A new class of fused quinazolines has been designed and synthesized via copper-catalyzed Ullmann type C–N coupling followed by intramolecular cross-dehydrogenative coupling reaction in moderate to good yields. The synthesized compounds were tested for in vitro antibacterial activity against three Gram negative ( Escherichia coli , Pseudomonas putida , and Salmonella typhi ) and two Gram positive ( Bacillus subtilis , and Staphylococcus aureus ) bacteria. Among all tested compounds, 8ga , 8gc , and 8gd exhibited promising minimum inhibitory concentration (MIC) values (4–8 μg/mL) for all bacterial strains tested as compared to the positive control ciprofloxacin. The synthesized compounds were also evaluated for their in vitro antifungal activity against Aspergillus niger and Candida albicans and compounds 8ga , 8gc , and 8gd having potential antibacterial activity also showed pronounced antifungal activity (MIC values 8–16 μg/mL) against both strains. The bactericidal assay by propidium iodide and live–dead bacterial cell screening using a mixture of acridine orange/ethidium bromide (AO/Et·Br) showed considerable changes in the bacterial cell membrane, which might be the cause or consequence of cell death. Moreover, the hemolytic activity for most potent compounds ( 8ga , 8gc , and 8gd ) showed their safety profile toward human blood cells.

According to the World Health Organization, antibiotic resistance is a global health threat. Of particular importance are infections caused by multidrug-resistant Gram-negative bacteria including Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa for which limited treatment options exist. Multiple and simultaneously occurring resistance mechanisms including outer membrane impermeability, overexpression of efflux pumps, antibiotic-modifying enzymes, and modification of genes and antibiotic targets have made antibiotic drug development more difficult against these pathogens. One strategy to cope with these challenges is the use of outer membrane permeabilizers that increase the intracellular concentration of antibiotics when used in combination. In some circumstances, this approach can rescue antibiotics from resistance or repurpose currently marketed antibiotics. Tobramycin-based hybrid antibiotic adjuvants that combine two outer membrane-active components have been previously shown to potentiate antibiotics by facilitating transit through the outer membrane, resulting in increased antibiotic accumulation within the cell. Herein, we extended the concept of tobramycin-based hybrid antibiotic adjuvants to tobramycin-based chimeras by engineering up to three different membrane-active antibiotic warheads such as tobramycin, 1-(1-naphthylmethyl)-piperazine, ciprofloxacin, and cyclam into a central 1,3,5-triazine scaffold. Chimera 4 (TOB-TOB-CIP) consistently synergized with ciprofloxacin, levofloxacin, and moxifloxacin against wild-type and fluoroquinolone-resistant P. aeruginosa. Moreover, the susceptibility breakpoints of ceftazidime, aztreonam, and imipenem were reached using the triple combination of chimera 4 with ceftazidime/avibactam, aztreonam/avibactam, and imipenem/relebactam, respectively, against β-lactamase-harboring P. aeruginosa. Our findings demonstrate that tobramycin-based chimeras form a novel class of antibiotic potentiators capable of restoring the activity of antibiotics against P. aeruginosa.

A novel regioselective synthesis of 2-aminoquinolines and 2-arylquinoline-3-carbonitriles is described via copper-mediated tandem reaction.

A simple and efficient one-pot protocol has been demonstrated for the synthesis of imidazo[1,2-c]quinazoline derivatives through a copper catalyzed tandem reaction between substituted 2-(2-bromophenyl)-1H-imidazoles and formamide. The synthetic protocol involves initial Ullmann-type C-N coupling followed by intramolecular dehydrative cyclization. The method uses readily available 2-(2-bromophenyl)-1H-imidazoles as the starting materials to afford imidazo[1,2-c]quinazolines in moderate to good yields and provided 610 mg (71%) yield of 3a from a gram scale reaction.

An easy and efficient organocatalytic approach to the synthesis of 2‐substituted quinazolines is described based on the reaction between 2‐aminobenzylamines and aldehydes or alcohols or amines. Three organocatalytic platforms were investigated, using 3‐nitropyridine, pyridine N‐oxide, and vitamin B3. Having established the new catalytic systems, the tandem transformations of 2‐aminobenzylamines to give substituted quinazolines were achieved in excellent yields and with a broad substrate scope, with no formation of toxic side‐products. The investigated conditions are not restricted to the use of aldehydes; the protocol also works well with alcohols or amines as substrates. These are oxidized in situ to the corresponding aldehydes to achieve the successful transformation. A mechanistic proposal has been drawn up based on control experiments. We found that under aerobic conditions, catalytic amounts of H2O2 can be generated; this plays a key role in the efficacy of the described approach. The green chemistry metrics of the developed method are also presented. The E factor of 8.18 mg/1 mg demonstrates that the reported method is an excellent complement to previous protocols.

Highlights L-Rham induces apoptosis-independent cell death in high grade serous ovarian cancer (HGSOC) cells. L-Rham-induced cell death is dose and time dependent in HGSOC cells grown as 2D or 3D cultures. L-Rham is as effective as paclitaxel to reduce tumor burden and metastasis in a CAM model. L-Rham significantly reduces tumor formation in a low tumor burden model. L-Rham blocks ascites formation.

A simple and efficient strategy for the synthesis of imidazopyridine-fused indoles has been developed that involves one-pot sequential Knoevenagel condensation of readily available active methylene azoles with N-substituted-1H-indole-3-carboxaldehydes or N-substituted-1H-indole-2-carboxaldehydes followed by palladium-catalyzed intramolecular cross dehydrogenative coupling reaction. A series of 36 derivatives was prepared by using this strategy. The products were obtained in moderate to excellent (32-94%) yields and showed broad substrate scope with tolerance of various functional groups and was amiable for gram scale preparation without problems.

A tandem multicomponent approach has been described for the synthesis of quinazolinones, imidazo[1,2‐c]quinazolines and imidazo[4,5‐c]quinolines. The reaction involves a copper‐catalyzed reductive amination through azidation followed by reduction and oxidative amination of C(sp3)–H bonds of N,N‐dimethylacetamide in the presence of TBHP (tert‐butylhydroperoxide) as oxidant. The method uses the easily available sodium azide as a nitrogen source and DMA (N,N‐dimethylacetamide) as a one‐carbon source for the synthesis of these N‐fused heterocycles in good to excellent yields. The reaction can also be used for gram‐scale synthesis.