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Diabetes mellitus, particularly type 2 diabetes, is a growing global health challenge characterized by chronic hyperglycemia due to insulin resistance. One therapeutic approach to managing this condition is the inhibition of α-glucosidase, an enzyme involved in carbohydrate digestion, to reduce postprandial blood glucose levels. In this study, a series of thiosemicarbazide-linked quinoline-piperazine derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity, to identify new agents for type 2 diabetes management. Structure-activity relationship (SAR) analysis revealed that the nature and position of substituents on the aryl ring significantly impacted the inhibitory potency. Among the synthesized derivatives, the 2,5-dimethoxy phenyl substitution (7j) exhibited the most potent activity with an IC 50 value of 50.0 µM, demonstrating a 15-fold improvement compared to the standard drug acarbose. Kinetic studies identified compound 7j as a competitive inhibitor, with a K i value of 32 µM. Molecular docking simulations demonstrated key interactions between compound 7j and the active site of α-glucosidase, while molecular dynamics simulations confirmed the stability of the enzyme-ligand complex, reflected in low RMSD and RMSF values., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Three new thiosemicarbazide derivatives are described in terms of synthesis, structure and biological activity. N'-(Morpholine-4-carbonothioyl)-4-(4-phenylpiperazin-1-yl)picolinohydrazonamide 2-methyltetrahydrofuran hemisolvate, 2C 21 H 27 N 7 OS·C 5 H 10 O, 1, determined at 100 K, has orthorhombic (Pca2 1 ) symmetry and exhibits disorder. 4-(4-Phenylpiperazin-1-yl)-N'-(piperidine-1-carbonothioyl)picolinohydrazonamide-dimethylformamide-water (1/1/0.285), C 22 H 29 N 7 S·C 3 H 7 NO·0.285H 2 O, 2, determined at 100 K, has monoclinic (P2 1 /c) symmetry. 4-(4-Phenylpiperazin-1-yl)-N'-(pyrrolidine-1-carbonothioyl)picolinohydrazonamide, C 21 H 27 N 7 S, 3, determined at 100 K, has triclinic (P1) symmetry and exhibits disorder. Compounds 1 and 2 contain solvent molecules in their structure. All three studied compounds adopt the zwitterionic form and were tested for their microbiological activity on a model panel of Gram-positive and Gram-negative bacteria, as well as selected yeasts.

Sixteen thio/semicarbazide-based benzyloxy derivatives (BT1-BT16) were synthesized and evaluated for their inhibitory activities against monoamine oxidases (MAOs). Most compounds showed better inhibitory activity against MAO-B than against MAO-A. BT1, BT3, and BT5 showed the greatest inhibitory activity with an identical IC 50 value of 0.11 µM against MAO-B, followed by BT6 and BT7 (IC 50  = 0.12 µM) and BT2 (IC 50  = 1.68 µM). The selectivity index of BT5 was the highest (363.64) for MAO-B, whereas that of BT1 was 88.73. BT1 and BT5 were reversible MAO-B inhibitors, based on the results of dialysis experiments. In inhibition kinetics, BT1 and BT5 were competitive MAO-B inhibitors with K i values of 0.074 ± 0.0020 and 0.072 ± 0.0079 µM, respectively. Additionally, in the in-vitro parallel artificial membrane penetration assay, BT1 and BT5 crossed the blood-brain barrier. Cytotoxicity and possible neuroprotective effects of the lead compounds were assessed using IMR 32 cells. Levels of the antioxidant superoxide dismutase, catalase, and glutathione peroxidase in IMR 32 cells were increased by pretreatment with lead compounds. Five lead molecules (BT1, BT3, BT5, BT6, and BT7) were used for the docking studies. A significant pi-pi interaction with Tyr 326 was observed and molecular dynamics studies were performed for the most promising BT1-MAO-B complex. These results suggested that BT1 and BT5 could be used therapeutically for the treatment of various neurodegenerative diseases., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Hydrazinecarboxamides (semicarbazides) are increasingly recognized as a versatile scaffold in developing potential antimicrobial agents. In addition to a brief overview of the synthetic methods to prepare them, this review comprehensively analyses their antimicrobial properties. These derivatives have demonstrated potent activity against a broad spectrum of mycobacteria, bacterial and fungal pathogens, highlighting their potential to address critical human health challenges, including neglected diseases, and to combat growing antimicrobial resistance. They have also been investigated for their antiviral and antiparasitic properties. The review also summarizes structure-activity relationships, known mechanisms of action and emphasizes the crucial role of the hydrazinecarboxamide moiety in facilitating interactions with biological targets. The combination of hydrazinecarboxamides with other bioactive scaffolds (primaquine, isoniazid, etc.) has led to an identification of promising drug candidates, including those active against resistant strains, offering a promising approach for future innovations in the field of antimicrobial therapy. Attention is also drawn to limitations of hydrazinecarboxamides (poor physicochemical properties, cytotoxicity to human cells, and insufficient target selectivity), which may hinder their clinical application., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In recent years, extensive research has focused on cannabidiol (CBD), a well-studied non-psychoactive component of the plant-derived cannabinoids. CBD has shown significant therapeutic potential for treating various diseases and disorders, including antioxidants and anti-inflammatory effects. Due to the promising therapeutic effect of CBD in a wide variety of diseases, synthetic derivatization of this compound has attracted the attention of drug discovery in both industry and academia. In the current research, we focused on the derivatization of CBD by introducing Schiff base moieties, particularly (thio)-semicarbazide and aminoguanidine motifs, at the 3-position of the olivetolic ring. We have designed, synthesized, and characterized new derivatives based on CBD's framework, specifically aminoguanylhydrazone- and (thio)-semicarbazones-CBD-aldehyde compounds. Their antioxidant potential was assessed using FRAP and DPPH assays, alongside an evaluation of their effect on LDL oxidation induced by Cu 2+ and AAPH. Our findings suggest that incorporating the thiosemicarbazide motif into the CBD framework produces a potent antioxidant, warranting further investigation.

