The new thiazolidine-2,4-dione-based hybrids with promising antimycobacterial activity: design, synthesis, biological evaluation, and drug interaction analysis.

The ever-increasing drug-resistant tuberculosis (TB) has invigorated the focus on the discovery and development of novel therapeutic agents and treatment options. Thiazolidinone-based compounds have shown good antitubercular properties . Here, we report the design and synthesis of a number of new derivatives inspired by the structure of thiazolidine-2,4-dione (TZD).

Evaluation of the antidermatophytic activity of potassium salts of N-acylhydrazinecarbodithioates and their aminotriazole-thione derivatives.

Nowadays, dermatophyte infections are relatively easy to cure, especially since the introduction of orally administered antifungals such as terbinafine and itraconazole. However, these drugs may cause side effects due to liver damage or their interactions with other therapeutics. Hence, the search for new effective chemotherapeutics showing antidermatophyte activity seems to be the urge of the moment.

Combined In Silico and In Vitro Analyses to Assess the Anticancer Potential of Thiazolidinedione-Thiosemicarbazone Hybrid Molecules.

The number of people affected by cancer and antibiotic-resistant bacterial infections has increased, such that both diseases are already seen as current and future leading causes of death globally. To address this issue, based on a combined in silico and in vitro approach, we explored the anticancer potential of known antibacterials with a thiazolidinedione-thiosemicarbazone (TZD-TSC) core structure. A cytotoxicity assessment showed encouraging results for compounds -, with IC values against T98G and HepG2 cells in the low micromolar range.

Effect of Linker Elongation on the VGSC Affinity and Anticonvulsant Activity among 4-Alkyl-5-aryl-1,2,4-triazole-3-thione Derivatives.

The main aim of the current project was to investigate the effect of the linker size in 4-alkyl-5-aryl-1,2,4-triazole-3-thione derivatives, known as a group of antiepileptic drug candidates, on their affinity towards voltage-gated sodium channels (VGSCs). The rationale of the study was based both on the SAR observations and docking simulations of the interactions between the designed ligands and the binding site of human VGSC. HYDE docking scores, which describe hydrogen bonding, desolvation, and hydrophobic effects, obtained for 5-[(3-chlorophenyl)ethyl]-4-butyl/hexyl-1,2,4-triazole-3-thiones, justified their beneficial sodium channel blocking activity.

Non-Covalent Isotope Effects.

In this Perspective, we present examples of isotope effects that originate from noncovalent interactions, mainly hydrogen bonding, electrostatics, and confinement. They are traditionally widely used in isotopic enrichment processes, as well as in studies of mechanisms of different (bio)chemical and physical phenomena. We then show the emerging areas of their applications, mainly medical and material sciences.

TZD-Based Hybrid Molecules Act as Dual Anti- and Anti- Agents.

Two distinct intracellular pathogens, namely and cause major public health problems worldwide. In addition, serious and challenging health problems of co-infections of with have been recorded, especially in developing countries. Due to this fact, as well as the frequent cases of resistance to the current drugs, novel anti-infectious therapeutics, especially those with dual (anti- and anti-) modes of action, are needed.

4-Arylthiosemicarbazide derivatives - Pharmacokinetics, toxicity and anti-Toxoplasma gondii activity in vivo.

The increasing resistance of Toxoplasma gondii to drugs and side effects of therapy indicate that specific treatment for these parasites is still needed. The 4-arylthiosemicarbazide derivatives seem to be a solution to this challenge because they have low cytotoxicity against host cells and high anti-T. gondii activity.

Inhibition of by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine.

A safer treatment for toxoplasmosis would be achieved by improving the selectivity profile of novel chemotherapeutics compared to the standard therapy pyrimethamine (PYR) and sulfadiazine (SDZ). We previously reported on the identification of the compounds with imidazole-thiosemicarbazide scaffold as potent and selective anti- ( agents. In our current research, we report on the optimisation of this chemical scaffold leading to the discovery cyclic analogue with -triazole core structure.

Environment-friendly transesterification to seawater-degradable polymers expanded: Computational construction guide to breaking points.

Marine plastic pollution caused by non-biodegradable polymers is a major worldwide concern. So-called "biodegradable" polymers should reduce plastic pollution in the environment by the safeguard of biodegradation. However, many polyesters degrade very slowly in seawater.

4-Arylthiosemicarbazide Derivatives as Toxoplasmic Aromatic Amino Acid Hydroxylase Inhibitors and Anti-inflammatory Agents.

Approximately one-third of the human population is infected with the intracellular cosmopolitan protozoan (), and a specific treatment for this parasite is still needed. Additionally, the increasing resistance of 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.

Unprecedently large Cl/Cl equilibrium isotopic fractionation on nano-confinement of chloride anion.

Confinement can result in unusual properties leading to new, exciting discoveries in the nano-realm. One such consequence of confinement at the nanoscale is extremally large isotopic fractionation, especially at sub-van der Waals distances. Herein, on the example of chlorine isotope effects, we show that at conditions of nanoencapsulation these effects may reach values by far larger than observed for the bulk environment, which in the case of nanotubes can lead to practical applications (e.

Imidazole-Thiosemicarbazide Derivatives as Potent Anti- Compounds with Antibiofilm Activity.

() 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 have led to the re-emergence of tuberculosis as a global pandemic.

RNA-Inspired and Accelerated Degradation of Polylactide in Seawater.

Marine plastic pollution is a worldwide challenge making advances in the field of biodegradable polymer materials necessary. Polylactide (PLA) is a promising biodegradable polymer used in various applications; however, it has a very slow seawater degradability. Herein, we present the first library of PLA derivatives with incorporated "breaking points" to vary the speed of degradation in artificial seawater from years to weeks.

