Plant-Based Products Originating from Serbia That Affect P-glycoprotein Activity.

Our review paper evaluates the impact of plant-based products, primarily derived from plants from Serbia, on P-glycoprotein (P-gp) activity and their potential in modulating drug resistance in cancer therapy. We focus on the role and regulation of P-gp in cellular physiology and its significance in addressing multidrug resistance in cancer therapy. Additionally, we discuss the modulation of P-gp activity by 55 natural product drugs, including derivatives for some of them, based on our team's research findings since 2011.

Novel hybrid compounds of sclareol and doxorubicin as potential anticancer nanotherapy for glioblastoma.

Two novel hybrid compounds, CON1 and CON2, have been developed by combining sclareol (SC) and doxorubicin (DOX) into a single molecular entity. These hybrid compounds have a 1:1 molar ratio of covalently linked SC and DOX. They have demonstrated promising anticancer properties, especially in glioblastoma cells, and have also shown potential in treating multidrug-resistant (MDR) cancer cells that express the P-glycoprotein (P-gp) membrane transporter.

Direct glyphosate soil monitoring at the triazine-based covalent organic framework with the theoretical study of sensing principle.

Covalent organic frameworks (COFs) are emerging as promising sensing materials due to their controllable structure and function properties, as well as excellent physicochemical characteristics. Here, specific interactions between a triazine-based COF and a mass-used herbicide - glyphosate (GLY) have been utilized to design a disposable sensing platform for GLY detection. This herbicide has been extensively used for decades, however, its harmful environmental impact and toxicity to humans have been recently proven, conditioning the necessity for the strict control and monitoring of its use and its presence in soil, water, and food.

Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells.

The synthesis of 24 hybrid molecules, consisting of naturally occurring sclareol (SCL) and synthetic 1,2,4-triazolo[1,5-a]pyrimidines (TPs), is described. New compounds were designed with the aim of improving the cytotoxic properties, activity, and selectivity of the parent compounds. Six analogs (12a-f) contained 4-benzylpiperazine linkage, while 4-benzyldiamine linkage was present in eighteen derivatives (12g-r and 13a-f).

Unraveling the anti-virulence potential and antifungal efficacy of 5-aminotetrazoles using the zebrafish model of disseminated candidiasis.

Candida albicans remains the main causal agent of candidiasis, the most common fungal infection with disturbingly high mortality rates worldwide. The limited diversity and efficacy of clinical antifungal drugs, exacerbated by emerging drug resistance, have resulted in the failure of current antifungal therapies. This imposes an urgent demand for the development of innovative strategies for effective eradication of candidal infections.

Controlling Pd-Catalyzed N-Arylation and Dimroth Rearrangement in the Synthesis of ,1-Diaryl-1-tetrazol-5-amines.

The Pd-catalyzed N-arylation method for the synthesis of eighteen ,1-diaryl-1-tetrazol-5-amine derivatives is reported. By running the reactions at 35 °C, compounds were isolated as single isomers since the undesired Dimroth rearrangement was completely suppressed. Furthermore, the Dimroth rearrangement of ,1-diaryl-1-tetrazol-5-amines was rationalized by conducting comprehensive experiments and NMR analysis as well as density functional theory (DFT) calculations of thermodynamic stability of the compounds.

Aminoquinolines afford resistance to cerebral malaria in susceptible mice.

Objectives: Malaria treatment is impeded by increasing resistance to conventional antimalarial drugs. Here we explored the activity of ten novel benzothiophene, thiophene and benzene aminoquinolines.

Methods: In vitro testing was performed by the lactate dehydrogenase assay in chloroquine (CQ)-sensitive Plasmodium falciparum strain 3D7 and CQ-resistant (CQ) P.

Chemo- and biocatalytic esterification of marchantin A and cytotoxic activity of ester derivatives.

Chemical and biocatalytic synthesis of seven previously undescribed marchantin A ester derivatives has been presented. Chemical synthesis afforded three peresterified bisbibenzyl products (TE1-TE3), while enzymatic method, using lipase, produced regioselective monoester derivatives (ME1-ME4). The antiproliferative activities of all prepared derivatives of marchantin A were tested on MRC-5 healthy human lung fibroblast, A549 human lung cancer, and MDA-MB-231 human breast cancer cell lines.

Aromatic Guanylhydrazones for the Control of Heme-Induced Antibody Polyreactivity.