Uric acid, the metabolic product of purines, relies on xanthine oxidase (XOD) for production. XOD is a target for the development of drugs for hyperuricemia (HUA) and gout. Currently, treatment options remain limited for gout patients. 3, 4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a derivative of the natural product protocatechualdehyde with good biological activity. In this work, we identify a DHNB thiosemicarbazide class of compounds that targets XOD. 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazone can effectively inhibit XOD activity (IC50 value: 0.0437 μM) and exhibits a mixed inhibitory effect. In a mouse model of acute hyperuricemia, a moderate dose (10 mg/kg.w) of 3,4-dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide effectively controlled the serum uric acid content and significantly inhibited serum XOD activity. In addition, 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide showed favorable safety profiles, and mice treated with the target compound did not show any symptoms of general toxicity following a single dose of 500 mg/kg. In the allopurinol group, 50 % of the mice died. These results provide a structural framework and mechanism of XOD inhibition that may facilitate the design of hyperuricemia and gout treatments., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Heterocyclic compounds, particularly those containing azole rings, have shown extensive biological activity, including anticancer, antibacterial, and antifungal properties. Among these, the imidazole ring stands out due to its diverse therapeutic potential. In the presented study, we designed and synthesized a series of imidazole derivatives to identify compounds with high biological potential. We focused on two groups: thiosemicarbazide derivatives and hydrazone derivatives. We synthesized these compounds using conventional methods and confirmed their structures via nuclear magnetic resonance spectroscopy (NMR), MS, and elemental analysis, and then assessed their antibacterial and antifungal activities in vitro using the broth microdilution method against Gram-positive and Gram-negative bacteria, as well as Candida spp. strains. Our results showed that thiosemicarbazide derivatives exhibited varied activity against Gram-positive bacteria, with MIC values ranging from 31.25 to 1000 µg/mL. The hydrazone derivatives, however, did not display significant antibacterial activity. These findings suggest that structural modifications can significantly influence the antimicrobial efficacy of imidazole derivatives, highlighting the potential of thiosemicarbazide derivatives as promising candidates for further development in antibacterial therapies. Additionally, the cytotoxic activity against four cancer cell lines was evaluated. Two derivatives of hydrazide-hydrazone showed moderate anticancer activity.

Introduction: Intestinal parasitic infections are neglected diseases and, due to the increasing resistance of parasites to available drugs, they pose an increasing therapeutic challenge. Therefore, there is a great need for finding new compounds with antiparasitic activity., Objectives: In this work, new thiosemicarbazide and 1,2,4-triazole derivatives were synthesized and tested for their anthelmintic activity., Methods: The synthesis was carried out by classical methods of organic chemistry. Anthelmintic activity tests were carried out in vitro (Rhabditis sp., Haemonchus contortus, Strongylidae sp.) in vivo (Heligmosomoides polygyrus/bakeri), and in silico analysis was performed., Results: Quinoline-6-carboxylic acid derivative compounds were designed and synthesized. The highest activity in the screening tests in the Rhabditis model was demonstrated by compound II-1 with a methoxyphenyl substituent LC 50  = 0.3 mg/mL. In the next stage of the research, compound II-1 was analyzed in the H. contortus model. The results showed that compound II-1 was active and had ovicidal (percentage of dead eggs > 45 %) and larvicidal (percentage of dead larvae > 75 %) properties. Studies in the Strongylidae sp. model confirmed the ovicidal activity of compound II-1 (percentage of dead eggs ≥ 55 %). In vivo studies conducted in the H. polygyrus/bakeri nematode model showed that the number of nematodes decreased by an average of 30 % under the influence of compound II-1. In silico studies have shown two possible modes of action of compound II-1, i.e. inhibition of tubulin polymerization and SDH. The test compound did not show any systemic toxic effects. Its influence on drug metabolism related to the activity of cytochrome CYP450 enzymes was also investigated., Conclusion: The results obtained in the in vitro, in vivo, and in silico studies indicate that the test compound can be described as a HIT, which in the future may be used in the treatment of parasitic diseases in humans and animals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

The search for new antibacterial compounds is still a huge challenge for scientists. Each new chemotherapy drug is not 100% effective when introduced into treatment. Bacteria quickly become resistant to known structures. One promising group of new compounds is thiosemicarbazides. In the presented work, we looked for the relationship between structure and antibacterial activity within the group of thiosemicarbazide derivatives. This is a continuation of our previous work. Here, we decided to check to what extent the position of the 3-methoxyphenyl substituent affects potency. We obtained new structures that differ in the positions of the substituent in the thiosemicarbazide skeleton. Based on the obtained results of the biological tests, it can be concluded that the substituent in position 1 of thiosemicarbazide derivatives significantly determines their activity. Generally, among the substituents used, trifluoromethylphenyl turned out to be the most promising. The MIC values for compounds with this substituent are 64 µg/mL towards Staphylococci sp. Using molecular docking, we tried to explain the mechanism behind the antibacterial activity of the tested compounds.

In 2020, breast cancer became the most frequently diagnosed type of cancer, with nearly 2.3 million new cases diagnosed. However, with early diagnosis and proper treatment, breast cancer has a good prognosis. Here, we investigated the effect of thiosemicarbazide derivatives, previously identified as dual inhibitors targeting topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1), on two distinct types of breast cancer cells (MCF-7 and MDA-MB-231). The investigated compounds ( 1 - 3 ) selectively suppressed the growth of breast cancer cells and promoted apoptosis via caspase-8- and caspase-9-related pathways. Moreover, these compounds caused S-phase cell cycle arrest and dose-dependently inhibited the activity of ATP-binding cassette transporters (MDR1, MRP1/2 and BCRP) in MCF-7 and MDA-MB-231 cells. Additionally, following incubation with compound 1, an increased number of autophagic cells within both types of the investigated breast cancer cells was observed. During preliminary testing of ADME-Tox properties, the possible hemolytic activities of compounds 1 - 3 and their effects on specific cytochrome P450 enzymes were evaluated.

A novel biologically active thiosemicarbazide derivative ligand L ( N-[(phenylcarbamothioyl)amino]pyridine-3-carboxamide ) and a series of its five metal(II) complexes, namely: [Co(L)Cl 2 ], [Ni(L)Cl 2 (H 2 O)], [Cu(L)Cl 2 (H 2 O)], [Zn(L)Cl 2 ] and [Cd(L)Cl 2 (H 2 O)] have been synthesized and thoroughly investigated. The physicochemical characterization of the newly obtained compounds has been performed using appropriate analytical techniques, such as 1 H and l3 C nuclear magnetic resonance (NMR), inductively coupled plasma (ICP), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR) and magnetic measurements. In order to study the pharmacokinetic profile of the compounds, ADMET analysis was performed. The in vitro studies revealed that the synthesized compounds exhibit potent biological activity against A549 human cancer cell line.

Approximately one-third of the human population is infected with the intracellular cosmopolitan protozoan Toxoplasma gondii ( Tg ), and a specific treatment for this parasite is still needed. Additionally, the increasing resistance of Tg to drugs has become a challenge for numerous research centers. The high selectivity of a compound toward the protozoan, along with low cytotoxicity toward the host cells, form the basis for further research, which aims at determining the molecular targets of the active compounds. Thiosemicarbazide derivatives are biologically active organic compounds. Previous studies on the initial preselection of 58 new 4-arylthiosemicarbazide derivatives in terms of their anti- Tg activity and selectivity made it possible to select two promising derivatives for further research. One of the important amino acids involved in the proliferation of Tg and the formation of parasitophorous vacuoles is tyrosine, which is converted by two unique aromatic amino acid hydroxylases to levodopa. Enzymatic studies with two derivatives (R: para -nitro and meta -iodo) and recombinant aromatic amino acid hydroxylase (AAHs) obtained in the E. coli expression system were performed, and the results indicated that toxoplasmic AAHs are a molecular target for 4-arylthiosemicarbazide derivatives. Moreover, the drug affinity responsive target stability assay also confirmed that the selected compounds bind to AAHs. Additionally, the anti-inflammatory activity of these derivatives was tested using THP1-Blue™ NF-κB reporter cells due to the similarity of the thiosemicarbazide scaffold to thiosemicarbazone, both of which are known NF-κB pathway inhibitors.

