Novel 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide based thiosemicarbazides as potent and selective inhibitors of tumor-associated human carbonic anhydrase IX and XII: Synthesis, cytotoxicity, and molecular modelling studies.

In the pursuit of discovering new selective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, a small collection of novel thiosemicarbazides (5a-5t) were designed and synthesized starting from 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide which was evaluated as a potent inhibitor of different CA isoforms in a previous study. The newly synthesized compounds were examined against four human carbonic anhydrases (hCA), namely transmembrane tumor-related hCA IX/XII and cytosolic widespread off-targets hCA I/II. In enzyme inhibition assays, all nineteen compounds display up to ∼340-fold selectivity for hCA IX/XII over off-target isoforms hCA I/II. Four compounds have enzyme inhibition values (Ki) lower than 10 nM against tumor-associated isoforms hCA IX/XII including two compounds in the subnanomolar range (5r and 5s; hCA XII; Ki: 0.69 and 0.87 nM). The potential binding interactions of the most potent compounds against hCA IX and XII, compounds 5s and 5r, respectively, were investigated using ensemble docking and molecular dynamics studies. Cell viability assays using human colorectal adenocarcinoma cell line HT-29 and healthy skin fibroblasts CCD-86Sk show that compound 5e selectively inhibits HT-29 cancer cell proliferation (IC50: 53.32 ± 7.74 µM for HT-29; IC50: 74.64 ± 14.15 µM for CCD-986Sk). Finally, Western blot assays show that compounds 5e and 5r significantly reduce the expression of hCA XII in HT-29 cells. Moreover, 5e shows better cytotoxic activity in hypoxia compared to normoxic conditions. Altogether, the newly designed compounds show stronger inhibition of the tumor-associated hCA IX and XII isoforms and several tested compounds show selective cytotoxicity as well as downregulation of hCA XII expression.

New phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamides as dual inhibitors against α-glucosidase and PTP-1B for the treatment of type 2 diabetes.

This study describes the design, synthesis, and evaluation of a novel series of phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamide derivatives (7a-l) as dual inhibitors of α-glucosidase and protein tyrosine phosphatase 1-B (PTB-1B). The latter enzymes are two important targets in the treatment of type 2 diabetes. The in vitro obtained data demonstrated that all title compounds 7a-l were more potent than the standard inhibitor acarbose against α-glucosidase while only four derivatives (7a, 7g, 7h, and 7h) were more potent than the standard inhibitor suramin against PTP-1B. Furthermore, these data showed that the most potent α-glucosidase inhibitor was compound 7i, with sixfold higher inhibitory activity than acarbose, and the most potent PTP-1B inhibitor was compound 7a with 3.5-fold higher inhibitory activity than suramin. Kinetic studies of compounds 7i and 7a revealed that they inhibited their target enzymes in a competitive mode. The docking study demonstrated that compounds 7i and 7a well occupied the active site pockets of α-glucosidase and PTP-1B, respectively. In silico pharmacokinetic and toxicity assays of the most potent compounds were performed, and the obtained results were compared with those of the standard inhibitors.

Experimental and Computational Studies on the Interaction of DNA with Hesperetin Schiff Base CuII Complexes.

