Thiosemicarbazone Derivatives Research Articles

Transition Metal Catalyst Free and Single‐Step Synthesis of Significant Thiosemicarbazones via Oxidative Coupling Strategy

AbstractThe efficacy and selectivity of the transition metal‐free catalysis have been emphasized in constructing thiosemicarbazone derivatives from the dehydrogenative coupling of alcohols and thiosemicarbazides under aerobic conditions. A broad spectrum of thiosemicarbazones was obtained in good‐to‐excellent yields up to 90 %, with water as the only by‐product. The catalytic synthesis worked in an atom‐economical fashion in the absence of any oxidant with only 1 mmol of the base loading per mmol of the substrates. Further, the impact of different temperatures, solvents, bases, and base loading of the coupling reaction has been explored. A probable pathway that involves the generation of an aldehyde intermediate to thiosemicarbazones, which releases only water has been proposed.

Novel Thiosemicarbazone Derivatives from Furan-2-Carbaldehyde: Synthesis, Characterization, Crystal Structures, and Antibacterial, Antifungal, Antioxidant, and Antitumor Activities

Ten new thiosemicarbazone derivatives, furan-2-carbaldehyde thiosemicarbazone (1), 3-methyl-furan-2-carbaldehyde thiosemicarbazone (2), 5-hydroxymethyl-furan-2-carbaldehyde thiosemicarbazone (3), 5-trifluoromethyl-furan-2-carbaldehyde thiosemicarbazone (4), 5-nitro-furan-2-carbaldehyde thiosemicarbazone (5), 5-phenyl-furan-2-carbaldehyde thiosemicarbazone (6), 5-(2-fluorophenyl)-furan-2-carbaldehyde thiosemicarbazone (7), 5-(4-methoxyphenyl)-furan-2-carbaldehyde thiosemicarbazone (8), 5-(1-naphthyl)-furan-2-carbaldehyde thiosemicarbazone (9), and 5-(1H-Pyrazol-5-yl)-furan-2-carbaldehyde thiosemicarbazone (10) were synthesized by condensing thiosemicarbazide with the respective furan-2-carbaldehyde in methanol. The prepared compounds were characterized by spectroscopic studies (FT-IR and NMR) and electrospray mass spectrometry. The molecular structures of 2, 6, 7, and 8 have also been determined by X-ray crystallography. Compounds 2, 6, and 7 crystallize in the E conformation about the N1-C6, N1-C11, and N1-C11 bonds, respectively, while 8 adopts the Z conformation about the N1-C12 bond with the presence of an intramolecular N2-H…O2 hydrogen bond. All prepared thiosemicarbazone derivatives were evaluated for their in vitro antibacterial, antifungal, and antitumor activities against Staphylococcus aureus strains, Candida albicans/Candida tropicalis fungi, and seven human tumor cell lines (HuTu80, H460, DU145, M-14, HT-29, MCF-7, and LNCaP), respectively. The antioxidant activity was also studied by the DPPH assay. Compound 5 exhibited significant antibacterial activity against Staphylococcus aureus ATCC700699 (MIC = 1 μg/mL) compared to the nitrofurantoin and gentamicin reference drugs (MIC = 1–25 and 10->100 μg/mL, respectively). Compound 4 was ten times less active than amphotericin B (MIC = 5 μg/mL) against Candida albicans (ATCC90028 and ATCC10231), while 1 exhibited a moderate effect of scavenging of DPPH radical (IC50 = 40.9 μg/mL) in comparison to ascorbic acid reference compound (IC50 = 22.0 μg/mL). Among all the studied thiosemicarbazones, 5 showed a higher cytotoxic activity (IC50 = 13.36–27.73 μΜ) in relation to the other tested compounds (IC50 = 34.84—>372.34 μΜ) against all tested cell lines, except the LNCaP cell line, exhibiting its highest antiproliferative activity (IC50 = 13.36 μΜ) on the HuTu80 cell line. Besides, 8 and 9 exhibited high antitumor activity (IC50 = 13.31 and 7.69 μΜ, respectively) against the LNCaP cells.

