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The presented study depicts the synthesis of 11 carborane-thiazole conjugates with anticancer activity, as well as an evaluation of their biological activity as inhibitors of two enzymes: tyrosinase and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The overexpression of tyrosinase results in the intracellular accumulation of melanin and can be observed in melanoma. The overexpression of 11β-HSD1 results in an elevation of glucocorticoid levels and has been associated with the aggravation of metabolic disorders such as type II diabetes mellitus and obesity. Recently, as the comorbidity of melanomas and metabolic disorders is being recognized as an important issue, the search for new therapeutic options has intensified. This study demonstrates that carborane-thiazole derivatives inhibit both enzymes, exerting beneficial effects. The antiproliferative action of all newly synthesized compounds was evaluated using three cancer cell lines, namely A172 (human brain glioblastoma), B16F10 (murine melanoma) and MDA-MB-231 (human breast adenocarcinoma), as well as a healthy control cell line of HUVEC (human umbilical vein endothelial cells). The results show that 9 out of 11 newly synthesized compounds demonstrated similar antiproliferative action against the B16F10 cell line to the reference drug, and three of these compounds surpassed it. To the best of our knowledge, this study is the first to demonstrate dual inhibitory action of carborane-thiazole derivatives against both tyrosinase and 11β-HSD1. Therefore, it represents the first step towards the simultaneous treatment of melanoma and comorbid diseases such as type II diabetes mellitus.

Carbazole is an aromatic heterocyclic organic compound consisting of two fused benzene rings and a pyrrole ring and is a very valuable building structure for the design of many compounds for use in various fields of chemistry and medicine. This study presents three new carbazole-based thiazole derivatives that differ in the presence of a different halogen atom: chlorine, bromine, and fluorine. Experimental studies and quantum-chemical simulations show the effect of changing a halogen atom on the physicochemical, biological, and linear and nonlinear optical properties. We have also found that carbazoles C-Cl, C-Br, and C-F exhibit high tyrosinase inhibitory activity, with IC 50 values in the range of 68-105 µM with mixed mechanism of action. Finally, molecular docking to the active site of Concanavalin A (ConA) and bioavailability for all compounds were evaluated.

The tyrosinase pathway takes part in the enzymatic process of food browning and is primarily responsible for food spoilage - manifesting itself from a decrease in its nutritional value to a deterioration of taste, which consequently leads to a gradual loss of shelf life. Finding safe and bio-based tyrosinase inhibitors and anti-browning agents may be of great importance in agriculture and food industries. Herein, we showed that Cyrene™ exhibits tyrosinase inhibitory activity (IC 50 : 268.2 µM), the 1.44 times higher than ascorbic acid (IC 50 : 386.5 μM). Binding mode studies demonstrated that the carbonyl oxygen of Cyrene™ coordinates with both copper ions. Surprisingly, both hydroxyl groups of Cyrene gem-diol perform a monodentate binding mode with both copper ions, at similar distances. This fact suggests that both compounds could have a similar binding mode and, as consequence, similar biological activities in tyrosinase inhibition assays and anti-browning activities., 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 Elsevier Ltd. All rights reserved.)

The seven N-phthalimide derivatives substituted with the amine group at the 3-C position in the phenylene ring were synthesized. The effect of N-substituent chemical structure was investigated. The thermal, electrochemical and optical studies were performed and supported by the density functional theory calculations (DFT). The electrochemical investigations of the synthesized low-molecular phthalimides revealed the one oxidation and reduction process with the HOMO energy level under - 5.81 eV and energy-band gap below 3 eV. The N-phthalimide derivatives were emitted light in a blue spectral region in solutions (in polar and non-polar) with the quantum yield between 2 and 68%, dependent on the substituent at the nitrogen atom, solvent and concentration. The N-phthalimide derivatives were emissive also in a solid state as a thin film and powder. They were tested as a component of the active layer with PVK:PBD matrix and as an independent active layer in the organic light-emitting diodes. The registered electroluminescence spectra exhibited the maximum emission band in the 469-505 nm range, confirming the possibility of using N-phthalimides with PVK:PBD matrix as the blue emitters., (© 2023. The Author(s).)