The interactions with calf thymus DNA (CT-DNA) of three Schiff bases formed by the condensation of hesperetin with benzohydrazide (HHSB or L1H3), isoniazid (HIN or L2H3), or thiosemicarbazide (HTSC or L3H3) and their CuII complexes (CuHHSB, CuHIN, and CuHTSC with the general formula [CuLnH2(AcO)]) were evaluated in aqueous solution both experimentally and theoretically. UV-Vis studies indicate that the ligands and complexes exhibit hypochromism, which suggests helical ordering in the DNA helix. The intrinsic binding constants (Kb) of the Cu compounds with CT-DNA, in the range (2.3-9.2) × 106, from CuHTSC to CuHHSB, were higher than other copper-based potential drugs, suggesting that π-π stacking interaction due to the presence of the aromatic rings favors the binding. Thiazole orange (TO) assays confirmed that ligands and Cu complexes displace TO from the DNA binding site, quenching the fluorescence emission. DFT calculations allow for an assessment of the equilibrium between [Cu(LnH2)(AcO)] and [Cu(LnH2)(H2O)]+, the tautomer that binds CuII, amido (am) and not imido (im), and the coordination mode of HTSC (O-, N, S), instead of (O-, N, NH2). The docking studies indicate that the intercalative is preferred over the minor groove binding to CT-DNA with the order [Cu(L1H2am)(AcO)] > [Cu(L2H2am)(AcO)] ≈ TO ≈ L1H3 > [Cu(L3H2am)(AcO)], in line with the experimental Kb constants, obtained from the UV-Vis spectroscopy. Moreover, dockings predict that the binding strength of [Cu(L1H2am)(AcO)] is larger than [Cu(L1H2am)(H2O)]+. Overall, the results suggest that when different enantiomers, tautomers, and donor sets are possible for a metal complex, a computational approach should be recommended to predict the type and strength of binding to DNA and, in general, to macromolecules.

The Importance of Substituent Position for Antibacterial Activity in the Group of Thiosemicarbazide Derivatives.

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.

New Thiosemicarbazide Derivatives with Multidirectional Biological Action.

Over the years, several new medicinal substances have been introduced for the treatment of diseases caused by bacteria and parasites. Unfortunately, due to the production of numerous defense mechanisms by microorganisms and parasites, they still pose a serious threat to humanity around the world. Therefore, laboratories all over the world are still working on finding new, effective methods of pharmacotherapy. This research work aimed to synthesize new compounds derived from 3-trifluoromethylbenzoic acid hydrazide and to determine their biological activity. The first stage of the research was to obtain seven new compounds, including six linear compounds and one derivative of 1,2,4-triazole. The PASS software was used to estimate the potential probabilities of biological activity of the newly obtained derivatives. Next, studies were carried out to determine the nematocidal potential of the compounds with the use of nematodes of the genus Rhabditis sp. and antibacterial activity using the ACCT standard strains. To determine the lack of cytotoxicity, tests were performed on two cell lines. Additionally, an antioxidant activity test was performed due to the importance of scavenging free radicals in infections with pathogenic microorganisms. The conducted research proved the anthelmintic and antibacterial potential of the newly obtained compounds. The most effective were two compounds with a 3-chlorophenyl substituent, both linear and cyclic derivatives. They demonstrated higher efficacy than the drugs used in treatment.

Synthesis and Biological Evaluation of New Compounds with Nitroimidazole Moiety.

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.

A two-in-one thiosemicarbazide and whole pine needle-based adsorbent for rapid and efficient adsorption of methylene blue dye and mercuric ions.

Herein, we report the synthesis of an oxidized pine needle-thiosemicarbazone Schiff base (OPN-TSC) from whole pine needles (WPN) as a dual-purpose adsorbent to remove a cationic dye, methylene blue (MB), and Hg2+ ions in separate processes. The adsorbent was synthesized by periodate oxidation of WPN followed by a reaction with thiosemicarbazide. The syntheses of OPN and OPN-TSC were confirmed by FTIR, XRD, FESEM, EDS, BET, and surface charge analysis. The emergence of new peaks at 1729 cm-1 (-CHO stretching) and 1639 cm-1 (-COO- stretching) in the FTIR spectrum of OPN confirmed the oxidation of WPN to OPN. FTIR spectrum of OPN-TSC has a peak at 1604 cm-1 (C = N stretching), confirming the functionalization of OPN to OPN-TSC. XRD studies revealed an increase in the crystallinity of OPN and a decrease in the crystallinity of OPN-TSC because of the attachment of thiosemicarbazide to OPN. The values of %removal for MB and Hg2+ ions by OPN-TSC were found to be 87.36% and 98.2% with maximum adsorption capacity of 279.3 mg/g and 196 mg/g for MB and Hg2+ ions, respectively. The adsorption of MB followed pseudo-second-order kinetics with correlation coefficient (R2 of 0.99383) and Freundlich isotherm (R2 = 0.97239), whereas Hg2+ ion removal demonstrated the Elovich (R2 = 0.97076) and Langmuir isotherm (R2 = 0.95110). OPN-TSC is regenerable with significant recyclability up to 10 cycles for both the adsorbates. The studies established OPN-TSC as a low-cost, sustainable, biodegradable, environmentally benign, and promising adsorbent for the removal of hazardous cationic dyes and toxic metal ions from wastewater and industrial effluents, especially the textile effluents.

