Alzheimer's disease (AD) is an incurable and progressive neurodegenerative disorder that causes cognitive capabilities and memory loss and damage to brain functionality and structure. From diverse possibilities for drug development, the inhibition of acetylcholinesterase (AChE) remains as dominant treatment of symptoms. In our continued investigation of long-chain derivatives of 4-aminoquinoline containing an adamantyl (Ad) group, six new derivatives that differ in the substitution at the terminal amino group or the Ad moiety were synthesised. Their inhibition of AChE, in silico drug-likeness, the potential for passing through the blood-brain barrier (BBB) and possible binding modes with AChE for the most active compounds were investigated. It was shown that introducing OH, Br or acetamide group increases the inhibitory potency compared with less polar compounds containing the benzyl group as the second substituent at the amino group. Analysis of in silico obtained parameters defined by Lipinsky's rule showed that neither compound is likely to cross the BBB because of violation of at least one of the rules, in general, log P and a number of rotatable bonds (RB). Docking of the most active compounds to AChE suggests that compounds act as dual-binding site inhibitors since they have simultaneous interaction with catalytic and peripheral anionic sites of AChE. The substituents on the Ad could be the ones that determine the mode of binding into the enzyme and provide interactions that stabilise the complex between the compound and AChE.

Thiosemicarbazones (TSCs) are well known for their diverse biological activities and wide-ranging applications. This study assessed the drug- likeness and antioxidant potential of previously synthesized steroidal TSCs with promising cytotoxicity. While all tested androstane TSCs are drug-like, they have poor water solubility, strong plasma protein binding ability, and low blood-brain barrier permeability. Mono-TSCs show better absorption parameters, but bis- TSCs are stronger antioxidants, with compound 4 being 4.5 times more active than ascorbic acid. All tested TSCs could be considered potential cytotoxic and antioxidant agents.

In this paper, we aimed to evaluate whether simple, low molecular mass benzoquinone derivatives, featuring different substituents in para- and meta-position relative to the tert-butyl group, possess biological activities against major targets associated with Alzheimer’s disease. The 1,4-benzoquinone derivatives studied herein inhibited both cholinesterases in the micromolar concentration range, generally showing a preference for butyrylcholinesterase over acetylcholinesterase; formed complexes with biometal ions Fe2+, Cu2+ and Zn2+; and displayed a certain BACE1 inhibition. Moreover, the tested compounds displayed certain antioxidant activity via either electron transfer or hydrogen atom transfer mechanisms. The antioxidant capacity of the unsubstituted tert-butyl-1,4-benzoquinone (compound 1) was three times lower than that of the standard antioxidant BHT, while 2,6-disubstituted derivatives (compounds 15 and 7) exhibited peroxyl radical scavenging activity comparable to that of Trolox. Taken together with in silico-predicted low toxicity, good intestinal absorption and favorable oral bioavailability, the presented 1,4-benzoquinone derivatives are promising scaffolds for the design of more complex molecules with enhanced cholinesterase and BACE1 inhibitory activity. Furthermore, they could serve as functional substituents in other structural scaffolds to combine and enhance their biological activities.

Anti-DPPH activity and in silico lipophilicity of six steroidal semi- and thiosemicarbazones were determined. As expected, sulfur derivatives exhibited higher activity than oxygen analogues. Lipophilicity determined by the shake-flask method (logP=4.5±0.2) for androstane thiosemicarbazone with the best antioxidative activity of 0.298 mM was in good agreement with the value obtained by calculation using the Chemaxon calculator (logP=4.62).

In silico assessment of drug-likeness of 15 steroidal mono- and bis-thiazolidinones was performed. Androstrane (1−5) and progesterone types (6) mono-derivatives had no violations of Lipinski’s rule of five, while bis-derivatives had slightly higher molecular masses than 500 Da, and cholestane derivatives (8−9) showed high lipophilicity and Caco-2 permeability. All examined compounds showed great intestinal absorption potential.

The synthesis of four N-2-alkylated aza-galactofagomine (AGF) analogues was achieved by intermolecular reductive hydrazination or alkylation of suitably protected AGF. The synthesized compounds were evaluated as potential /3-glucosidase inhibitors. The preliminary screening of inhibitor activity, conducted with sweet almond /3-glucosidase immobilized in agar, as well as the standard inhibition assay with the same enzyme, showed the inhibitory potency of the synthesized analogues. In addition, these results are in a good agreement with the docking analysis of the human acid /3-glucosidase, the enzyme implicated in Gaucher's disease.