Nur77 is an orphan nuclear receptor that participates in the occurrence and development of a variety of tumors. Many agonists of Nur77 have been reported to have significant anticancer effects. Our previous studies have found that the introduction of bicyclic aromatic rings, such as naphthalyl and quinoline groups, into the N '-methylene position of indoles' Nur77 modulators can effectively improve the anti-tumor activity of the target compounds. Following our previous studies, a series of novel 1-(2-(6-methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-substituted semicarbazide/thiosemicarbazide derivatives 9a - 9w were designed and synthesized in four steps from 6-methoxy-2-acetonaphthone and N -dimethylformamide dimethylacetal. All compounds were characterized by 1 H-NMR, 13 C-NMR and HRMS, and their anti-tumor activity on various cancer cell lines such as A549, HepG2, HGC-27, MCF-7 and HeLa are also evaluated. From the series of compounds, 9h exhibited the most potent anti-proliferative activity against several cancer cells. Colony formation and cell cycle experiments showed that compound 9h inhibited cell growth and arrested the cell cycle. Additionally, 9h leads to the cleavage of PARP. We initially explored the mechanism of 9h -induced apoptosis and found that compound 9h can upregulate Nur77 expression and triggered Nur77 nuclear export, indicating the occurrence of Nur77-mediated apoptosis. These results suggested that 9h may be a promising anti-tumor leading compound for the further research.

Mycobacterium tuberculosis ( Mtb ) is an intracellular pathogenic bacterium and the causative agent of tuberculosis. This disease is one of the most ancient and deadliest bacterial infections, as it poses major health, social and economic challenges at a global level, primarily in low- and middle-income countries. The lack of an effective vaccine, the long and expensive drug therapy, and the rapid spread of drug-resistant strains of Mtb have led to the re-emergence of tuberculosis as a global pandemic. Here, we assessed the in vitro activity of new imidazole-thiosemicarbazide derivatives (ITDs) against Mtb infection and their effects on mycobacterial biofilm formation. Cytotoxicity studies of the new compounds in cell lines and human monocyte-derived macrophages (MDMs) were performed. The anti- Mtb activity of ITDs was evaluated by determining minimal inhibitory concentrations of resazurin, time-kill curves, bacterial intracellular growth and the effect on biofilm formation. Mutation frequency and whole-genome sequencing of mutants that were resistant to ITDs were performed. The antimycobacterial potential of ITDs with the ability to penetrate Mtb -infected human macrophages and significantly inhibit the intracellular growth of tubercle bacilli and suppress Mtb biofilm formation was observed.

We report herein anti-proliferation effects of 4-arylthiosemicarbazides, with a cyclopentane substitution at N 1 position, on highly virulent RH strain of Toxoplasma gondii . Among them, the highest in vitro anti- Toxoplasma activity was found with the meta -iodo derivative. Further experiments demonstrated inhibitory effects of thiosemicarbazides on tyrosinase (Tyr) activity, and good correlation was found between percentage of Tyr inhibition and IC 50 Tg . To confirm the concept that thiosemicarbazides are able to disrupt tyrosine metabolism in Toxoplasma tachyzoites, the most potent Tyr inhibitors were tested for their efficacy of T. gondii growth inhibition. All of them significantly reduced the number of tachyzoites in the parasitophorous vacuoles (PVs) compared to untreated cells, as well as inhibited tachyzoites growth by impeding cell division. Collectively, these results indicate that compounds with the thiosemicarbazide scaffold are able to disrupt tyrosine metabolism in Toxoplasma tachyzoites by deregulation of their crucial enzyme tyrosine hydroxylase (TyrH).

Original results are presented in the field of research that addresses the extension of the reaction of residue of acyl-thiosemicarbazide fixation on the structure of 5-nitrobenzimidazole by a sulphonic group. The aim of the study is the increase of new thiosemicarbazide derivatives' applicative potential in the field of biochemistry, with a wide range of medical applications. The newly obtained compounds were characterized by using elemental analysis and spectral analysis (FT-IR and 1 H NMR). A study regarding the optimization of the chemical reactions was made. The performed in vitro biological tests confirmed the tuberculostatic activity of three newly obtained compounds against Mycobacterium tuberculosis .

A series of aryl phenoxy methyl triazole conjugated with thiosemicarbazides were designed, synthesized, and evaluated for their tyrosinase inhibitory activities in the presence of l-dopa and l-tyrosine as substrates. All the compounds showed tyrosinase inhibition in the sub-micromolar concentration. Among the derivatives, compound 9j bearing benzyl displayed exceptionally high potency against tyrosinase with IC 50 value of 0.11 μM and 0.17 μM in the presence of l-tyrosine and l-dopa as substrates which is significantly lower than that of kojic acid as the positive control with an IC 50 value of 9.28 μM for l-tyrosine and 9.30 μM for l-dopa. According to Lineweaver-Burk plot, 9j demonstrated an uncompetitive type of inhibition in the kinetic assay. Also, in vitro antioxidant activities determined by DPPH assay recorded an IC 50 value of 68.43 μM for 9i. The melanin content of 9j was determined on B16F10 melanoma human cells which demonstrated a significant reduction of the melanin content. Moreover, the binding energies corresponding to the same ligand as well as computer-aided drug-likeness and pharmacokinetic studies were also carried out. Compound 9j also possessed metal chelation potential correlated to its high anti-TYR activity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Compounds targeting bacterial topoisomerases are of interest for the development of antibacterial agents. Our previous studies culminated in the synthesis and characterization of small-molecular weight thiosemicarbazides as the initial prototypes of a novel class of gyrase and topoisomerase IV inhibitors. To expand these findings with further details on the mode of action of the most potent compounds, enzymatic studies combined with a molecular docking approach were carried out, the results of which are presented herein. The biochemical assay for 1-(indol-2-oyl)-4-(4-nitrophenyl) thiosemicarbazide ( 4 ) and 4-benzoyl-1-(indol-2-oyl) thiosemicarbazide ( 7 ), showing strong inhibitory activity against Staphylococcus aureus topoisomerase IV, confirmed that these compounds reduce the ability of the ParE subunit to hydrolyze ATP rather than act by stabilizing the cleavage complex. Compound 7 showed better antibacterial activity than compound 4 against clinical strains of S. aureus and representatives of the Mycobacterium genus. In vivo studies using time-lapse microfluidic microscopy, which allowed for the monitoring of fluorescently labelled replisomes, revealed that compound 7 caused an extension of the replication process duration in Mycobacterium smegmatis , as well as the growth arrest of bacterial cells. Despite some similarities to the mechanism of action of novobiocin, these compounds show additional, unique properties, and can thus be considered a novel group of inhibitors of the ATPase activity of bacterial type IIA topoisomerases.

