New -phenylpyrrolamide inhibitors of DNA gyrase with improved antibacterial activity.

This study presents the discovery of a new series of -phenylpyrrolamide inhibitors of bacterial DNA gyrase with improved antibacterial activity. The most potent inhibitors had low nanomolar IC values against DNA gyrase (IC; 2-20 nM) and topoisomerase IV (22i, IC = 143 nM). Importantly, none of the compounds showed activity against human DNA topoisomerase IIα, indicating selectivity for bacterial targets.

Benzothiazole DNA gyrase inhibitors and their conjugates with siderophore mimics: design, synthesis and evaluation.

Benzothiazole-based bacterial DNA gyrase and topoisomerase IV inhibitors are promising new antibacterial agents with potent activity against Gram-positive and Gram-negative bacterial strains. The aim of this study was to improve the uptake of these inhibitors into the cytoplasm of Gram-negative bacteria by conjugating them to the small siderophore mimics. The best conjugate 18b displayed potent DNA gyrase and topoisomerase IV inhibition.

Exploring the 5-Substituted 2-Aminobenzothiazole-Based DNA Gyrase B Inhibitors Active against ESKAPE Pathogens.

We present a new series of 2-aminobenzothiazole-based DNA gyrase B inhibitors with promising activity against ESKAPE bacterial pathogens. Based on the binding information extracted from the cocrystal structure of DNA gyrase B inhibitor , in complex with GyrB24, we expanded the chemical space of the benzothiazole-based series to the C5 position of the benzothiazole ring. In particular, compound showed low nanomolar inhibition of DNA gyrase (IC < 10 nM) and broad-spectrum antibacterial activity against pathogens belonging to the ESKAPE group, with the minimum inhibitory concentration < 0.

Design of New Potent and Selective Thiophene-Based K1.3 Inhibitors and Their Potential for Anticancer Activity.

The voltage-gated potassium channel K1.3 has been recognized as a tumor marker and represents a promising new target for the discovery of new anticancer drugs. We designed a novel structural class of K1.

New bisphenol A and bisphenol S analogs: Evaluation of their hERα agonistic and antagonistic activities using the OECD 455 in-vitro assay and molecular modeling.

Bisphenol A (BPA) and bisphenol S (BPS) are agonists of hERα receptors and due to BPA regulations in many countries, several substitutes that are close analogs to BPA and BPS were developed. In the presented study, we have determined human estrogen receptor (hER)α agonist and antagonist activities with the validated OECD assay with the hERα-Hela9903 cell line for five different chemical classes of BPA and BPS analogs. This study also defined clear structure-activity relationships for agonist and antagonist activities of the 12 bisphenols on hERα, which are supported by molecular docking studies.

Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors.

Heat shock protein 90 (Hsp90) is a chaperone responsible for the maturation of many cancer-related proteins, and is therefore an important target for the design of new anticancer agents. Several Hsp90 N-terminal domain inhibitors have been evaluated in clinical trials, but none have been approved as cancer therapies. This is partly due to induction of the heat shock response, which can be avoided using Hsp90 C-terminal-domain (CTD) inhibition.

Discovery of K 1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges.

The K 1.3 voltage-gated potassium ion channel is involved in many physiological processes both at the plasma membrane and in the mitochondria, chiefly in the immune and nervous systems. Therapeutic targeting K 1.

Practical Synthesis and Application of Halogen-Doped Pyrrole Building Blocks.

A practical access to four new halogen-substituted pyrrole building blocks was realized in two to five synthetic steps from commercially available starting materials. The target compounds were prepared on a 50 mg to 1 g scale, and their conversion to nanomolar inhibitors of bacterial DNA gyrase B was demonstrated for three of the prepared building blocks to showcase the usefulness of such chemical motifs in medicinal chemistry.

3D Pharmacophore-Based Discovery of Novel K10.1 Inhibitors with Antiproliferative Activity.

(1) Background: The voltage-gated potassium channel K10.1 (Eag1) is considered a near- universal tumour marker and represents a promising new target for the discovery of novel anticancer drugs. (2) Methods: We utilized the ligand-based drug discovery methodology using 3D pharmacophore modelling and medicinal chemistry approaches to prepare a novel structural class of K10.

New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens.

The rise in multidrug-resistant bacteria defines the need for identification of new antibacterial agents that are less prone to resistance acquisition. Compounds that simultaneously inhibit multiple bacterial targets are more likely to suppress the evolution of target-based resistance than monotargeting compounds. The structurally similar ATP binding sites of DNA gyrase and topoisomerase Ⅳ offer an opportunity to accomplish this goal.

Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation.

