379261-85-5

Upstream product

• 159783-41-2 methyl 3-isopropyloxy-4-nitrobenzoate 
• 619-14-7 3-hydroxy-4-nitro-benzoic acid 
• 713-52-0 methyl 3-hydroxy-4-nitrobenzoate 
• 403-21-4 3-fluoro-4-nitrobenzoic acid 
• 67-63-0 isopropyl alcohol 
• 75-26-3 isopropyl bromide 

Downstream Products

• 1006031-13-5 methyl 3-isopropoxy-4-(3-isopropoxy-4-(3-isopropoxy-4-nitro-benzoylamino)-benzoylamino)-benzoate 
• 1006030-98-3 methyl 3-propoxy-4-(3-benzyloxy-4-(3-isopropyloxy-4-nitro-benzoylamino)-benzoylamino)-benzoate 
• 1006031-06-6 C₄₁H₄₆N₄O₁₁ 
• 1006031-11-3 C₅₁H₅₇N₅O₁₃ 
• 1006031-12-4 C₆₃H₅₉N₅O₁₃ 
• 1006030-83-6 methyl 3-isopropoxy-4-(3-isopropoxy-4-nitro-benzoylamino)-benzoate 
• 1147135-00-9 C₁₉H₂₈N₂O₆ 
• 1318208-92-2 isopropyl 3-isopropoxy-4-(3-isopropoxy-4-nitrobenzamido)benzoate 
• 1373319-43-7 methyl 3-isopropoxy-4-(6-isopropoxy-5-(3-isopropoxy-4-nitrobenzamido)picolinamido)benzoate 
• 1006030-92-7 methyl 3-isopropoxy-4-(3-isopropoxy-4-amino-benzoylamino)-benzoate 
• 1006031-03-3 methyl 3-isopropoxy-4-(3-isopropoxy-4-(3-isopropoxy-4-amino-benzoylamino)-benzoylamino)-benzoate 
• 1190360-14-5 3-isopropoxy-4-(3-isopropoxy-4-(3-isopropoxy-4-amino-benzoylamido)-benzoylamido)-benzoic acid 
• 1373319-41-5 methyl 3-isopropoxy-4-(3-isopropoxy-4-(6-isopropoxy-5-nitropicolinamido)benzamido)benzoate 
• 1373319-45-9 methyl 4-(4-(5-amino-6-isopropoxypicolinamido)-3-isopropoxybenzamido)-3-isopropoxybenzoate 

Relevant academic research and scientific papers

Cystobactamid 507: Concise Synthesis, Mode of Action, and Optimization toward More Potent Antibiotics

Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids—a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure–activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor-groove binding as part of the drug–target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919-2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram-negative bacteria.

Design, Synthesis, and Conformational Analysis of Oligobenzanilides as Multifacial α-Helix Mimetics

The design, synthesis, and conformational analysis of an oligobenzanilide helix mimetic scaffold capable of simultaneous mimicry of two faces of an α-helix is reported. The synthetic methodology provides access to diverse monomer building blocks amenable to solid-phase assembly in just four synthetic steps. The conformational flexibility of model dimers was investigated using a combination of solid and solution state methodologies supplemented with DFT calculations. The lack of noncovalent constraints allows for significant conformational plasticity in the scaffold, thus permitting it to successfully mimic residues i, i+2, i+4, i+6, i+7, and i+9 of a canonical α-helix.

NOVEL CYSTOBACTAMIDE DERIVATIVES

The present invention relates to novel derivatives of cystobactamides of formula (lb) and the use thereof for the treatment or prophylaxis of bacterial infections.

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 IC50 values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1–50 μM range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 μM, 1.56 μM, 0.78 μM and 0.72 μM, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 μM on both strains, and MIC value of 32 μM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action.

A structure—activity relationship study of bis-benzamides as inhibitors of androgen receptor—coactivator interaction

The interaction between androgen receptor (AR) and coactivator proteins plays a critical role in AR-mediated prostate cancer (PCa) cell growth, thus its inhibition is emerging as a promising strategy for PCa treatment. To develop potent inhibitors of the

New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity

The ATP binding site located on the subunit B of DNA gyrase is an attractive target for the development of new antibacterial agents. In recent decades, several small-molecule inhibitor classes have been discovered but none has so far reached the market. We present here the discovery of a promising new series of N-phenylpyrrolamides with low nanomolar IC50 values against DNA gyrase, and submicromolar IC50 values against topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compound in the series has an IC50 value of 13 nM against E. coli gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative 11a, with an IC50 value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 μM against Enterococcus faecalis, and 3.13 μM against wild type S. aureus, methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine β-naphthylamide (PAβN) is 4.6 μM.

Synthesis and Evaluation of N-Phenylpyrrolamides as DNA Gyrase B Inhibitors

ATP-competitive inhibitors of DNA gyrase and topoisomerase IV are among the most interesting classes of antibacterial drugs that are unrepresented in the antibacterial pipeline. We developed 32 new N-phenylpyrrolamides and evaluated them against DNA gyrase and topoisomerase IV from E. coli and Staphylococcus aureus. Antibacterial activities were studied against Gram-positive and Gram-negative bacterial strains. The most potent compound displayed an IC50 of 47 nm against E. coli DNA gyrase, and a minimum inhibitory concentration (MIC) of 12.5 μm against the Gram-positive Enterococcus faecalis. Some compounds displayed good antibacterial activities against an efflux-pump-deficient E. coli strain (MIC=6.25 μm) and against wild-type E. coli in the presence of efflux pump inhibitor PAβN (MIC=3.13 μm). Here we describe new findings regarding the structure–activity relationships of N-phenylpyrrolamide DNA gyrase B inhibitors and investigate the factors that are important for the antibacterial activity of this class of compounds.

Biosynthesis of branched alkoxy groups: Iterative methyl group alkylation by a cobalamin-dependent radical SAM enzyme

The biosynthesis of branched alkoxy groups, such as the unique t-butyl group found in a variety of natural products, is still poorly understood. Recently, cystobactamids were isolated and identified from Cystobacter sp as novel antibacterials. These metab

Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers

The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly wiTheR and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.

Assessment of Bromodomain Target Engagement by a Series of BI2536 Analogues with Miniaturized BET-BRET

Evaluating the engagement of a small molecule ligand with a protein target in cells provides useful information for chemical probe optimization and pharmaceutical development. While several techniques exist that can be performed in a low-throughput manner, systematic evaluation of large compound libraries remains a challenge. In-cell engagement measurements are especially useful when evaluating compound classes suspected to target multiple cellular factors. In this study we used a bioluminescent resonant energy transfer assay to assess bromodomain engagement by a compound series containing bromodomain- and kinase-biasing polypharmacophores based on the known dual BRD4 bromodomain/PLK1 kinase inhibitor BI2536. With this assay, we discovered several novel agents with bromodomain-selective specificity profiles and cellular activity. Thus, this platform aids in distinguishing molecules whose cellular activity is difficult to assess due to polypharmacologic effects.