Depletion kinetics of semicarbazide in giant river prawn (Macrobrachium rosenbergii) following nitrofurazone oral administration and its occurrence in an aquaculture farm.

Semicarbazide (SEM), a marker residue used to monitor the use of prohibited drug nitrofurazone (NFZ), is commonly found in wild crustaceans, implying the natural origin. However, the difference between endogenous and exogenous SEM has rarely been investigated. So, tissue-bound SEM was determined in samples collected from giant river prawns cultured in an aquaculture farm and in samples from an experiment where giant river prawns were fed twice a day with NFZ at 30 mg/kg for 5 days. At day 10 of drug withdrawal, muscle SEM of the NFZ-fed prawn was 17.78 ng/g and depleted to 1.18 ng/g at day 90 (half-life 20.31 days) which was significantly higher than the control prawn (usually ≤ 0.1 ng/g). In contrast, the average SEM in the shell was independent of NFZ treatment. SEM was not found in the aquaculture farm samples, implying that the SEM in cultured prawn did not originate from SEM contamination.

Design and evaluation of semicarbazide-embeddedd stationary phases for liquid chromatography.

Semicarbazide, as a derivative of urea, constitutes a great variety of functional molecules for different needs. Herein, novel stationary phases with an incorporated semicarbazide group were proposed. Using aliphatic (docosanoyl, C22) and aromatic (benzoyl, Bz) hydrazides, the semicarbazide-embedded ligands were synthesized before chemical modification of the silica gel, allowing for an accurate interpretation of the chromatographic properties of the corresponding packings. The new stationary phases were water-wettable, due to the presence of highly polar groups. In particular, Bz-semicarbazide (Bz-SCD) stationary phase was sufficiently hydrophilic to run in hydrophilic interaction (HILIC) mode, whilst the C22 (C22-SCD) equivalent, in spite of its reversed-phase nature, was markedly less hydrophobic than the referenced polar-embedded ones. The versatility of C22-SCD was demonstrated with a large selection of analytes, including geometric isomers and standard mixtures of polycyclic aromatic hydrocarbons, sulfonamides, sulfonylurea, substituted ureas, pyridines and carbamates, fat-soluble colorants, antifungal metabolites, angiotensin II receptor blockers and calcium channel blockers.

Diels-Alder clickable furan-thiosemicarbazide cellulose for selective ruthenium (III) imprinting.

Developing an efficient adsorbent for Ru3+ ions in wastewater is crucial for both environmental protection and resource recovery. This study introduces a novel approach using cellulose-based adsorbents, specifically modified with furan-thiosemicarbazide (FTC), to enhance their selectivity for Ru3+ ions. By cross-linking the Ru3+/FTC-modified cellulose (FTC-CE) complex with a bis(maleimido)ethane (BME) cross-linker, we created a Ru3+ ion-imprinted sorbent (Ru-II-CE) that exhibits a strong affinity and selectivity for Ru3+ ions. The synthesis process was thoroughly characterized using NMR and FTIR spectroscopy, while the surface morphology of the sorbent particles was examined with scanning electron microscopy. The Ru-II-CE sorbent demonstrated exceptional selectivity for Ru3+ among competing metal cations, achieving optimal adsorption at a pH of 5. Its adsorption capacity was notably high at 215 mg/g, fitting well with the Langmuir isotherm model, and it followed pseudo-second-order kinetics. This study highlights the potential of FTC-CE for targeted Ru3+ removal from wastewater, offering a promising solution for heavy metal decontamination.