A total of fourteen pyrazoline derivatives were synthesized through cyclo-condensation reactions by chalcone derivatives with different types of semicarbazide. These compounds were characterized by IR, 1D-NMR ( 1 H, 13 C and Distortionless Enhancement by Polarization Transfer - DEPT-135) and 2D-NMR (COSY, HSQC and HMBC) as well as mass spectroscopy analysis (HRMS). The synthesized compounds were tested for their antituberculosis activity against Mycobacterium tuberculosis H37Ra in vitro. Based on this activity, compound 4a showed the most potent inhibitory activity, with a minimum inhibitory concentration (MIC) value of 17 μM. In addition, six other synthesized compounds, 5a and 5c-5g , exhibited moderate activity, with MIC ranges between 60 μM to 140 μM. Compound 4a showed good bactericidal activity with a minimum bactericidal concentration (MBC) value of 34 μM against Mycobacterium tuberculosis H37Ra. Molecular docking studies for compound 4a on alpha-sterol demethylase was done to understand and explore ligand-receptor interactions, and to hypothesize potential refinements for the compound.

Vulvovaginal candidiasis is a serious health problem affecting numerous women around the world. Its treatment is based on antifungals which may not provide an effective cure because of the resistance presented by its etiological pathogens Candida spp. Candida albicans is the most prevalent species related to vulvovaginal candidiasis. Here, we evaluated the in vivo antifungal potential of thiosemicarbazide and thiosemicarbazide encapsulated within chitosan nanoparticles in a murine model of vulvovaginal candidiasis. The results demonstrated the antifungal capacity of free or nanoencapsulated thiosemicarbazide within chitosan to reduce the fungal load in the vaginal tissue of infected mice. In addition, histological analyses indicated the absence or a mild to moderate infection in thiosemicarbazide-treated groups. Statistical tests confirmed the existence of significant differences between the treated and the control groups. Therefore, our results suggest a potential application of thiosemicarbazide and encapsulated thiosemicarbazide as an alternative vulvovaginal candidiasis therapy.

Background: Identification of novel Ure inhibitors with high potency has received considerable attention. Methodology & results: Ure inhibition was determined using the indophenol method, the affinities to Ure were estimated via surface plasmon resonance. Seventeen new plus ten known N -monosubstituted thiosemicarbazides were synthesized and identified as novel Ure inhibitors. Out of these compounds, compound b5 shows excellent activity against both crude Ure from Helicobacter pylori (IC 50  = 0.04 μM) and Ure in living cell (IC 50  = 0.27 μM), with the potency being over 600-fold higher than clinical used drug acetohyroxamic acid, respectively. Surface plasmon resonance demonstrated the high affinity ( K d .#x00A0;= 6.32 nM) of b5 to Ure. Conclusion: This work provides a class of novel and promising Ure inhibitors.

Parasitic infections caused by different species of intestinal helminths still poses a threat to public health. There is a need to search for new, effective anthelmintic drugs. A series of novel thiosemicarbazides were synthesized and evaluated for their in vitro anthelmintic activity. The preliminary results showed that the most of synthesized compounds were very active. 4-Phenyl-1-[(1-methyl-4-nitroimidazol-2-yl)carbonyl]thiosemicarbazide and 4-(3-chlorophenyl)-1-[(1-methyl-4-nitroimidazol-2-yl)carbonyl]thiosemicarbazide showed a 100% mortality of nematodes and a high anthelmintic activity in both tested concentrations.

Antimicrobial resistance spurred by the overuse and misuse of antibiotics is a major global health concern, and of the Gram positive bacteria, S. aureus is a leading cause of mortality and morbidity. Alternative strategies to treat S. aureus infections, such as combination therapy, are urgently needed. In this study, a checkerboard method was used to evaluate synergistic interactions between nine thiosemicarbazides (4-benzoyl-1-(2,3-dichloro-benzoyl)thiosemicarbazides 1 - 5 and 4-aryl-1-(2-fluorobenzoyl)thiosemicarbazides 6 - 9 ) and conventional antibiotics against S. aureus ATCC 25923, which were determined as the fractional inhibitory concentration indices (FICIs). For these experiments, amoxicillin, gentamicin, levofloxacin, linezolid, and vancomycin were selected to represent the five antimicrobial classes most commonly used in clinical practice. With one exception of 7 -vancomycin combination, none of the forty-five thiosemicarbazide-antibiotic combinations tested had an antagonistic effect, showing promising results with respect to a combination therapy. The synergic effect was observed for the 2 -linezolid, 4 -levofloxacin, 5 -linezolid, 6 -gentamicin, 6 -linezolid, and 7 -levofloxacin combinations. No interactions were seen in combination of the thiosemicarbazide with gentamicin or vancomycin, whereas all combinations with linezolid acted in additive or synergism, except for 6 -gentamicin and 7 -linezolid. The 4-(4-chlorophenyl)-1-(2-fluorobenzoyl)thiosemicarbazide 6 showed a clear preference for the potency; it affected synergistically in combinations with gentamicin or linezolid and additively in combinations with amoxicillin, levofloxacin, or vancomycin. In further studies, the inhibitory potency of the thiosemicarbazides against S. aureus DNA gyrase and topoisomerase IV was examined to clarify the molecular mechanism involved in their synergistic effect in combination with levofloxacin. The most potent synergist 6 at concentration of 100 µM was able to inhibit ~50% activity of S. aureus DNA gyrase, thereby suggesting that its anti-gyrase activity, although weak, may be a possible factor contributing to its synergism effect in combination with linezolid or gentamycin.

hiosemicarbazide is a useful structural moiety that has the biological potential. Optimization of this structure can result in groundbreaking discovery of a new class of therapeutic agents. In the light of this, 1-(2,4-dichlorophenoxy)acetyl-4-(1-naphthyl)thiosemicarbazide ( 1 ) and 1,4-bis[(2,4-dichlorophenoxy)acetylthiosemicarbazide]phenyl ( 2 ) were synthesized and characterized by spectroscopic method. Cytotoxicity of obtained compounds was evaluated on MKN74 gastric cancer cell line and human skin fibroblast BJ based on methylthiazolyldiphenyl-tetrazolium bromide (MTT) test. The apoptosis/necrosis and cell cycle analysis were conducted using image cytometry. Additionally, in DNA of treated cells, abasic sites (AP) and double strands breaks (DSB) presence were measured. Intercalating properties of active compounds were evaluated using the UV-spectroscopic method. Among newly synthesized derivatives, compound 2 showed toxic effects on gastric cancer cells with simultaneous lack of toxicity to normal fibroblasts. Cell cycle analysis revealed that both compounds influence cell division mainly at the stage of replication. Simultaneously with DNA synthesis disorders, DNA damages like AP-sites and DSBs were observed. Spectroscopic studies revealed possible DNA intercalating properties of tested compounds. Obtained results indicate that the newly synthesized thiosemicarbazide derivatives are a promising group of compounds with potential anticancer activity resulted from interactions with DNA and cell cycle interrupt., Competing Interests: References