Machine Learning augmented docking studies of aminothioureas at the SARS-CoV-2-ACE2 interface.

The current pandemic outbreak clearly indicated the urgent need for tools allowing fast predictions of bioactivity of a large number of compounds, either available or at least synthesizable. In the computational chemistry toolbox, several such tools are available, with the main ones being docking and structure-activity relationship modeling either by classical linear QSAR or Machine Learning techniques. In this contribution, we focus on the comparison of the results obtained using different docking protocols on the example of the search for bioactivity of compounds containing N-N-C(S)-N scaffold at the S-protein of SARS-CoV-2 virus with ACE2 human receptor interface.

4-Arylthiosemicarbazide derivatives as a new class of tyrosinase inhibitors and anti- agents.

We report herein anti-proliferation effects of 4-arylthiosemicarbazides, with a cyclopentane substitution at 1 position, on highly virulent RH strain of . Among them, the highest anti- activity was found with the -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.

1,3,4-Thiadiazoles Effectively Inhibit Proliferation of .

Congenital and acquired toxoplasmosis caused by the food- and water-born parasite () is one of the most prevalent zoonotic infection of global importance. is an obligate intracellular parasite with limited capacity for extracellular survival, thus a successful, efficient and robust host cell invasion process is crucial for its survival, proliferation and transmission. In this study, we screened a series of novel 1,3,4-thiadiazole-2-halophenylamines functionalized at the C5 position with the imidazole ring (-) for their effects on host cell invasion and proliferation.

Thiosemicarbazide Derivatives Decrease the ATPase Activity of Topoisomerase IV, Inhibit Mycobacterial Growth, and Affect Replication in .

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.

New organometallic ruthenium(ii) complexes with purine analogs - a wide perspective on their biological application.

Three half-sandwich organometallic ruthenium(ii) complexes containing purine analogs such as triazolopyrimidines of general formula [(η-p-cym)Ru(L)Cl], where p-cym represents p-cymene and L is 5,6,7-trimethyl-1,2,4-triazolo[1,5-a]pyrimidine (tmtp for 1), 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine (detp for 2) and 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO for 3), have been synthesized and characterized by elemental analysis, infrared, multinuclear magnetic resonance spectroscopic techniques (H, C, N), and single-crystal X-ray diffraction (for 1 and 2). All these complexes have been thoroughly screened for their in vitro cytotoxicity against MCF-7 and HeLa cell lines as well as L929 murine fibroblast cells, indicating [(η-p-cym)Ru(HmtpO)Cl] (3) as the most active representative against the HeLa cell line and simultaneously being 64-fold less toxic to normal L929 murine fibroblast cells than cisplatin. At the same time, 3 has shown antimetastatic activity comparable to NAMI-A against HeLa cells both after 24 and 48 h of treatment in a wound healing assay.

Isotopic Consequences of Host-Guest Interactions; Noncovalent Chlorine Isotope Effects.

Although weak intermolecular interactions are the essence of most processes of key importance in medicine, industry, environment, and life cycles, their characterization is still not sufficient. Enzymatic dehalogenations that involve chloride anion interaction within a host-guest framework is one of the many examples. Recently published experimental results on host-guest systems provided us with models suitable to assess isotopic consequences of these noncovalent interactions.

Antibacterial Activity of Fluorobenzoylthiosemicarbazides and Their Cyclic Analogues with 1,2,4-Triazole Scaffold.

The development of drug-resistant bacteria is currently one of the major challenges in medicine. Therefore, the discovery of novel lead structures for the design of antibacterial drugs is urgently needed. In this structure-activity relationship study, a library of , , and -fluorobenzoylthiosemicarbazides, and their cyclic analogues with 1,2,4-triazole scaffold, was created and tested for antibacterial activity against Gram-positive bacteria strains.

Docking and QSAR of Aminothioureas at the SARS-CoV-2 S-Protein-Human ACE2 Receptor Interface.

Docking of over 160 aminothiourea derivatives at the SARS-CoV-2 S-protein-human ACE2 receptor interface, whose structure became available recently, has been evaluated for its complex stabilizing potency and subsequently subjected to quantitative structure-activity relationship (QSAR) analysis. The structural variety of the studied compounds, that include 3 different forms of the N-N-C(S)-N skeleton and combinations of 13 different substituents alongside the extensive length of the interface, resulted in the failure of the QSAR analysis, since different molecules were binding to different parts of the interface. Subsequently, absorption, distribution, metabolism, and excretion (ADME) analysis on all studied compounds, followed by a toxicity analysis using statistical models for selected compounds, was carried out to evaluate their potential use as lead compounds for drug design.

Cytotoxic Properties of 1,3,4-Thiadiazole Derivatives-A Review.

During recent years, small molecules containing five-member heterocyclic moieties have become the subject of considerable growing interest for designing new antitumor agents. One of them is 1,3,4-thiadiazole. This study is an attempt to collect the 1,3,4-thiadiazole and its derivatives, which can be considered as potential anticancer agents, reported in the literature in the last ten years.

Synthesis and Anthelmintic Activity of New Thiosemicarbazide Derivatives-A Preliminary Study.

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.

Synergistic Effects of Thiosemicarbazides with Clinical Drugs against .

Antimicrobial resistance spurred by the overuse and misuse of antibiotics is a major global health concern, and of the Gram positive bacteria, is a leading cause of mortality and morbidity. Alternative strategies to treat 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 - and 4-aryl-1-(2-fluorobenzoyl)thiosemicarbazides -) and conventional antibiotics against ATCC 25923, which were determined as the fractional inhibitory concentration indices (FICIs).