A potential therapeutic agent for the treatment of hyperuricemia and gout: 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide.

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.

A portable smartphone platform utilizing dual-sensing signals for visual determination of semicarbazide in food samples.

Semicarbazide (SEM) is a metabolite of antibiotic nitrofurazone and a food contaminant in food production, showing potential carcinogenic, mutagenic, teratogenic, and toxic effects on human health. It is urgent to develop a highly efficient and sensitive assay for visual detection of SEM. In this paper, a pyrrolopyrrole cyanine fluorescent probe (PPCy-1) was reported for visualization and quantitative analysis of SEM through a chromophore reaction sensing mechanism for the first time. The probe towards SEM exhibited a fast response (10 min), a low detection limit (0.18 µM), high selectivity, and distinct dual ratiometric fluorescence turn-on and colorimetric modes. Its practicability was further verified by detecting SEM in meat, water, and honey samples with satisfactory recovery values. More importantly, a smartphone-assisted portable testing platform was constructed based on a PPCy-1-immobilized test paper or a polyamide thin film with a color scanning APP for real-time and on-site detection of SEM. This work provides low-cost, convenient, and rapid assays for visual SEM detection, which have potential applications in food safety monitoring.

Preparation of iota-carrageenan@bentonite@4-phenyl-3-thiosemicarbazide ternary hydrogel for adsorption of Losartan potassium and sulfamethoxazole.

A rising quantity of drugs has been discharged into the aquatic environment, posing a substantial hazard to public health. In the current work, a novel hydrogel (i.Carr@Bent@PTC), comprised of iota-carrageenan, bentonite, and 4-phenyl-3-thiosemicarbazide, was successfully prepared. The introduction of 4-phenyl-3-thiosemicarbazide and bentonite in iota-carrageenan significantly increased the mechanical strength of iota-carrageenan hydrogel and improved its degree of swelling, which can be attributed to the hydrophilic properties of PTC and Bent. The recorded contact angle was 70.8°, 59.1°, 53.9°, and 34.6° for pristine i.Carr, i.Carr@Bent, and i.Carr@Bent@PTC, respectively. The low contact angle measurement of the Bent and PTC loaded-i.Carr hydrogel was attributed to the hydrophilic Bent and PTC. The ternary i.Carr@Bent@PTC hydrogel demonstrated broad pH adaptability and excellent adsorption capacities for sulfamethoxazole (SMX) and losartan potassium (LP), i.e., 467.61 mg. g-1 and 274.43 mg. g-1 at 298.15 K, respectively. The pseudo-first-order (PSO) model provided a better fit for the adsorption kinetics. The adsorption of SMX and LP can be better explained by employing the Sips and Langmuir isotherm models. As revealed by XPS and FTIR investigations, π-π stacking, complexation, electrostatic interaction, and hydrogen bonding were primarily involved in the adsorption mechanisms.

Novel thiosemicarbazide-based ß-carboline derivatives as α-glucosidase inhibitors: Synthesis and biological evaluation.