The aim of this study was to investigate the effects of tert-butylquinone (TBQ) and its alkylthio and arylthio derivatives on DNA in vitro, using acellular and cellular test systems. Direct interaction with DNA was studied using the plasmid pUC19. Cytotoxic (MTS assay) and genotoxic (comet assay and γH2AX focus assays) effects, and their influence on the cell cycle were studied in the HepG2 cell line. Our results show that TBQ and its derivatives did not directly interact with DNA. The strongest cytotoxic effect on the HepG2 cells was observed for the derivative 2-tert-butyl-5,6-(ethylenedithio)-1,4-benzoquinone (IC50 64.68 and 55.64 μM at 24-h and 48-h treatment, respectively). The tested derivatives did not significantly influence the cell cycle distribution in the exposed cellular populations. However, all derivatives showed a genotoxic activity stronger than that of TBQ in the comet assay, with 2-tert-butyl-5,6-(ethylenedithio)-1,4-benzoquinone producing the strongest effect. The same derivative also induced DNA double-strand breaks in the γH2AX focus assay.

We developed new iminosugar-based glycosidase inhibitors against SARS-CoV-2. Known drugs (miglustat, migalastat, miglitol, and swainsonine) were chosen as lead compounds to develop three classes of glycosidase inhibitors (alpha-glucosidase, alpha-galactosidase, and mannosidase). Molecular modelling of the lead compounds, synthesis of the compounds with the highest docking scores, enzyme inhibition tests, and in vitro antiviral assays afforded rationally designed inhibitors. Two highly active alpha-glucosidase inhibitors were discovered, where one of them is the most potent iminosugar-based anti-SARS-CoV-2 agent to date (EC90 = 1.94 mu M in A549-ACE2 cells against Omicron BA.1 strain). However, galactosidase inhibitors did not exhibit antiviral activity, whereas mannosidase inhibitors were both active and cytotoxic. As our iminosugar-based drug candidates act by a host-directed mechanism, they should be more resilient to drug resistance. Moreover, this strategy could be extended to identify potential drug candidates for other viral infections.

Fe(III) and Mn(II) complexes with condensation product of thiosemicarbazide and 2-acetylthiazole (HL1, (E)-2-(1-(thiazol-2-yl)ethylidene)hydrazine-1-carbothioamide) have been synthesized and characterized by single-crystal X-ray diffraction, IR spectroscopy, and elemental analysis. In both complexes, the thiosemicarbazone ligand is coordinated in deprotonated form through the NNS donor set of atoms. However, while Fe(III) complex is in the doublet ground state with distorted octahedral geometry, the coordination environment around Mn(II) is distorted trigonal-prismatic, and the sextet state is found to be the ground state. DFT calculations were performed to rationalize spin state preferences, and continuous shape measure describes the deviation from ideal six-coordinated polyhedral geometries in the ground and excited states. Antimicrobial activity (against a panel of Gram-negative and Gram-positive bacteria, two yeast, and one fungal strain), brine shrimp assay, and DPPH radical scavenging activity of both complexes were evaluated, and these results relate to the electronic structure of the complexes.

Biological activity of 2-tert-butyl-1,4-benzoquinone (TBQ) and its derivatives, 2-tert-butyl-5-(2-propylthio)-1,4-benzoquinone, 2-tert-butyl-5--(propylthio)-1,4-benzoquinone, 2-tert-butyl-5,6-(ethylenedithio)-1,4-benzo-quinone, 2-tert-butyl-5-(phenylthio)-1,4-benzoquinone and 2-tert-butyl-6-(phe-nylthio)-1,4-benzoquinone, were tested for their antioxidant, antibacterial, toxic, cytotoxic and genotoxic potential. Using the DPPH test, all derivatives showed good antioxidant activity, better than ascorbic acid, and the 2-tert--butyl-5-(propylthio)-1,4-benzoquinonederivative showed the strongest effect. Better antibacterial potential was observed against Gram-positive bacteria in the broth microdilution method in which the 2-tert-butyl-5-(phenylthio)-1,4--benzoquinonederivative showed the strongest activity (MIC = 15.6 mu M). The results of toxicity tests, using the Brine shrimp test, indicated that the deri-vatives lose their toxic potential compared to TBQ, except for 2-tert-butyl-6--(phenylthio)-1,4-benzoquinone,which showed a 3 times stronger effect. Cyto-toxicity was assessed by the MTT assay in 24 and 72 h treatments in MRC-5, HS 294T and A549 cell lines in threefold decreasing gradient (11, 33 and 100 mu M). Modifications potentiate the cytotoxic effect, and the strongest effect was observed with the 2-tert-butyl-5,6-(ethylendithio)-1,4-benzoquinone derivative. In addition, the genotoxic potential was examined in the MRC-5 cell line using the comet assay. All tested derivatives of TBQ showed a genotoxic effect at all applied subtoxic concentrations. In general, the chemical modifications of TBQ enhanced its biological activity.