Microwave-assisted solvent-free synthesis of some novel thiazole substituted thiosemicarbazone analogues: Antimicrobial and anticancer studies.

The increased resistance to antibiotics has compelled researchers to devise novel active compounds targeting multidrug-resistant pathogenic microorganisms. A series of thiosemicarbazone derivatives were synthesized by reacting thiosemicarbazide with 2-aryl-4-formylthiazole, 2-aryl-5-formyl-4-methylthiazole, and/or 5-acetyl-2-aryl-4-methylthiazole compounds. These thiosemicarbazone-based thiazole adducts were evaluated for their inhibitory activities against tuberculosis H37Ra and Bovis BCG mycobacteria. Their cytotoxicity was assessed against two cancer cell lines: colonic carcinoma (HCT-116) and cervical cancer (HeLa). Notably, these thiosemicarbazones exhibited minimal cytotoxic effects on these cell lines even at their highest concentrations. Furthermore, the prepared thiosemicarbazone derivatives demonstrated significant antimicrobial efficacy against Bacillus subtilis and Staphylococcus aureus (gram-positive bacterial pathogens) as well as Escherichia coli and Pseudomonas fluorescens (gram-negative bacterial pathogens). While most of the prepared thiosemicarbazone derivatives exhibited moderate activity against Candida albicans (a fungal strain), their performance was notable. The thiosemicarbazone-based thiazole adducts were also successfully synthesized using a solvent-free approach under microwave irradiation. Compared with conventional reflux methods, the microwave-assisted technique yielded high thiazole yields within just 5 minutes, obviating the need for catalysis. This study signifies significant strides toward the rational design of more potent antimycobacterial agents.

Structural, optimization of and mechanistic insights into a new thiosemicarbazone derivative as a highly sensitive and selective chemosensor for Hg2+ recognition using DFT, COSMO-RS, RSM, and molecular dynamics simulation approaches

A new thiosemicarbazone derivative, N-(2-hydroxyphenyl)-2-[1-(pyridin-4-yl)ethylidene]hydrazinecarbothioamide (HPEH), has been synthesized, characterized, and further developed as a highly selective and sensitive colorimetric chemosensor for Hg2+ recognition in environmental water samples. Structural conformers of HPEH were successfully identified using a combination of the potential energy surface (PES) and time-dependent density functional theory (TD-DFT) methods. The synthesized HPEH was successfully characterized further and analyzed based on its harmonic vibrational frequencies, NMR spectra, and electronic transitions using the DFT approach. Sigma profiles were generated using the COSMO-RS approach to identify a compatible medium for HPEH to act as a chemosensor. The conditions for the highly sensitive and selective detection of Hg2+ by HPEH were successfully optimized using the statistical response surface methodology approach. The optimum sensing of HPEH occurred in an 8:2 v/v DMSO/pH 7.8 solution at a 20:60 μM HPEH/Hg2+ concentration and after a reaction time of 18 min, with statistically significant independent variables (p < 0.05) for all parameters. Under optimal conditions, the lowest Hg2+ concentration detected by HPEH was 3.56 µM, indicating that HPEH can serve as an alternative and comparable probe for the detection of Hg2+ in aqueous systems. Using the optimized results, the interaction between HPEH and Hg2+ in the chemosensor system was successfully modeled, and the model was subsequently used with the TD-DFT, non-covalent interaction-reduced density gradient (NCI-RDG), and molecular dynamics approaches to gain mechanistic insights into the interaction. The results showed that the newly synthesized HPEH, in addition to being cost-effective, could serve as a suitable alternative and comparable chemosensor for Hg2+ recognition in water samples, with the advantages of being efficient, portable, and eco-friendly, and offering rapid analysis without the need of specialized training.

