongly inhibited the activity of thioredoxin reductase (TrxR), which suggests inhibition of TrxR to be part of its mechanism of action.

Antimony(III) complexes with pyridine-derived thiosemicarbazones: Structural studies and investigation on the antitrypanosomal activity

The antimony(III) complexes [Sb(2Fo4Ph)Cl2] (1), [Sb(2Ac4Ph)Cl2] (2) and [Sb(2Bz4Ph)Cl2] (3) were prepared with N(4)-phenyl-2-formyl- (H2Fo4Ph), 2-acetyl- (H2Ac4Ph) and 2-benzoylpyridine (H2Bz4Ph) thiosemicarbazones. The antimony(III) complexes presented antitrypanosomal activity against the epimastigote and trypomastigote forms of Trypanosoma cruzi. Complexes (1) and (2) exhibited higher activity than the reference drugs benznidazole and nifurtimox.

Antimony(III) complexes with 2-benzoylpyridine-derived thiosemicarbazones: Cytotoxicity against human leukemia cell lines

The antimony(III) complexes [Sb(2Bz4DH)Cl 2] ( 1), [Sb(H2Bz4M)Cl 3]·2H 2O ( 2) and [Sb(2Bz4Ph)Cl 2] ( 3) were obtained with 2-benzoylpyridine thiosemicarbazone (H2Bz4DH) and its N(4)-methyl (H2Bz4M) and N(4)-phenyl (H2Bz4Ph) derivatives. H2Bz4DH, H2Bz4Ph and complexes ( 1– 3) exhibited high cytotoxic activity against HL-60 and Jurkat human leukemia cell lines. When these compounds were tested against HL-60 cells with ectopic expression of BcrAbl, Bcl-2 or Bcl-X L, which confer resistance to apoptosis against a variety of death-inducing agents, the cytotoxicity was much lower, indicating apoptosis to be part of their mechanism of action. The cytotoxic activity of complexes 2 and 3 against HL-60 and Jurkat cells was significantly higher than that of the corresponding thiosemicarbazones, suggesting coordination to be an interesting strategy of cytotoxic dose reduction.

Synthesis, Cytotoxic and Antimalarial Activities of Benzoyl Thiosemicarbazone Analogs of Isoquinoline and Related Compounds

Thiosemicarbazone analogs of papaveraldine and related compounds 1–6 were synthesized and evaluated for cytotoxic and antimalarial activities. The cytotoxic activity was tested against HuCCA-1, HepG2, A549 and MOLT-3 human cancer cell lines. Thiosemicarbazones 1–5 displayed cytotoxicity toward all the tested cell lines, while compounds 2–5 selectively showed potent activity against the MOLT-3 cell lines. Significantly, N(4)-phenyl-2-benzoylpyridine thiosemicarbazone 4 exhibited the most potent activity against HuCCA-1, HepG2, A549 and MOLT-3 cell lines with IC50 values of 0.03, 4.75, 0.04 and 0.004 µg/mL, respectively. In addition, 2-benzoylpyridine thio-semicarbazones 3 and 4 showed antimalarial activity against Plasmodium falciparum with IC50 of 10-7 to < 10-6 M. The study demonstrates the quite promising activity of analog 4 as a lead molecule for further development.

Cytotoxicity and structure–activity relationships of four α-N-heterocyclic thiosemicarbazone derivatives crystal structure of 2-acetylpyrazine thiosemicarbazone

A series of thiosemicarbazone ligands, HL 1 (2-acetylpyrazine thiosemicarbazone), HL 2 (2-acetylpyrazine N(4)-methylthiosemicarbazone), HL 3 (2-benzoylpyridine thiosemicarbazone) and HL 4 (2-benzoylpyridine N(4)-methylthiosemicarbazone), have been synthesized. The crystal structure of HL 1 has been determined by single-crystal X-ray diffraction. Hydrogen bonds link the different components to stabilize the crystal structure. The antitumor activity of the four ligands were tested against K562 leucocythemia and BEL7402 liver cancer cell lines. All the thiosemicarbazones showed significant antitumor activity. Different substituents on the ligands show different levels of antitumor activity. By comparison with the other thiosemicarbazone species studied, HL 4 with substitution at N(4) position in thiosemicarbazone along with 2-benzoylpyridine is the most active thiosemicarbazone ligand with IC 50 = 0.002 μm in the K562 leucocythemia cell line and 0.138 μm in the BEL7402 liver cancer cell line, respectively.