In this paper, the previously synthesized Cu(II) complex ([CuL1(N-3) (CH3OH)]BF4) with N,N,N-trimethyl-2-oxo-2-(2-(1-(thiazol-2-yl)ethylidene)-hydrazinyl)ethan-1-aminium chloride, has been characterized and its biological activity has been studied in detail. The Cu(II) complex consists of ligand coordinated in a deprotonated, formally neutral zwitter-ionic form, via NNO atoms, one azido ligand and one methanol molecule. The Cu(II) complex was selected due to results of the cytotoxic activity, the brine shrimp test and DPPH radical scavenging activity, which were previously performed. The effects of Cu(II) complex on cell cycle phase distribution of cervical adenocarcinoma HeLa cells were investigated in order to examine the mechanisms of its anticancer activity. The measurement of intracellular ROS levels in HeLa and HaCaT cell lines were evaluated in order to explore their possible generation and the role in cytotoxic activity. The possible anti-invasive and anti-angiogenic properties of Cu(II) complex were evaluated. DNA binding experiments, including fluorescence displacement study and DNA cleavage experiments, were performed in order to obtain information on the type of DNA-metal complex interactions.

In this work synthesis, characterization and crystal structures of 1, Zn(II) complex ([ZnL1(NCS)2]), with (E)-1-(2-oxo-2-(2-(quinolin-2-ylmethylene)hydrazinyl)ethyl)pyridin-1-ium chloride (HL1Cl) and 2, Bi(III) complex ([BiHL2Cl4] × 1/2CH3OH), with (E)-N,N,N-trimethyl-2-oxo-2-(2-(1-(thiazol-2-yl)ethylidene)hydrazinyl)ethan-1-aminium chloride (HL2Cl), have been reported. Zn(II) complex possesses a distorted trigonal bipyramidal geometry while surroundings around Bi(III) ion are extended pentagonal bipyramidal. Antimicrobial activity, brine shrimp assay and DPPH radical scavenging activity of both complexes, including previously synthesized complexes with HL2Cl ligand (Zn(II) and Ni(II)) and complexes with (E)-N,N,N-trimethyl-2-oxo-2-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)ethan-1-aminium chloride (HL3Cl) (Zn(II), Cu(II), Cd(II), Co(II), Fe(III), Ni(II)), were evaluated. For the most active complexes, cytotoxic activity against five malignant cancer cell lines (HeLa, A375, MCF7, PC-3 and A549) and normal cell line HaCaT, as well as generation of reactive oxygen species (ROS), was tested.

In this work, Pt(II) complexes of previously synthesized steroidal thiosemicarbazones were synthesized and characterized. The ligands and their metal complexes were studied by analytical and spectroscopic data (elemental analysis, IR, 1D-NMR and 2D-NMR, HSQC, HMBC, NOESY, COSY), the analysis of which enabled complete 1H and 13C assignments of each compound including E and Z isomers. All the synthesized ligands and complexes were screened for their cytotoxic and antimicrobial activity. The results demonstrate that the new steroidal thiosemicarbazone complexes were significantly less cytotoxic than the corresponding steroidal thiosemicarbazones. In addition, complexes showed lower antimicrobial activity than the standard drugs, similar to the activity of the starting thiosemicarbazones.

In this paper, Cu(II), Mn(II) and Zn(II) complexes with N,N,N-trimethyl-2-oxo-2-(2-(1-(thiazol-2-yl)ethylidene)hydrazinyl)ethan-1-aminium chloride (HL1Cl) were synthesized and characterized by single-crystal X-ray diffraction, IR spectroscopy, elemental analysis and DFT calculations. In all three complexes, a ligand (L1) is coordinated in a deprotonated formally neutral zwitterionic form via NNO donor set atoms. Cu(II) and Zn(II) form mononuclear penta-coordinated complexes [CuL1(N3)(CH3OH)]BF4 and [ZnL1(N3)2], respectively, while Mn(II) forms a binuclear [Mn2L12(μ-1,1-N3)2(N3)2]·2CH3OH complex, with unusual distorted trigonal-prismatic geometry around the metal centers. The antimicrobial activity of these complexes was tested against a panel of Gram-negative and Gram-positive bacteria, two yeasts and one fungal strain. The binuclear Mn(II) complex showed antifungal activity of similar intensity to amphotericin B. Based on the results of the brine shrimp test and DPPH radical scavenging activity, the most active Cu(II) and Mn(II) complexes were selected for evaluation of cytotoxic activity against five malignant cancer cell lines (HeLa, A375, MCF7, PC-3 and A549) and one normal cell line HaCaT. Both complexes showed significant activity. It should be pointed out that the activity of the Mn(II) complex against the MCF7 breast cancer cell line is only slightly weaker than that of cisplatin, but with selectivity to the tumor cell line in comparison to normal HaCaT cells, which is non-existent in the case of cisplatin.