In a healthy immune repertoire, there exists a fraction of polyreactive antibodies that can bind to a variety of unrelated self- and foreign antigens. Apart from naturally polyreactive antibodies, in every healthy individual, there is a fraction of antibody that can gain polyreactivity upon exposure to porphyrin cofactor heme. Molecular mechanisms and biological significance of the appearance of cryptic polyreactivity are not well understood.

Development of an efficient biocatalytic system based on bacterial laccase for the oxidation of selected 1,4-dihydropyridines.

Biocatalytic oxidations mediated by laccases are gaining importance due to their versatility and beneficial environmental effects. In this study, the oxidation of 1,4-dihydropyridines has been performed using three different types of bacterial laccase-based catalysts: purified laccase from Bacillus licheniformis ATCC 9945a (BliLacc), Escherichia coli whole cells expressing this laccase, and bacterial nanocellulose (BNC) supported BliLacc catalysts. The catalysts based on bacterial laccase were compared to the commercially available Trametes versicolor laccase (TvLacc).

Production of bacterial nanocellulose (BNC) and its application as a solid support in transition metal catalysed cross-coupling reactions.

Bacterial nanocellulose (BNC) emerged as an attractive advanced biomaterial that provides desirable properties such as high strength, lightweight, tailorable surface chemistry, hydrophilicity, and biodegradability. BNC was successfully obtained from a wide range of carbon sources including sugars derived from grass biomass using Komagataeibacter medellinensis ID13488 strain with yields up to 6 g L in static fermentation. Produced BNC was utilized in straightforward catalyst preparation as a solid support for two different transition metals, palladium and copper with metal loading of 20 and 3 wt%, respectively.

Benzothiazole carbamates and amides as antiproliferative species.

A series of new benzothiazole-based carbamates and amides were synthesized and their antiproliferative activity was determined. Derivatives with profound activity were identified and further investigated for their possible mechanism of action. It was found that these compounds induce specific apoptosis, G2/M cell cycle arrest and decrease ROS level in MCF-7 human breast cancer cell line.

Mononuclear silver(I) complexes with 1,7-phenanthroline as potent inhibitors of Candida growth.

Mononuclear silver(I) complexes with 1,7-phenanthroline (1,7-phen), [Ag(NO-O,O') (1,7-phen-N7)] (1) and [Ag(1,7-phen-N7)]X, X = ClO (2), CFSO (3), BF (4) and SbF (5) were synthesized and structurally characterized by NMR (H and C), IR and UV-Vis spectroscopy and ESI mass spectrometry. The crystal structures of 1, 3 and 4 were determined by single-crystal X-ray diffraction analysis. In all these complexes, 1,7-phen coordinates to the Ag(I) ion in a monodentate fashion via the less sterically hindered N7 nitrogen atom.

Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction.

Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of biological activities, including recently described excellent antifungal properties.

Human serum albumin binding of certain antimalarials.

Interactions between eight in-house synthesized aminoquinolines, along with well-known chloroquine, and human serum albumin (HSA) have been studied by fluorescence spectroscopy. The synthesized aminoquinolines, despite being structurally diverse, were found to be very potent antimalarials. Fluorescence measurements indicate that three compounds having additional thiophene or benzothiophene substructure bind more strongly to HSA than other studied compounds.

Consensus-based comparison of chromatographic and computationally estimated lipophilicity of benzothiepino[3,2-c]pyridine derivatives as potential antifungal drugs.

Lipophilicity is one of the essential properties influencing drug absorption, excretion and metabolism. It is used for screening viable drug candidates. Chromatographic behavior of thiepino[3,2-c:6,7-c']dipyridine and 16 benzothiepino[3,2-c]pyridine derivatives as potential antifungal drugs was studied using thin-layer chromatography under typical reversed-phase conditions and two microemulsion chromatographic systems.

Synthesis and anti-Candida activity of novel benzothiepino[3,2-c]pyridine derivatives.

A novel series of thiepine derivatives were synthesized and evaluated as potential antimicrobials. All the synthesized compounds were evaluated for their antimicrobial activities in vitro against the fungi Candida albicans (ATCC 10231), C. parapsilosis (clinical isolate), Gram-negative bacterium Pseudomonas aeruginosa (ATCC 44752), and Gram-positive bacterium Staphylococcus aureus (ATCC 25923).

Synthesis and evaluation of thiophene-based guanylhydrazones (iminoguanidines) efficient against panel of voriconazole-resistant fungal isolates.