Tyrosinase plays important roles in many different disease related processes, and the development of its inhibitors is particularly important in biotechnology. In this study, thirty-nine 3-/4-alkoxyphenylethylidenethiosemicarbazides were synthesized as novel tyrosinase inhibitors based on structure-based molecular design. Our experimental results demonstrated that thirty-one of them possess remarkable tyrosinase inhibitory activities with IC 50 value below 1 µM, and 5a, 6e, 6g and 6t did not display any toxicity to 293T cell line at the concentration of 1000 µmol/L. According to the inhibitory activities, several compounds were selected for detail investigation on the structure-activity relationships (SARs), mechanisms of enzyme inhibition, inhibitory kinetics and cytotoxicity. In particular, the interaction between the selected inhibitors and the active center of tyrosinase was considered and discussed in detail based on their structural characteristics. Taken together, the results presented here demonstrated that the newly designed compounds are promising candidates for the treatment of tyrosinase-related disorders and further development of them may have significant contribution in biomedical science.

The reaction of 4-(adamantan-1-yl)-3-thiosemicarbazide 3 with various aromatic aldehydes yielded the corresponding thiosemicarbazones 4a-g . 1-Adamantyl isothiocyanate 2 was reacted with 1-methylpiperazine or piperidine to yield the corresponding N -(adamantan-1-yl)carbothioamides 5 and 6 , respectively. The latter was reacted with benzyl or substituted benzyl bromides to yield the S -arylmethyl derivatives 7a-c . Attempted cyclization of 1,3-bis(adamantan-1-yl)thiourea 8 with chloroacetic acid via prolonged heating to the corresponding thiazolidin-4-one 9 resulted in desulfurization of 8 to yield its urea analogue 10 . The thiazolidin-4-one 9 and its 5-arylidene derivatives 11a,b were obtained via microwave-assisted synthesis. The in vitro antimicrobial activity of the synthesized compounds was evaluated against a panel of Gram-positive and Gram-negative bacteria and yeast-like pathogenic fungus Candida albicans . Compounds 7a-c displayed marked broad spectrum antibacterial activities (minimal inhibitory concentration (MIC), 0.5-32 μg/mL) and compounds 4a and 4g showed good activity against Candida albicans . Nine representative compounds were evaluated for anti-proliferative activity towards three human tumor cell lines. Compounds 7a-c displayed significant generalized anti-proliferative activity against all the tested cell lines with IC 50 < 10 μM.

Background: Acridine and thiourea derivatives are important compounds in medicinal chemistry due to their diverse biological properties including anticancer and antimicrobial effects. However, literature reveals some side effects associated with use of acridines. It is suggested that hybrid molecules may reduce the side effects and enhance the beneficial properties due to synergistic activity. The objectives of the present study are to synthesize and evaluate the anticancer and antimicrobial properties of new hybrids of acridine thiosemicarbazides derivatives. Results: The structures of the synthesized compounds 4a-4e were elucidated by MS and NMR spectra. In antimicrobial assay, Compound 4c exhibited potent antimicrobial activity compared to the other four compounds. In anticancer studies, we observed that compounds 4a , 4b , 4d and 4e exhibited high cytotoxicity against the MT-4 cell line, with IC50 values of 18.42 ± 1.18, 15.73 ± 0.90, 10.96 ± 0.62 and 11.63 ± 0.11 μM, respectively. The evaluation of anticancer effects, and the associated mechanism reveals that, the anticancer activities may be related to Topo I inhibitory activity, apoptosis and cell-cycle. Molecular docking studies revealed that the presence of planar naphtho-fused rings and a flexible thiourea group together, could improve DNA-intercalation and inhibition of DNA-Topo I activity. Conclusions: The results of this study demonstrate that the rational design of target derivatives as novel antimicrobial or antitumor leads is feasible.

The aim of this study was to investigate the antiepileptic effects of duloxetine in the maximal electroshock test and convulsions induced by four compounds: Pentylenetetrazole, 3-mercaptopropionic acid, thiosemicarbazide, and bicuculline. Duloxetine exhibited moderate anticonvulsive activity with an ED 50 (median effective dose) of 48.21 mg/kg in the maximal electroshock test in mice. The anticonvulsive action of duloxetine was also confirmed in chemical-induced seizure tests, where this drug decreased tonic convulsions. Single administration of duloxetine (6.25-25 mg/kg) significantly increased the anticonvulsant effects of valproate, carbamazepine, and oxcarbazepine in the maximal electroshock test. Furthermore, pretreatment with thiosemicarbazide (an inhibitor of GABA synthesis enzyme) significantly increased the ED 50 of duloxetine, suggesting the GABAergic system may contribute to the anticonvulsive action of duloxetine. These results support the use of duloxetine in the treatment of coexisting depression and epilepsy.

One of the key stages in the development of new therapies in the treatment of toxoplasmosis is the identification of new non-toxic small molecules with high specificity to Toxoplasma gondii . In the search for such structures, thiosemicarbazide-based compounds have emerged as a novel and promising leads. Here, a series of imidazole-thiosemicarbazides with suitable properties for CNS penetration was evaluated to determine the structural requirements needed for potent anti- Toxoplasma gondii activity. The best 4-arylthiosemicarbazides 3 and 4 showed much higher potency when compared to sulfadiazine at concentrations that are non-toxic to the host cells, indicating a high selectivity of their anti-toxoplasma activity.

A series of thiosemicarbazide derivatives was designed and synthesized by reaction of carboxylic acid hydrazide with isothiocyanates. The molecular structures of the investigated thiosemicarbazides were confirmed and characterized by spectroscopic analysis. The conformational preference of carbonylthiosemicarbazide chain and intra- and intermolecular interactions in the crystalline state were characterized using X-ray analysis. The antituberculosis activity of the target compounds were tested in vitro against four Mycobacterium strains: M. H37Ra, M. phlei , M. smegmatis , M. timereck . The most active compounds were those with 2-pyridine ring. They exhibited lower minimal inhibitory concentration (MIC) values in the range 7.81⁻31.25 μg/mL in comparison to the other isomers. Compound 5 had activity against M. smegmatis at a concentration of 7.81 μg/mL whereas compound 2 had activity against all tested strains at a concentration of 15.625 μg/mL. The molecular docking studies were performed for investigated compounds using the Mycobacterium tuberculosis glutamine synthetase MtGS as their molecular target.

Aim: To perform the proteomic profile of Paracoccidioides lutzii after treatment with the compound camphene thiosemicarbazide (TSC-C) in order to study its mode of action., Methods: Proteomic analysis was carried out after cells were incubated with TSC-C in a subinhibitory concentration. Validation of the proteomic results comprised the azocasein assay, western blot and determination of the susceptibility of a mutant to the compound., Results: Proteins related to metabolism, energy and protein fate were regulated after treatment. In addition, TSC-C reduces the proteolytic activity of the protein extract similarly to different types of protease inhibitors., Conclusion: TSC-C showed encouraging antifungal activity, working as a protease inhibitor and downregulating important pathways impairing the ability of the fungi cells to produce important precursors.