Tert-butylquinone (TBQ) and its alkylamino and aralkylamino derivatives are of high interest as a potential antitumor agent. Therefore, it was necessary to investigate if the compounds exert undesirable activities such as interaction with DNA molecule which could result in negative side effects in the case of their use in the diseases treatment. The major aim of this study was to investigate genotoxic potential of TBQ and selected derivatives in an acellular model by using plasmid DNA, in the prokaryotic model by the SOS/umuC assay in Salmonella typhimurium TA1535/pSK1002 and in eukaryotic models by using comet assay in human fetal lung cell line (MRC-5) and human liver cancer cell line (HepG2). Results indicated that in the acellular model TBQ and its derivatives do not interact with plasmid pUC19. In the prokaryotic model, only TBQ exerted weak genotoxic potential and only at highly cytotoxic concentrations. In eukaryotic models, genotoxic potential was detected mainly at the highest concentrations of the tested substances but the effect was lower in both cell lines in comparison with benzo[a]pyrene and etoposide which were used as positive controls. Weak genotoxic potential of tested compounds recommends them as good candidates for further testing in development of new antitumor agents.

In this study, mutagenic and genotoxic potential of anti-tumor compounds avarol, avarone, and its derivatives 3 '-methoxyavarone, 4 '-(methylamino)avarone and 3 '-(methylamino)avarone was evaluated and compared to cytostatics commonly used in chemotherapy (5-fluorouracil, etoposid, and cisplatin). Mutagenic potential of selected hydroquinone and quinones was assessed in prokaryotic model by the SOS/umuC assay in Salmonella typhimurium TA1535/pSK1002. Genotoxic potential was also assessed in eukaryotic models using comet assay in human fetal lung cell line (MRC-5), human adenocarcinoma epithelial cell line (A549), and in human peripheral blood cells (HPBC). The results indicated that avarol and avarone do not exert mutagenic/genotoxic potential. Among the studied avarone derivatives, mutagenic potential was detected by SOS/umuC test for 3 '-(methylamino)avarone, but only after metabolic activation. The results of comet assay indicated that 3 '-methoxyavarone and 3 '-(methylamino)avarone have a significant impact on the level of DNA damage in the MRC-5 cell line. Genotoxic potential was not observed in A549 cells or HPBC probably due to a different uptake rate for the compounds and lower in metabolism rate within these cells.

Eleven new steroidal mono- and bis(semicarbazones) 2a-e, 4d and 3a-e have been prepared starting from various 3-oxo-alpha,beta-unsaturated steroids. Mono-semicarbazones 2a-e were further subjected to ethyl chloroacetate in boiling absolute ethanol but, instead of expected intramolecular cyclocondensation reaction products, the new carbazate esters 5a-e were obtained. The structures of all synthesized compounds and identification of each E/Z isomer were deduced by elemental analysis, HRMS, NMR, and IR spectroscopy. Preliminary screening for the cytotoxic activity in vitro of the new compounds has been conducted against three cancer cell lines, K562, Jurkat and HeLa cells. HeLa cells were the most sensitive while K562 cells were the least sensitive to the cytotoxic action of the novel steroid derivatives. Compounds 2e, 3c and 5e were found to have the best but still moderate cytotoxic effects. All tested compounds showed very weak antimicrobial activities. These results demonstrate that the replacement of thioxo group with carbonyl group in steroidal hydrazone derivatives resulted in decrease in their biological activity.

In this paper, the synthesis of fourteen alkylamino and arylamino derivatives of sesquiterpene quinone avarone and its model compound tert-butylquinone is described. Branched, cyclic, allylic and benzylic alkylamino/arylamino groups were introduced into the quinone moiety. For all the obtained derivatives, their biological activity and redox properties were studied. The cytotoxic activity of the synthesized derivatives towards multidrug resistant (MDR) human non-small cell lung carcinoma NCI-H460/R cells, their sensitive counterpart NCI-H460 and human normal keratinocytes (HaCaT) was investigated. The antimicrobial activity towards Gram-positive and Gram-negative bacteria, and fungal cultures was determined. Some of the synthesized derivatives showed selectivity for cancer cells, including MDR cells. Regarding their cell death induction potential, the most promising compounds were allylamino derivatives, preferentially triggering apoptosis, with high selectivity for cancer cells, including MDR cells. Several compounds showed promising antimicrobial activity, comparable to those of commercial antibiotic and antimycotic agents.

In this work, three novel silver(I) complexes with an almost completely rigid and bulky monodentate ligand, 1-adamantanamine, were synthesized. The aliphatic amine, 1-adamantanamine, is the sole electron donor ligand in these complexes. In addition to spectroscopic characterization, the basic biological activities of the new compounds were investigated and their minimum inhibitory concentrations were determined. The antifungal and antibacterial activities indicate that these compounds could potentially be applied as new therapeutics.