A series of new thiophene-based guanylhydrazones (iminoguanidines) were synthesized in high yields using a straightforward two-step procedure. The antifungal activity of compounds was evaluated against a wide range of medicaly important fungal strains including yeasts, molds, and dermatophytes in comparison to clinically used drug voriconazole. Cytotoxic properties of compounds were also determined using human lung fibroblast cell line and hemolysis assay.

Quantitative structure retention/activity relationships of biologically relevant 4-amino-7-chloroquinoline based compounds.

The chromatographic behaviour of series of 4-amino-7-chloroquinoline (4,7-ACQ) based compounds was studied by reversed-phase thin-layer chromatography (RPTLC) with binary mobile phases containing water and the organic modifiers, DMSO or acetone. The lipophilicity of the studied compounds was determined by extrapolation of retention parameters RM to pure water content in mobile phase. In order to obtain some basic insight into the chromatographic behaviour and structural features of investigated compounds, PCA was performed on both chromatographic data (RM values) and calculated 2D and 3D structural descriptors.

Investigation into novel thiophene- and furan-based 4-amino-7-chloroquinolines afforded antimalarials that cure mice.

We herein report the design and synthesis of a novel series of thiophene- and furan-based aminoquinoline derivatives which were found to be potent antimalarials and inhibitors of β-hematin polymerization. Tested compounds were 3-71 times more potent in vitro than CQ against chloroquine-resistant (CQR) W2 strain with benzonitrile 30 being as active as mefloquine (MFQ), and almost all synthesized aminoquinolines (22/27) were more potent than MFQ against multidrug-resistant (MDR) strain C235. In vivo experiments revealed that compound 28 showed clearance with recrudescence at 40 mg/kg/day, while 5/5 mice survived in Thompson test at 160 mg/kg/day.

4-Amino-7-chloroquinolines: probing ligand efficiency provides botulinum neurotoxin serotype A light chain inhibitors with significant antiprotozoal activity.

Structurally simplified analogues of dual antimalarial and botulinum neurotoxin serotype A light chain (BoNT/A LC) inhibitor bis-aminoquinoline (1) were prepared. New compounds were designed to improve ligand efficiency while maintaining or exceeding the inhibitory potency of 1. Three of the new compounds are more active than 1 against both indications.

The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease.

Botulinum neurotoxins (BoNTs), composed of a family of seven serotypes (categorized A-G), are the deadliest of known biological toxins. The activity of the metalloprotease, light chain (LC) component of the toxins is responsible for causing the life-threatening paralysis associated with the disease botulism. Herein we report significantly more potent analogs of novel, lead BoNT serotype A LC inhibitor 2,5-bis(4-amidinophenyl)thiophene (K(i) = 10.

A chemotype that inhibits three unrelated pathogenic targets: the botulinum neurotoxin serotype A light chain, P. falciparum malaria, and the Ebola filovirus.

A 1,7-bis(alkylamino)diazachrysene-based small molecule was previously identified as an inhibitor of the botulinum neurotoxin serotype A light chain metalloprotease. Subsequently, a variety of derivatives of this chemotype were synthesized to develop structure-activity relationships, and all are inhibitors of the BoNT/A LC. Three-dimensional analyses indicated that half of the originally discovered 1,7-DAAC structure superimposed well with 4-amino-7-chloroquinoline-based antimalarial agents.

An alignment independent 3D QSAR study of the antiproliferative activity of 1,2,4,5-tetraoxanes.

An alignment-free 3D QSAR study on antiproliferative activity of the thirty-three 1,2,4,5-tetraoxane derivatives toward two human dedifferentiated cell lines was reported. GRIND methodology, where descriptors are derived from GRID molecular interaction fields (MIF), were used. It was found that pharmacophoric pattern attributed to the most potent derivatives include amido NH of the primary or secondary amide, and the acetoxy fragments at positions 7 and 12 of steroid core which are, along with the tetraoxane ring, common for all studied compounds.

New chimeric antimalarials with 4-aminoquinoline moiety linked to a tetraoxane skeleton.

The synthesis of the chimeric molecules consisting of two pharmacophores, tetraoxane and 7-chloro-4-aminoquinoline, is reported. The tetraoxanes 2, 4, and 8 show relatively potent in vitro antimalarial activities, with IC90 values for the Plasmodium falciparum strain W2 of 2.26, 12.