Synthesis and evaluation of antipyrine derivatives bearing a thiazole moiety as antibacterial and antifungal agents

One of the best ways to design new biocidal agents is synthesizing hybrid molecules. So, new series of antipyrine-bearing thiazole moiety were synthesized using 4-antipyrinecarboxaldehyde thiosemicarbazones 1a–e. Cyclization of thiosemicarbazone derivatives 1a–e with ethyl 2-chloroacetate, ethyl 2-chloropropanoate, 1-chloropropan-2-one (chloroacetone) and 2-bromo-1-phenylethanone (phenacyl bromide) afforded the corresponding thiazolidin-4-ones 2a–e, 5-methyl-thiazolidin-4-ones 3a–e, 4-methylthiazoles 4a–e and 4-phenylthiazoles 5a–e, respectively. The antibacterial and antifungal activates for the synthesized compounds were investigated.

5-Methoxyisatin N(4)-Pyrrolidinyl Thiosemicarbazone (MeOIstPyrd) Restores Mutant p53 and Inhibits the Growth of Skin Cancer Cells, In Vitro.

A series of novel thiosemicarbazone derivatives containing 5-methoxy isatin were designed and synthesized with modification on N(4) position. Derivatives considering structure-activity relationship have been designed and synthesized by condensing thiosemicarbazide with 5-methoxy isatin. The synthesized compounds were characterized by elemental analysis, FT-IR spectroscopy, UV-visible spectroscopy, NMR (1H, 13C) spectroscopy, mass spectrometry, and a single-crystal study. Biological evaluation of the synthesized compounds revealed that MeOIstPyrd is the most promising compound against skin cancer cell line, A431, with an IC50 value of 0.9 μM. In addition, MeOIstPyrd also exhibited low toxicity against the normal human fibroblast and the human embryonic kidney 293 cell line, HLF-1, and HEK293, respectively. Furthermore, the mechanistic study revealed that MeOIstPyrd efficiently inhibited cell proliferation, migration, and spheroid formation by activating the mitochondrial intrinsic apoptotic pathway. MeOIstPyrd also induces DNA damage and activates p53 irrespective of the p53 status. It increases the half-life of p53 and stabilizes p53 by phosphorylating it at ser15. Moreover, MeOIstPyrd was found to bind to MDM2 in the p53 sub-pocket and, therefore, block p53-MDM2 interaction. Our result exhibited potential anticancer activity of MeOIstPyrd in the A431 cell line and its ability in restoring mutant p53, which is an interesting and promising strategy for cancer therapeutics.

Pro-angiogenic effect of a synthetic Cu(II) complex [CuII(L)2] [LH = tautomeric thiolate form of 2-ethoxybenzaldehyde-N(4)-dihexyl-3-thiosemicarbazone

Synthesis and structural characterization of a thiosemicarbazone derivative of Cu(II) [CuII(L)2] [LH = tautomeric thiolate form of 2-ethoxybenzaldehyde-N(4)-dihexyl-3-thiosemicarbazone (L1)] (1) is reported. From the structural characterization data, the metal centre in 1 is found to have in square planar geometry. Both the free ligand (L1) and the metal complex (1) showed pro-angiogenic activity on fertilized chicken eggs. In Chorio-Allantoic Membrane (CAM) assay, L1 was found to promote blood capillary growth by 31.5% in 24 h, whereas for 1 it was 40.0%. In aortic arch assay also, 1 showed better angiogenic potential than the free L1.

Structural, NBO, HOMO-LUMO Analysis Using DFT and Molecular Docking Analysis of Bioactive 3,4-Difluoroacetophenone-Thiosemicarbazone as a Potential Anticancer Agent