The discovery of multi-targeting ligands of bacterial enzymes is an important strategy to combat rapidly spreading antimicrobial resistance. Bacterial DNA gyrase and topoisomerase IV are validated targets for the development of antibiotics. They can be inhibited at their catalytic sites or at their ATP binding sites.

Rational design of balanced dual-targeting antibiotics with limited resistance.

Antibiotics that inhibit multiple bacterial targets offer a promising therapeutic strategy against resistance evolution, but developing such antibiotics is challenging. Here we demonstrate that a rational design of balanced multitargeting antibiotics is feasible by using a medicinal chemistry workflow. The resultant lead compounds, ULD1 and ULD2, belonging to a novel chemical class, almost equipotently inhibit bacterial DNA gyrase and topoisomerase IV complexes and interact with multiple evolutionary conserved amino acids in the ATP-binding pockets of their target proteins.

Synthesis, Antiproliferative Effect, and Topoisomerase II Inhibitory Activity of 3-Methyl-2-phenyl-1-indoles.

A series of 3-methyl-2-phenyl-1-indoles was prepared and investigated for antiproliferative activity on three human tumor cell lines, HeLa, A2780, and MSTO-211H, and some structure-activity relationships were drawn up. The GI values of the most potent compounds ( and ) were lower than 5 μM in all tested cell lines. For the most biologically relevant derivatives, the effect on human DNA topoisomerase II relaxation activity was investigated, which highlighted the good correlation between the antiproliferative effect and topoisomerase II inhibition.

Design and characterization of a novel structural class of Kv1.3 inhibitors.

The voltage-gated potassium channel K1.3 is involved in multiple autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus type 1 and psoriasis. In many auto-immune diseases better treatment options are desired as existing therapies are often ineffective or become less effective over time, for which K1.

Design, synthesis and biological evaluation of novel DNA gyrase inhibitors and their siderophore mimic conjugates.

Bacterial DNA gyrase is an important target for the development of novel antibacterial drugs, which are urgently needed because of high level of antibiotic resistance worldwide. We designed and synthesized new 4,5,6,7-tetrahydrobenzo[d]thiazole-based DNA gyrase B inhibitors and their conjugates with siderophore mimics, which were introduced to increase the uptake of inhibitors into the bacterial cytoplasm. The most potent conjugate 34 had an IC of 58 nM against Escherichia coli DNA gyrase and displayed MIC of 14 µg/mL against E.

In vitro estrogenic activity of binary and multicomponent mixtures with bisphenol A.

Bisphenol A and its analogs are environmental contaminants with well known estrogenic and anti-androgenic activities. In studies of human biomonitoring, simultaneous exposure to multiple bisphenols was shown in different biological samples, at picomolar to low nanomolar concentrations. Evaluation of their combined toxicities will therefore be a more realistic and reliable predictor for estimation of health risks than evaluation of only the single chemicals.

An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors.

ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC values of 6.

ATP-competitive DNA gyrase and topoisomerase IV inhibitors as antibacterial agents.

Introduction: The bacterial topoisomerases DNA gyrase and topoisomerase IV are validated targets for development of novel antibacterial agents. Fluoroquinolones inhibit the catalytic GyrA and/or ParC(GrlA) subunit and have been commonly used, although these have toxicity liabilities that restrict their use. The ATPase GyrB and ParE(GrlB) subunits have been much less explored and after withdrawal of novobiocin, there are no further marketed inhibitors .

Endocrine activities and adipogenic effects of bisphenol AF and its main metabolite.

Bisphenol AF (BPAF) is a fluorinated analog of bisphenol A (BPA), and it is a more potent estrogen receptor (ER) agonist. BPAF is mainly metabolized to BPAF-glucuronide (BPAF-G), which has been reported to lack ER agonist activity and is believed to be biologically inactive. The main goal of the current study was to examine the influence of the metabolism of BPAF via glucuronidation on its ER activity and adipogenesis.

Benzothiazole-based Compounds in Antibacterial Drug Discovery.

Numerous compounds with a benzothiazole scaffold that have been described in the literature show promising activities against several Gram-positive and Gramnegative bacteria, and also against Mycobacterium tuberculosis. Benzothiazole-based antibacterial compounds bind to different biological targets in bacterial cells and have been shown to be inhibitors of enzymes that are important for essential processes in the bacterial cells, such as cell-wall synthesis, cell division, and DNA replication, or are important for different biosynthetic pathways of essential compounds in bacterial cells, such as the biosynthesis of histidine and biotin. This review focuses on the antibacterial potential of benzothiazole-based compounds, in terms of their specific interactions with targets in bacterial cells.