A series of 1-[(4'-chlorophenyl)carbonyl-4-(aryl)thiosemicarbazide derivatives 1-25 was synthesized and characterized by spectroscopic techniques such as EI-MS and 1 H NMR. All compounds were screened for urease inhibitory activity in vitro and demonstrated excellent inhibitory activity in the range of IC 50  = 0.32 ± 0.01-25.13 ± 0.13 μM as compared to the standard thiourea (IC 50  = 21.25 ± 0.13 μM). Amongst the potent analogs, compounds 3 (IC 50  = 2.31 ± 0.01 μM), 6 (IC 50  = 2.14 ± 0.04 μM), 10 (IC 50  = 1.14 ± 0.06 μM), 20 (IC 50  = 2.15 ± 0.05 μM), and 25 (IC 50  = 0.32 ± 0.01 μM) are many folds more active than the standard. Structure-activity relationship (SAR) was rationalized by looking at the effect of diversely substituted aryl ring on inhibitory potential which predicted that regardless of the nature of substituents, their positions on aryl ring is worth important for the potent activity. Furthermore, to verify these interpretations, in silico study was performed on all compounds and a good correlation was perceived between the biological evaluation and docking study of compounds., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Paracoccidioidomycosis (PCM) is a neglected human systemic disease caused by species of the genus Paracoccidioides. The disease attacks the host's lungs and may disseminate to many other organs. Treatment involves amphotericin B, sulfadiazine, trimethoprim-sulfamethoxazole, itraconazole, ketoconazole, or fluconazole. The treatment duration is usually long, from 6 months to 2 years, and many adverse effects may occur in relation to the treatment; co-morbidities and poor treatment adherence have been noted. Therefore, the discovery of more effective and less toxic drugs is needed. Thiosemicarbazide (TSC) and a camphene derivative of thiosemicarbazide (TSC-C) were able to inhibit P. brasiliensis growth at a low dosage and were not toxic to fibroblast cells. In order to investigate the mode of action of those compounds, we used a chemoproteomic approach to determine which fungal proteins were bound to each of these compounds. The compounds were able to inhibit the activities of the enzyme formamidase and interfered in P. brasiliensis dimorphism. In comparison with the transcriptomic and proteomic data previously obtained by our group, we determined that TSC and TSC-C were multitarget compounds that exerted effects on the electron-transport chain and cell cycle regulation, increased ROS formation, inhibited proteasomes and peptidases, modulated glycolysis, lipid, protein and carbohydrate metabolisms, and caused suppressed the mycelium to yeast transition., Competing Interests: The authors have declared that no competing interests exist.

In order to discover novel eco-friendly lead compounds for plant pathogenic fungi control, a series of benzaldehyde thiosemicarbazide derivatives with a piperidine moiety have been designed and synthesized. Fungicidal activities of all the synthesized compounds were evaluated in vitro. The results indicated that all the title compounds exhibited moderate to good fungicidal activities. Compound 3b displayed excellent activities against Pythium aphanidermatum , Rhizoctonia solani , Valsa mali , and Gaeu-mannomyces graminsis , with EC 50 values lower than 10 μg/mL. Especially, in the case of Pythium aphanidermatum , its activity (EC 50 = 1.6 μg/mL) is superior to the commercial azoxystrobin (EC 50 = 16.9 μg/mL) and close to fluopicolide (EC 50 = 1.0 μg/mL). Initial structure-activity relationship (SAR) analysis showed that the heterocyclic piperidine group can influence the biological activities of the title compounds significantly. The fungicidal activity of compounds with piperidine is better than that of compounds without piperidine. The highly-active compound 3b , with its simple structure and easy synthetic route, is worthy to be further studied as a new lead fungicide., Competing Interests: The authors declare no conflict of interest.

Advanced glycation endproducts (AGEs) can promote intracellular reactive oxygen species production, and the levels of AGEs are highly correlated with cardiovascular disease and diabetes complications. Acetohydroxamic acid (acetH) is a bacterial urease inhibitor drug used to treat kidney stones and infections in the urinary tract, and hydroxyurea (HU) is a drug used for antineoplasm and sickle cell diseases. Both acetH and HU are hydroxamic acid derivatives. It was found that acetH and HU at 2.5 or 5 mM showed anti-AGE formation by lowering the AGEs' fluorescent intensities and N ε -(carboxymethyl)lysine formation in bovine serum albumin/galactose models, and both showed better and significant differences ( P <0.05) compared to the positive control of aminoguanidine. Regarding radical scavenging activities, the half-inhibition concentrations (IC 50 ) of acetH against α,α-diphenyl-β-picrylhydrazyl radical and hydroxyl radical were 34.86 and 104.42 μM, respectively. The IC 50 of acetH against semicarbazide-sensitive amine oxidase was 10.56 μM, and acetH showed noncompetitive inhibition respective to the substrates (benzylamine). The antiglycation, antioxidant, and semicarbazide-sensitive amine oxidase inhibitory activities of acetH prove that it has the potential for treating cardiovascular disease and diabetes complications and it needs further investigation in animal models., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The high potential of quinoline containing natural products and their derivatives in medicinal chemistry led us to discover a novel series of compounds 6-23 based on the concept of molecular hybridization. Most of the synthesized analogues exhibited potent leishmanicidal potential. The most potent compound (23, IC 50 =0.10±0.001μM) among the series was found ∼70 times more lethal than the standard drug. The current series 6-23 conceded in the development of fourteen (14) extraordinarily active compounds against leishmaniasis. In silico analysis were also performed to probe the mode of action while all the compounds structure were established by NMR and Mass spectral analysis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The antifungal and antiaflatoxigenic effects of two series of coumarinyl thiosemicarbazides on Aspergillus flavus NRRL 3251 were studied. Fungi were grown in YES medium for 72 h at 29 °C in the presence of 0, 0.1, 1, and 10 μg mL-1 of coumarinyl thiosemicarbazides: one series with substitution in position 7 and another with substitution in position 4 of the coumarin core. Dry mycelia weight determination was used for antifungal activity estimation, while the aflatoxin B1 content in YES media, determined by the dilute and shoot LC-MS/MS technique, was used for the antiaflatoxigenic effect estimation. Standard biochemical assays were used for oxidative status marker (TBARS, SOD, CAT, and GPX) determination in A. flavus NRRL 3251 mycelia. Results show that 7-substituted-coumarinyl thiosemicarbazides possess a better antifungal and antiaflatoxigenic activity than 4-substituted ones. The most prominent substituted compound was the compound 3, N-(4-chlorophenyl)-2-(2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetyl)hydrazine-1-carbothioamide, which completely inhibited aflatoxin production at the concentration of 10 μg mL-1. Oxidative stress response of A. flavus exposed to the selected compounds points to the modulation of oxidative stress as a possible reason of aflatoxin production inhibition.