The thiosemicarbazone moiety serves as a structural template for the synthesis of a wide variety of N- and S-containing heterocyclic compounds which have proven in-vitro antitumor activity against A549 and MCF-7 cell lines and normal breast and lung cells. In this study, we have reported comprehensive theoretical studies using density functional theory (DFT) on molecular structure, molecular electrostatic potential (MEP), Natural Bond Analysis (NBO) and HOMO-LUMO analysis of an important thiosemicarbazone compound 3,4-difluoroacetophenone-thiosemicarbazone (DFAT). Pale yellow crystals were recently synthesized by mixing of 3,4-difluoroacetophenone and thiosemicabazide ethanolic solution and then crystallized by slow evaporation process. Anti-tumor activity of DFAT ligand was explained in terms of intra-molecular charge delocalization which gives insight into inter and intra-molecular interactions. Molecular docking studies of DFAT verified its inhibitory nature against 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) (PDB ID: 3HB5) protein associated with cancer disease. From docking studies, it is found that the titled molecule exhibits a maximum binding affinity of −5.9[Formula: see text]kcal/mol with respect to the target protein. Three hydrogen bonds were formed with residues SER11 having the bond distances 3.00[Formula: see text]Å, 2.50[Formula: see text]Å and 2.34[Formula: see text]Å respectively. The DFAT molecule also shows hydrogen bonding with ASP65, THR190 and GLY15 residue with a bond distance 2.02[Formula: see text]Å, 2.05[Formula: see text]Å and 1.83[Formula: see text]Å respectively. A comparative study of the titled molecule with other several thiosemicarbazone derivatives shows that DFAT has good binding affinity than that of referenced drugs and can be used as a more potent active pharmaceutical ingredient (API) for cancer treatment.

Isatin/thiosemicarbohydrazone hybrids: Facile synthesis, and their evaluation as anti-proliferatıve agents and metabolıc enzyme inhibitors

ABSTRACT. We are reporting a novel series of thiosemicarbazone derivatives derived from isatin (1-6), structural determination, and investigation of the inhibitory properties against proliferative, carbonic anhydrase, and cholinesterase enzymes. The anti-proliferative effects of the compounds were measured by XTT assay against MCF-7 and MDA-MB-231 cancerous cell lines. Compound 3 showed significant cytotoxic effects on both MCF-7 and MDA-MB-231 cell lines, with IC50 values of 8.19 μM and 23.41 μM, respectively. In addition, the compounds (1-6) inhibited the hCA I and II, their Ki values 2.01 ± 0.35 – 21.55 ± 2.56 and 1.24 ± 0.33 – 25.03 ± 5.48 µM, respectively. AChE was also successfully inhibited by these compounds (1-6), with Ki values ranging from 40.37 ± 8.23 to 125.43 ± 24.93 µM. The best Ki values for 3, 6, and 4 for α-glycosidase were 564.35 ± 72.06, 594.38 ± 52.04, and 683.437 ± 66.58 µM, respectively. Binding affinities were determined to be -6.697 kcal/mol, -8.251 kcal/mol, -9.932 kcal/mol, and -4.946 kcal/mol for hCA I, hCA II, AChE, and α-glucosidase enzymes, respectively. These findings reveal that the formed compounds containing isatin moieties were crucial in the enzyme inhibition.&#x0D; &#x0D; KEY WORDS: Isatin, Thiosemicarbazone, Anti-proliferative activity, Enzyme inhibition, Molecular docking&#x0D; &#x0D; Bull. Chem. Soc. Ethiop. 2023, 37(5), 1221-1236. &#x0D; DOI: https://dx.doi.org/10.4314/bcse.v37i5.14

Synthesis, structure, ADME and biological activity of three 2,6-disubstituted thiosemicarbazone derivatives.

Three new 2,6-disubstituted thiosemicarbazone derivatives of pyridine, namely, 2-{amino[6-(pyrrolidin-1-yl)pyridin-2-yl]methylidene}-N,N-dimethylhydrazine-1-carbothioamide, C13H20N6S, 2-{amino[6-(piperidin-1-yl)pyridin-2-yl]methylidene}-N,N-dimethylhydrazine-1-carbothioamide, C14H22N6S, and 2-[amino(6-phenoxypyridin-2-yl)methylidene]-N,N-dimethylhydrazine-1-carbothioamide monohydrate, C15H17N5OS·H2O, have been synthesized and characterized by NMR spectroscopy and low-temperature single-crystal X-ray diffraction. In addition, their antibacterial and anti-yeast activities have been determined. The ability of the tested compounds to inhibit bacterial growth was comparable to vancomycin as a reference drug. Compared to isoniazid (MIC 0.125 and 8 µg ml-1), the compounds showed the ability to inhibit the growth of Mycobacterium tuberculosis to a moderate degree for the standard strain and at the same level or higher (MIC 4-8 µg ml-1) for the resistant strain. All three compounds adopt the zwitterionic form in the crystal structure regardless of the presence or absence of solvent molecules.