In the quest for potent α-glucosidase inhibitors to combat diabetes, a series of novel thiosemicarbazide-based ß-carboline derivatives (CTL1∼36) were synthesized and evaluated. CTL1∼36 exhibited remarkable inhibitory effects against α-glucosidase, with IC50 values ranging from 2.81 to 12.40 µM, significantly surpassing the positive control acarbose (IC50 = 564.28 µM). Notably, CTL26 demonstrated the most potent inhibition (IC50 = 2.81 µM) and was characterized as a non-competitive inhibitor. Through a combination assay with fluorescence quenching, 3D fluorescence spectra, CD spectra, and molecular docking, we elucidated that CTL26 formed a complex with α-glucosidase via hydrogen bondings and hydrophobic interactions, leading to α-glucosidase conformation changes that impaired enzymatic activity. In vivo studies revealed that oral administration of CTL26 (25 and 50 mg/kg/d) reduced fasting blood glucose levels, enhanced glucose tolerance, and ameliorated lipid abnormalities in diabetic mice. These findings positioned CTL26 as a promising candidate for the development of α-glucosidase inhibitors with anti-diabetic potential.

Silver nanoparticle functionalized by glutamine and conjugated with thiosemicarbazide induces apoptosis in colon cancer cell line.

The high mortality rate of colon cancer indicates the insufficient efficacy of current chemotherapy. Thus, the discussion on engineered metal nanoparticles in the treatment of the disease has been considered. In this study, silver nanoparticles were functionalized with glutamine and conjugated with thiosemiccarbazide. Then, anticancer mechanism of Ag@Gln-TSC NPs in a colon cancer cell line (SW480) was investigated. Characterizing Ag@Gln-TSC NPs by FT-IR, XRD, EDS-mapping, DLS, zeta potential, and SEM and TEM microscopy revealed that the Ag@Gln-TSC NPs were correctly synthesized, the particles were spherical, with surface charge of - 27.3 mV, high thermal stability and low agglomeration level. Using MTT assay we found that Ag@Gln-TSC NPs were significantly more toxic for colon cancer cells than normal fibroblast cells with IC50 of 88 and 186 µg/mL, respectively. Flow cytometry analysis showed that treating colon cancer cells with Ag@Gln-TSC NPs leads to a considerable increase in the frequency of apoptotic cells (85.9% of the cells) and increased cell cycle arrest at the S phase. Also, several apoptotic features, including hyperactivity of caspase-3 (5.15 folds), increased expression of CASP8 gene (3.8 folds), and apoptotic nuclear alterations were noticed in the nanoparticle treated cells. Furthermore, treating colon cancer cells with Ag@Gln-TSC NPs caused significant down-regulation of the HULC Lnc-RNA and PPFIA4 oncogene by 0.3 and 0.6 folds, respectively. Overall, this work showed that Ag@Gln-TSC NPs can effectively inhibit colon cancer cells through the activation of apoptotic pathways, a feature that can be considered more in studies in the field of colon cancer treatment.

Tiossemicarbazonas heterocíclicas potencialmente antimaláricas: I. Aspectos estruturais / Potentially antimalarial heterocyclic thiosemicarbazones: I. Structural aspects

Com o objetivo de elucidar a estrutura de tiossemicarbazonas de aldeídos heterocíclicos, potencialmente antimaláricos, foram preparados quatro compostos desta classe, sendo analisados mediante espectrometria de infravermelho e de ressonância magnética protônica. A análise estrutural sugere grande conjugaçäo por deslocalizaçäo eletrônica, estabilizando a cadeia lateral em determinada configuraçäo, onde um dos prótons tioureídicos interage com o grupo carbonila e o outro com o átomo de nitrogênio da dupla ligaçäo

Efeito ansiolitico da semicarbazida dinamizada em ratos submetidos ao teste do labirinto em cruz elevado / Anxiolytic effects of synamised semicarbazide in rats

O presente trabalho mostra a acao preventiva da semicarbazida dinamizada (6CH) sobre a ansiedade produzida experimentalmente em animais(AU)

Efeito ansiolítico da semicarbazida dinamizada em ratos submetidos ao teste do labirinto em cruz elevado / Ansiolytic effects of semicarbazide dinamized in mice submitted to the \"labirinto em cruz elevado\"experiment

O presente trabalho mostra a açäo preventiva da semicarbazida dinamizada (6CH) sobre a ansiedade produzida experimentalmente em animais