Insulin secretagogues are used for treatment of type 2 diabetes. We attempted to discover novel small molecules to stimulate insulin secretion by using in silico similarity search using sulfonylureas as query, followed by measurement of insulin secretion. Among 38 compounds selected by in silico similarity search, we found three diphenylsemicarbazides and one quinolone that stimulate insulin secretion. We focused on compound 8 (C8), which had the strongest insulin-secreting effect. Based on the structure-activity relationship of C8-derivatives, we identified diphenylthiosemicarbazide (DSC) 108 as the most potent secretagogue. DSC108 increased the intracellular Ca2+ level in MIN6-K8 cells. Competitive inhibition experiment and electrophysiological analysis revealed sulfonylurea receptor 1 (SUR1) to be the target of DSC108 and that this diphenylthiosemicarbazide directly inhibits ATP-sensitive K+ (KATP) channels. Pharmacokinetic analysis showed that DSC108 has a short half-life in vivo. Oral administration of DSC108 significantly suppressed the rises in blood glucose levels after glucose load in wild-type mice and improved glucose tolerance in the Goto-Kakizaki (GK) rat, a model of type 2 diabetes with impaired insulin secretion. Our data indicate that DSC108 is a novel insulin secretagogue, and is a lead compound for development of a new anti-diabetic agent., Competing Interests: The authors have declared that no competing interests exist.

Hybrid bisindole-thiosemicarbazides analogs (1-18) were synthesized and screened for β-glucuronidase activity. All compounds showed varied degree of β-glucuronidase inhibitory potential when compared with standard d-saccharic acid 1,4-lactone (IC50=48.4±1.25μM). Compounds 4, 7, 9, 6, 5, 12, 17 and 18 showed exceptional β-glucuronidase inhibition with IC50 values ranging from 0.1 to 5.7μM. Compounds 1, 3, 8, 16, 13, 2 and 14 also showed better activities than standard with IC50 values ranging from 7.12 to 15.0μM. The remaining compounds 10, 11, and 15 showed good inhibitory potential with IC50 values 33.2±0.75, 21.4±0.30 and 28.12±0.25μM respectively. Molecular docking studies were carried out to confirm the binding interaction of the compounds., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Bacterial multidrug resistance (MDR) constitutes a major hurdle in the treatment of infectious diseases worldwide. The present study was designed to evaluate the antibacterial activities of synthetic p-toluenesulfonyl-hydrazinothiazoles against multidrug resistant Gram-negative bacteria., Methods: The broth microdilution method was used to determine the minimal inhibitory concentrations (MIC)., Results: The results demonstrated that the best activities were obtained with hydrazinoselenazoles. p-Chloro-benzyliden-selenosemicarbazide, 4-methyl-2-[(4-chloro-benzyliden)-hydrazinyl]-1,3-selenazole, p-chloro-benzoyl-selenosemicarbazide and 4-chloromethyl-2-[(4-chlorobenziliden)-N-acetyl-hydrazinyl]-1,3-selenazole were more active than the choramphenicol on Klebsiella pneumoniae KP63. Tested alone, the lowest MIC value of 16 mg/L was obtained with p-methoxy-benzyliden-selenosemicarbazide against Enterobacter aerogenes ATCC13048, K. pneumoniae ATCC112296 and KP55. Tested in the presence of an efflux pump inhibitor, phenylalanine arginine β-naphthylamide (PAβN), the activity of p-chloro-benzyliden-selenosemicarbazide, 4-methyl-2-[(4-chloro-benzyliden)-hydrazinyl]-1,3-selenazole, p-chloro-benzoyl-selenosemicarbazide and p-methoxy-benzyliden-selenosemicarbazide significantly increased with MIC values below 10 mg/L obtained respectively on 43.8 %, 31.3 %, 62.5 % and 100 % of the 16 tested bacterial strains. The lowest MIC value of 0.5 mg/L in the presence of PAβN was recorded with p-chloro-benzoyl-selenosemicarbazide against Escherichia coli ATCC8739 and KP55 as well as p-methoxy-benzyliden-selenosemicarbazide against E. aerogenes KP55. p-Chloro-benzyliden-selenosemicarbazide and p-chloro-benzoyl-selenosemicarbazide contained the same pharmacophore as p-methoxy-benzyliden-selenosemicarbazide., Conclusion: This study indicates that p-chloro-benzyliden-selenosemicarbazide, p-chloro-benzoyl-selenosemicarbazide and p-methoxy-benzyliden-selenosemicarbazide could be explored more to develop novel antimicrobial drugs to fight MDR bacterial infections.

Aim: To study the micronutrients that potentiate the action of anticonvulsant drugs, and in particular, of myo-inositol (vitamin B8)., Material and Methods: An experimental study of neurotrophic and anticonvulsant effects of a preparation based on myo-inositol (inofert) on thiosemicarbazide models of seizures was carried out., Results: Inofert significantly increased the latent time before the first convulsive seizure, reduced the severity of seizures (p<0.05) and reduced mortality in the models of thiosemicarbazide seizures. Myo-inositol enhanced anticonvulsant action of gabapentin and sodium valproate; neuroprotective effect of myo-inositol was also confirmed., Conclusion: The Inofert preparation, containing myo-inositol and folic acid, modulates the effects of drugs with both convulsive and anticonvulsive action, reduces the severity and duration of seizures caused by thiosemicarbazide and increases the survival rate of animals.

Lipophilicity, as one of the most important physicochemical parameters of bioactive molecules, was investigated for twenty-two thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azoles. The determination was carried out by reversed-phase thin-layer chromatography, using a binary isopropanol-water mobile phase. Chromatographically obtained lipophilicity parameters were correlated with calculated log P and log D and with some biological parameters, determined in order to evaluate the anti-inflammatory and antioxidant potential of the investigated compounds, by using principal component analysis (PCA). The PCA grouped the compounds based on the nature of their substituents (X, R and Y), indicating that their nature, electronic effects and molar volumes influence the lipophilicity parameters and their anti-inflammatory and antioxidant effects. Also, the results of the PCA analysis applied on all the experimental and computed parameters show that the best anti-inflammatory and antioxidant compounds were correlated with medium values of the lipophilicity parameters. On the other hand, the knowledge of the grouping patterns of the tested variables allows the reduction of the number of parameters, determined in order to establish the biological activity.

Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme known for its dual function in mediating inflammation and reactive oxygen species production. However, the role of SSAO inhibitors in limiting kidney fibrosis is unclear. We aimed to determine the effectiveness of a SSAO inhibitor (SSAOi; PXS4728A) as an antifibrotic agent using a 7-day unilateral ureteric obstruction (UUO) model of acute kidney fibrosis in 6- to 8-wk-old mice. The experimental groups were 1) Sham operated; 2) UUO; 3) UUO+SSAOi (2 mg/kg); 4) UUO+telmisartan, an angiotensin receptor blocker (3 mg/kg); and 5) UUO+SSAOi+telmisartan. Kidney tissue was analyzed for histological evidence of tubulointerstitial fibrosis, nitrotyrosine staining, and mRNA expression of markers associated with fibrosis and inflammation. Kidney SSAO activity was determined by radiometric [(14)C]benzylamine methodology. Our results show that SSAOi effectively suppresses UUO-mediated SSAO activity. Extracellular matrix markers, namely, fibronectin, collagen IV protein, and nitrotyrosine staining, were lower in UUO+SSAOi mice compared with untreated UUO mice. This was consistent with the attenuated mRNA expression of collagen IV and fibronectin. SSAOi effectively inhibited transforming growth factor-β1 (TGF-β1) and monocyte chemoattractant protein-1 (MCP-1) expression to a similar extent to that observed with telmisartan. Individually, SSAOi and telmisartan induced a reduction in interstitial leukocyte and macrophage accumulation. However, the combination of SSAOi and telmisartan was more effective at reducing inflammatory cell infiltration. These results demonstrate that SSAO inhibition significantly suppresses profibrotic and proinflammatory cytokine secretion, reduces oxidative stress, and limits inflammatory cell accumulation and extracellular matrix expression in an acute model of renal fibrosis., (Copyright © 2014 the American Physiological Society.)

New thiosemicarbazide derivatives 2-6 were synthesised by reacting 2-(ethylsulfanyl)benzohydrazide with various aryl isothiocyanates. The cyclisation of compounds 2-6 under reflux conditions in a basic medium (aqueous NaOH, 4 N) yielded compounds 7-11 that contain a 1,2,4-triazole ring. All of the synthesised compounds were screened for their antioxidant activities. Compounds 2, 3, and 7 showed better radical scavenging in a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, with IC50 values of 1.08, 0.22, and 0.74 µg/mL, respectively, compared to gallic acid (IC50, 1.2 µg/mL). Compound 3 also showed superior results in a ferric reducing antioxidant power (FRAP) assay (3054 µM/100 g) compared to those of ascorbic acid (1207 µM/100 g).

A series of 4-arylthiosemicarbazides substituted at the N1 position with a 5-membered heteroaryl ring was synthesized and evaluated in vitro for T. gondii inhibition proliferation and host cell cytotoxicity. At non-toxic concentrations for the host cells all studied compounds displayed excellent anti-parasitic effects when compared to sulfadiazine, indicating a high selectivity of their anti-T. gondii activity. The differences in bioactivity investigated by DFT calculations suggest that the inhibitory activity of 4-aryl-thiosemicarbazides towards T. gondii proliferation is connected with the electronic structure of the molecule. Further, these compounds were tested as potential antibacterial agents. No growth-inhibiting effect on any of the test microorganisms was observed for all the compounds, even at high concentrations.

Novel thiosemicarbazide derivatives were synthesised and evaluated for their anticonvulsant activity and neurotoxicity. Anticonvulsant activity was done for grand mal and petit mal types of epilepsies by maximal electroshock (MES) and pentylenetetrazol (PTZ) induced convulsions methods respectively. Rotarod test was done to determine neurotoxicity. Amongst synthesised compounds, N-(4-bromophenyl)2-[(2-phenylhydrazinyl) carbonothioyl] hydrazinecarbothioamide (5e) is a broad-spectrum anticonvulsant agent since it was active in both (MES) and (PTZ) induced seizure models with no neurotoxicity and N,N-(bis(chlorophenyl)hydrazine-1,2-dicarbothoamide (5g) acts as a selective agent for grand mal epilepsy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This article describes the synthesis of six 4-aryl-(thio)semicarbazides (series a and b) linked with diphenylacetyl moiety along with their pharmacological evaluation on the central nervous system in mice and computational studies, including conformational analysis and electrostatic properties. All thiosemicarbazides (series b) were found to exhibit strong antinociceptive activity in the behavioural model. Among them, compound 1-diphenylacetyl-4-(4-methylphenyl)thiosemicarbazide 1b was found to be the most potent analgesic agent, whose activity is connected with the opioid system. For compounds from series a significant anti-serotonergic effect, especially for compound 1-diphenylacetyl-4-(4-methoxyphenyl)semicarbazide 2b was observed. The computational studies strongly support the obtained results.

While applications of amine oxidases are increasing, few have been characterised and our understanding of their biological role and strategies for bacteria exploitation are limited. By altering the nitrogen source (NH4Cl, putrescine and cadaverine (diamines) and butylamine (monoamine)) and concentration, we have identified a constitutive flavin dependent oxidase (EC 1.4.3.10) within Rhodococcus opacus. The activity of this oxidase can be increased by over two orders of magnitude in the presence of aliphatic diamines. In addition, the expression of a copper dependent diamine oxidase (EC 1.4.3.22) was observed at diamine concentrations>1mM or when cells were grown with butylamine, which acts to inhibit the flavin oxidase. A Michaelis-Menten kinetic treatment of the flavin oxidase delivered a Michaelis constant (KM)=190μM and maximum rate (kcat)=21.8s(-1) for the oxidative deamination of putrescine with a lower KM (=60μM) and comparable kcat (=18.2s(-1)) for the copper oxidase. MALDI-TOF and genomic analyses have indicated a metabolic clustering of functionally related genes. From a consideration of amine oxidase specificity and sequence homology, we propose a putrescine degradation pathway within Rhodococcus that utilises oxidases in tandem with subsequent dehydrogenase and transaminase enzymes. The implications of PUT homeostasis through the action of the two oxidases are discussed with respect to stressors, evolution and application in microbe-assisted phytoremediation or bio-augmentation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The preliminary cytotoxic effect of 4-ethoxycarbonylmethyl-1-(piperidin-4-ylcarbonyl)-thiosemicarbazide hydrochloride (1)-a potent topoisomerase II inhibitor-was measured using a MTT assay. It was found that the compound decreased the number of viable cells in both estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231breast cancer cells, with IC(50) values of 146 ± 2 and 132 ± 2 μM, respectively. To clarify the molecular basis of the inhibitory action of 1, molecular docking studies were carried out. The results suggest that 1 targets the ATP binding pocket.

The in vitro antifungal potency of six series of 4-arylthiosemicarbazides was evaluated. Two isoquinoline derivatives with an ortho-methoxy or ortho-methyl group at the phenyl ring were the most potent antifungal agents. Molecular modeling studies and docking of all 4-arylthiosemicarbazides into the active sites of sterol 14α-demethylase (CYP51), topoisomerase II (topo II), L: -glutamine: D: -fructose-6-phosphate amidotransferase (GlcN-6-P), secreted aspartic proteinase (SAP), N-myristoyltransferase (NMT), and UDP-N-acetylmuramoyl-L: -alanine:D: -glutamate ligase (MurD) indicated the importance of both structural and electronic factors in ligand recognition and thus for the antifungal effectiveness of 4-arylthiosemicarbazides. A possible antifungal target was identified (NMT) and isoquinoline-thiosemicarbazides showed more favorable affinity than the native ligand.