3-acetyl-coumarin-substituted thiosemicarbazones and their ruthenium, rhodium and iridium metal complexes: An investigation of the antibacterial, antioxidant and cytotoxicity activities

A series of ruthenium, iridium and rhodium half-sandwich complexes containing 3-acetyl chromen-2-one-4(N)-substituted thiosemicarbazone derivatives have been prepared for use as antibacterial and anticancer agents. These complexes have been isolated as cationic bidentate (N, S) and neutral bidentate (N, S) complexes. The complexes have been characterized by spectral techniques (FT-IR, UV-Vis, NMR and HRMS) and single-crystal X-ray crystallography methods. The structure of complex 6 has been determined by a single-crystal X-ray diffraction study, which shows that coordination of the 3-acetyl chromen-2-one-4(N)-substituted thiosemicarbazone ligand to the metal occurs via azomethine nitrogen and thiolate sulfur atoms. Vitro antibacterial activity against gram-positive Staphylococcus aureus and gram-negative Escherichia coli, Klebsiella pneumonia strains and antioxidant activity have been evaluated. Also, the said complexes were tested for anticancer efficacy (in vitro for 48h) in Dalton's lymphoma (DL) cancer cell lines using cell cytotoxicity (MTT) and apoptosis tests. The results were compared with cisplatin (standard drug) under identical experimental conditions. The cell cytotoxicity results showed that complex 5 induced higher cytotoxicity in DL cells, followed by complex 4, 1, and 2.

Synthesis, spectroscopic characterizations, and comparison of experimental, and theoretical results of N-(3‑chloro-2-methyl phenyl)-2-(4-methoxybenzylidene)hydrazine-1-carbothioamide

By condensation of 4‑methoxy benzaldehyde with (3‑chloro-2-methyl phenyl)-3-thiosemicarbazide a novel thiosemicarbazone derivative, N-(3‑chloro-2-methyl phenyl)-2-(4-methoxybenzylidene)hydrazine-1-carbothioamide (3), were synthesized and purified to describe the X-ray crystal structures. The structure of the synthesized thiosemicarbazone compound (3) was elucidated using FT-IR, 1H, APT-13C NMR, and mass spectroscopic methods. The geometry from X-ray experiment of the compound has been compared using the Hartree-Fock (HF) and density functional theory (DFT) with the 6-31G+(d) basis set. The obtained results show that the calculated results can well reproduce the structure of the compound. MEP, FMO, and Hirshfeld surface analysis were also performed for the structure. In addition, thermal analysis and non-linear optical (NLO) properties were also investigated in this study.

Synthesis, anti-ferroptosis, anti-quorum sensing, antibacterial and DNA interaction studies of chromene-hydrazone derivatives

Nineteen chromene-hydrazone derivatives containing a variety of structural modifications on the hydrazone moiety were synthesized. Structure-activity correlations were investigated to determine the influence of structural variations on anti-ferroptosis, anti-quorum sensing, antibacterial, DNA cleavage and DNA binding properties. Ferroptosis inhibitory activity was determined by measuring the ability of the derivatives to reverse erastin-induced ferroptosis. Several of the derivatives were more effective than fisetin at inhibiting ferroptosis, with the thiosemicarbazone derivative being the most effective. Quorum sensing inhibition was evaluated using Vibrio harveyi, and both V. harveyi and Staphylococcus aureus were used to determine antibacterial activity. The semicarbazone and benzensulfonyl hydrazone derivatives showed moderate quorum sensing inhibition with IC50 values of 27 μM and 22 μM, respectively, while a few aryl hydrazone and pyridyl hydrazone derivatives showed bacterial growth inhibition, with MIC values ranging from 3.9 to 125 μM. In addition, the interaction of the hydrazone derivatives with DNA was investigated by gel electrophoresis, UV–Vis spectroscopy and molecular docking. All of the derivatives cleaved plasmid DNA and showed favorable interaction with B-DNA through minor groove binding. Overall, this work highlights a broad range of pharmacological applications for chromene-hydrazone derivatives.