Cancer represents the main cause of morbidity and mortality worldwide, constituting a serious health problem. In this context, melanoma represents the most aggressive and fatal type of skin cancer, with death rates increasing every year. Scientific efforts have been addressed to the development of inhibitors targeting the tyrosinase enzyme as potential anti-melanoma agents due to the importance of this enzyme in melanogenesis biosynthesis. Coumarin-based compounds have shown potential activity as anti-melanoma agents and tyrosinase inhibitors. In this study, coumarin-based derivatives were designed, synthesized, and experimentally evaluated upon tyrosinase. Compound FN-19 , a coumarin-thiosemicarbazone analog, exhibited potent anti-tyrosinase activity, with an IC 50 value of 42.16 ± 5.16 µM, being more active than ascorbic acid and kojic acid, both reference inhibitors. The kinetic study showed that FN-19 acts as a mixed inhibitor. Still, for this compound, molecular dynamics (MD) simulations were performed to determine the stability of the complex with tyrosinase, generating RMSD, RMSF, and interaction plots. Additionally, docking studies were performed to elucidate the binding pose at the tyrosinase, suggesting that the hydroxyl group of coumarin derivative performs coordinate bonds (bidentate) with the copper(II) ions at distances ranging from 2.09 to 2.61 Å. Then, MM/PBSA calculations revealed that van der Waals interactions are the most relevant intermolecular forces for complex stabilization. Furthermore, it was observed that FN-19 has a binding energy (Δ E MM ) value similar to tropolone, a tyrosinase inhibitor. Therefore, the data obtained in this study will be useful for designing and developing novel coumarin-based analogs targeting the tyrosinase enzyme.

Carbazole derivatives are the structural key of many biologically active substances, including naturally occurring and synthetic ones. Three novel (E)-2-(2-(4-9 H -carbazol-9-yl)benzylidene)hydrazinyl)triazole dyes were synthesized with different numbers of chlorine substituents attached at different locations. The presented research has shown the influence of the number and position of attachment of chlorine substituents on electrochemical, optical, nonlinear, and biological properties. The study also included the analysis of the use of the presented derivatives as potential fluorescent probes for in vivo and in vitro tests. Quantum-chemical calculations complement the conducted experiments.

A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) cell lines. Toxicity was tested on human normal skin fibroblasts (HSF) and normal colon fibroblasts (CCD-18Co). The growth inhibition mechanism of the most active derivative was analyzed through investigation of its effect on the distribution of cell cycle phases and ability to induce apoptosis and necrosis in RPMI 8226 and A549 cancer cells. The tyrosinase inhibitory potential was assessed, followed by molecular docking studies. Compounds 3a-3h show high anticancer activity against MDA-MB-231 and B16-F10 cell lines with IC 50 values of 1.51-3.03 µM. Moreover, the cytotoxic activity of the investigated compounds against HSF and CCD-18Co cells was 8-70 times lower than against the cancer cells or no toxicity was shown in our tests, with derivative 3a being particularly successful. The mechanism of action of compound 3a in RPMI 8226 cell was shown to be through induction of cell death through apoptosis. The derivatives show ability to inhibit the tyrosinase activity with a mixed mechanism of inhibition. The final molecular docking results showed for IC 50 distinct correlation with experiment.

Synthesis and investigation of anti-Toxoplasma gondii activity of novel thiazoles containing benzo [b]thiophene moiety are presented. Among the derivatives, compound 3k with adamantyl group shows exceptionally high potency against Me49 strain with IC 50 (8.74 μM) value which is significantly lower than the activity of trimethoprim (IC 50 39.23 μM). In addition, compounds 3a, 3b and 3k showed significant activity against RH strain (IC 50 51.88-83.49 μM). The results of the cytotoxicity evaluation showed that Toxoplasma gondii growth was inhibited at non-cytotoxic concentrations for the mammalian L929 fibroblast (CC 30 ∼ 880 μM). The most active compound 3k showed tyrosinase inhibition effect, with IC 50 value of 328.5 μM. The binding energies calculated for compounds 3a-3e, 3k are strongly correlated with the experimentally determined values of tyrosinase inhibition activity. Moreover, the binding energies corresponding to the same ligands and calculated for both tyrosinase and tyrosine hydroxylase are also correlated with each other, suggesting that tyrosinase inhibitors may also have an inhibitory effect on tyrosine hydroxylase. Compounds 3j and 3k have also very strong antioxidant activity (IC 50 15.9 and 15.5 μM), respectively, which is ten times higher than well-known antioxidant BHT., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