Thiosemicarbazone derivatives as potential inhibitors of acetylcholinesterase, butyrylcholinesterase and their molecular docking studies

Thiosemicarbazone derivatives as potential inhibitors of acetylcholinesterase, butyrylcholinesterase and their molecular docking studies

Inhibitory effects of 190 compounds against SARS-CoV-2 Mpr o protein: Molecular docking interactions.

COVID-19 has caused many deaths since the first outbreak in 2019. The burden on healthcare systems around the world has been reduced by the success of vaccines. However, population adherence and the occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are still challenging tasks to be affronted. In addition, the newly approved drug presents some limitations in terms of side effects and drug interference, highlighting the importance of searching for new antiviral agents against SARS-CoV-2. The SARS-CoV-2 main protease (Mpr o ) represents a versatile target to search for new drug candidates due to its essential role in proteolytic activities responsible for the virus replication. In this work, a series of 190 compounds, composed of 27 natural ones and 163 synthetic compounds, were screened in vitro for their inhibitory effects against SARS-CoV-2 Mpro . Twenty-five compounds inhibited Mpro with inhibitory constant values (Ki ) between 23.2 and 241 µM. Among them, a thiosemicarbazone derivative was the most active compound. Molecular docking studies using Protein Data Bank ID 5RG1, 5RG2, and 5RG3 crystal structures of Mpro revealed important interactions identified as hydrophobic, hydrogen bonding and steric interactions with amino acid residues in the active site cavity. Overall, our findings indicate the described thiosemicarbazones as good candidates to be further explored to develop antiviral leads against SARS-CoV-2. Moreover, the studies showed the importance of careful evaluation of test results to detect and exclude false-positive findings.

Synthesis, characterization, antibacterial activity of thiosemicarbazones derivatives and their computational approaches: Quantum calculation, molecular docking, molecular dynamic, ADMET, QSAR

The thiosemicarbazones and their derivatives have been recognized as antimicrobial agents against human pathogenic bacteria and fungi. Regarding these prospective, this study was designed to address the new antimicrobial agents from thiosemicarbazones and their derivatives. These derivatives were synthesized by multi-step synthesis methods, such as alkylation, acidification, esterification, and formed the 4-(4′-alkoxybenzoyloxy) thiosemicarbazones and its derivatives (THS1, THS2, THS3, THS4, and THS5). Afterward the synthesis, compounds were characterized by 1H NMR, FTIR spectra, and melting point. Later, the computational tools were applied to evaluate the drug likeness properties, bioavailability score, Lipinski rule, absorption, distribution, metabolism, excretion, and toxicity (ADMET). Secondly, the quantum calculations, for instance HOMO, LUMO and chemical descriptors, were calculated by the density functional theory (DFT). Finally, the molecular docking was performed against seven human pathogenic bacteria, black fungus (Rhizomucor mieh, Mucor lusitanicus, Mycolicibacterium smegmatis) and white fungus strains (Candida Auris, Aspergillus luchuensis, Candida albicans). To check and validate of molecular docking procedure and stability of docked complex for ligand and protein, the molecular dynamic was performed of docked complex. From the docking score with calculating the binding affinity, these derivatives could show a higher affinity than standard drug against all pathogens. From the computational details, it could be decided to do in-vitro test as antimicrobial activity against Staphylococcus aurious, Staphylococcus homonis, Salmonella typhi, and Shigella flexneria. The obtained result of antibacterial activity compared to standard drugs, and it was found that the synthesized compounds were almost same value of standard drug. Finally, it could be said from the in-vitro and in-silico study that the thiosemicarbazones derivatives are good antimicrobial agents.

Design, synthesis and biological evaluation of novel tetralone/indanone containing thiosemicarbazone derivatives with selective COX-2 inhibition as anticancer agents

Design, synthesis and biological evaluation of novel tetralone/indanone containing thiosemicarbazone derivatives with selective COX-2 inhibition as anticancer agents

Discovery of novel thiosemicarbazone derivatives with potent and selective anti-Candida glabrata activity

A series of 21 novel compounds containing a thiosemicarbazone moiety were designed and synthesised based on hit compound 1 from our in-house compound library screening. Most compounds showed potent antifungal activity in vitro against seven common pathogenic fungi. Notably, all compounds showed high potency against Candida glabrata 537 (MIC = ≤0.0156-2 µg/mL). Of note, compounds 5j and 5r displayed excellent antifungal activity against Candida krusei 4946 and Candida auris 922. Additionally, compounds 5j and 5r also showed high potency against 15 C. glabrata isolates with MIC values ranging from 0.0625 µg/mL to 4 µg/mL, with compound 5r being slightly superior to 5j. Moreover, compound 5r has certain effect against biofilm formation of C. glabrata. Furthermore, compound 5r has minimal cytotoxicity against HUVECs with an IC50 value of 15.89 µg/mL and no haemolysis at 64 µg/mL. Taken together, these results suggest that promising lead compound 5r deserves further investigation.

Natural products in crop protection: thiosemicarbazone derivatives of 3-acetyl-N-benzylindoles as antifungal agents and their mechanism of action.

Phytopathogenic fungi can cause a direct loss in economic value of agriculture. Especially Valsa mali Miyabe et Yamada, a devastating phytopathogenic disease especially threatening global apple production, is very difficult to control and manage. To discover new potential antifungal agents, a series of thiosemicarbazone derivatives of 3-acetyl-N-benzylindoles were prepared. Their antifungal activities were first tested against six typically phytopathogenic fungi including Curvularia lunata, Valsa mali, Alternaria alternate, Fusarium graminearum, Botrytis cinerea and Fusarium solani. Then their mechanism of action against V. mali was investigated. Derivatives displayed potent antifungal activity against V. mali. Notably, 3-acetyl-N-benzylindole thiosemicarbazone (IV-1: EC50 : 0.59 μg mL-1 ), whose activity was comparable to that of a commercial fungicide carbendazim (EC50 : 0.33 μg mL-1 ), showed greater than 98-fold antifungal activity of the precursor indole. Moreover, compound IV-1 displayed good protective and therapeutic effects on apple Valsa canker disease. By scanning electron microscope (SEM) and RNA-Seq analysis, it was demonstrated that compound IV-1 can destroy the hyphal structure and regulate the homeostasis of metabolism of V. mali via the ergosterol biosynthesis and autophagy pathways. 3-Acetyl-N-(un)substituted benzylindoles thiosemicarbazones (IV-1~IV-5) can be studied as leads for further structural modification as antifungal agents against V. mali. Particularly, these ergosterol biosynthesis and autophagy pathways can be used as target receptors for design of novel green pesticides for management of congeneric phytopathogenic fungi. This article is protected by copyright. All rights reserved.

Antiproliferative Activity and DNA Interaction Studies of a Series of N4,N4-Dimethylated Thiosemicarbazone Derivatives.

The exploitation of bioactive natural sources to obtain new anticancer agents with novel modes of action may represent an innovative and successful strategy in the field of medicinal chemistry. Many natural products and their chemical analogues have been proposed as starting molecules to synthesise compounds with increased biological potential. In this work, the design, synthesis, and characterisation of a new series of N4,N4-dimethylated thiosemicarbazone Cu(II), Ni(II), and Pt(II) complexes are reported and investigated for their in vitro toxicological profile against a leukaemia cell line (U937). The antiproliferative activity was studied by MTS assay to determine the GI50 value for each compound after 24 h of treatment, while the genotoxic potential was investigated to determine if the complexes could cause DNA damage. In addition, the interaction between the synthesised molecules and DNA was explored by means of spectroscopic techniques, showing that for Pt and Ni derivatives a single mode of action can be postulated, while the Cu analogue behaves differently.