We have designed novel tropinone-thiazole derivatives that showed high antiproliferative activity against a variety of cancer cell lines via caspase 3/7 activation mechanism. Among the derivatives, compounds 3b-3h were found to exhibit high activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast carcinoma (MCF-7), and skin melanoma (B16-F10) cancer cell lines, with IC 50 values of 5.43-11.06 μM. The lead compound 3g increases caspase 3/7 activity in A549 cells 25 times more than the control, and 2 times more than reference drug camptothecin. We have also found that tropinone-thiazole derivatives exhibit high tyrosinase inhibitory activity. The lead compounds 3g and 3h showed tyrosinase inhibition effect, with IC 50 values 3.22 and 3.51 μM, respectively. These inhibitory activities are 22 times higher than the activity of kojic acid (IC 50 72.27 μM) and 120 times higher than activity of ascorbic acid (IC 50 386.5 μM). For compounds 3g and 3h, the experimentally determined lipophilicity correlates very well with their enzymatic activities. These data suggest that presented compounds could constitute lead anticancer drug candidates., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Synthesis, characterization and investigation of antiproliferative activity of nine triazene salts against human cancer cells lines (MV-4-11, MCF-7, JURKAT, HT-29, Hep-G2, HeLa, Du-145 and DAUDI), and normal human mammary epithelial cell line (MCF7-10A) is presented. The structures of novel compounds were determined using 1 H and 13 C NMR, and GC-APCI-MS analyses. Among the derivatives, compound 2c , 2d , 2e and 2f has very strong activity against biphenotypic B myelomonocytic leukemia MV4-11, with IC 50 values from 5.42 to 7.69 µg/ml. The cytotoxic activity of compounds 2c - 2f against normal human mammary gland epithelial cells MCF-10A is 6-11 times lower than against cancer cell lines. Our results also show that compounds 2c and 2f have very strong activity against DAUDI and HT-29 with IC 50 4.91 µg/ml and 5.59 µg/ml, respectively. Their lipophilicity was determined using reversed-phase ultra-performance liquid chromatography and correlated with antiproliferative activity. Our UV-Vis spectroscopic results indicate also that triazene salts tends to interact with negatively charged DNA phosphate chain. To support the experiment, theoretical calculations of the 1 H NMR shifts were carried out within the Density Functional Theory.

Synthesis, characterization, and investigation of antiproliferative activities against human cancer cell lines (MV4-11, MCF-7, and A549) and Toxoplasma gondii parasite of twelve novel 2,4-diaminotriazine-thiazoles are presented. The toxicity of the compounds was studied at three different cell types, normal mouse fibroblast (Balb/3T3), mouse fibroblast (L929), and human VERO cells. The structures of novel compounds were determined using 1 H and 13 C NMR, FAB(+)-MS, and elemental analyses. Among the derivatives, 4a - k showed very high activity against MV4-11 cell line with IC 50 values between 1.13 and 3.21 µg/ml. Additionally, the cytotoxic activity of compounds 4a - k against normal mouse fibroblast Balb/3T3 cells is about 20-100 times lower than against cancer cell lines. According to our results, compounds 4a , 4b , 4d , and 4i have very strong activity against human breast carcinoma MCF-7, with IC 50 values from 3.18 to 4.28 µg/ml. Moreover, diaminotriazines 4a - l showed significant anti- Toxoplasma gondii activity, with IC 50 values 9-68 times lower than those observed for sulfadiazine. Molecular docking studies indicated DNA-binding site of hTopoI and hTopoII as possible anticancer targets and purine nucleoside phosphorylase as possible anti -toxoplasmosis target. Our UV-Vis spectroscopic results indicate also that diaminotriazine-thiazoles tends to interact with DNA by intercalation. Additionally, the structure and the interaction and binding energies of a model complex formed by compound 4a and two thymine molecules are investigated using quantum mechanical methods., Competing Interests: Compliance with ethical standardsThe authors declare that they have no conflict of interest.

A series of new prodrugs: [bis(2-chloroethylamino)phosphoryloxy]methyl acetate, [bis(2-chloroethylamino)phosphoryloxy]methyl pivalate and [bis(2-chloroethylamino)phosphoryloxy]methyl benzoate, was obtained in the reaction of isophosphoramide mustard (iPAM) with the corresponding acyloxymethyl halides. The cytotoxic activity of these new compounds is also shown. All compounds were highly active in the inhibition of cancer cell proliferation against the human lung (A594), prostate (PC-3) and breast (MCF-7) cancer cell lines.