Design and Synthesis of Imidazo/Benzimidazo[1,2-c]quinazoline Derivatives and Evaluation of Their Antimicrobial Activity

Abstract

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.

Synthesis and Antimicrobial Activity Evaluation of Imidazole‐Fused Imidazo[2,1‐b][1,3,4]thiadiazole Analogues

“…A hemolysis test is an important part of safety evaluation of drugs before they enter the market [35] . We conducted hemolysis tests using compounds 20 e and 21 a at 20, 200, and 500 μM [50,51] .…”

“…The above results indicate that the introduction of substituents at the 2‐, 5‐ and 6‐positions of the imidazo[2,1‐ b ][1,3,4]thiadiazole moiety can improve the antimicrobial activity. In addition, compounds containing an imidazole moiety, such as 8 [34] and 9 , [35] have been reported to have excellent antibacterial and antifungal activity.…”

Copper‐Catalyzed Cross‐Dehydrogenative Coupling Reactions

“…Nandawana et al developed a novel copper-catalyzed procedure for the synthesis of fused quinazolines (137) using 2-(2-bromophenyl)-1H-imidazole/benzimidazole (134) and azoles (135) through Ullmann-type CÀ N coupling and cross-dehydrogenative coupling. [47] The reaction between 2-(2-bromophenyl)-1H-imidazole/benzimidazole and various azoles such as imidazole, indole, and 1, 2, 4-triazole was carried out in the presence of 20 mol% CuI, 2 mmol K 2 CO 3 in DMF at 150°C for 2 h and further it undergoes CDC in the presence of Cu-(OAc) 2 .H 2 O for 2-5 h and afforded moderate to good yields (Scheme 42). Various substituted 2-(2-bromophenyl)-1Himidazole easily reacted with pyrazoles and imidazoles to furnish the required product in 45-60 % yield.…”

“…Nandawana et al developed a novel copper-catalyzed procedure for the synthesis of fused quinazolines (137) using 2-(2-bromophenyl)-1H-imidazole/benzimidazole (134) and azoles (135) through Ullmann-type CÀ N coupling and cross-dehydrogenative coupling. [47] The reaction between 2- 140) via copper-catalyzed C(sp 3 )À C(sp 2 ) bond formation through an arylation of carbonyl group followed by aerobic oxidative dehydrogenative CÀ N coupling reaction. [48] The reaction of 2-(2-bromophenyl)-quinazolin-4(3H)-one (138) with 5, 5dimethylcyclohexane-1, 3-dione (139) in DMF using 0.1 mmol CuBr and 1.2 equiv.…”

Synthesis, XRD, spectral (IR, UV–Vis, NMR) characterization and quantum chemical exploration of benzoimidazole‐based hydrazones: A synergistic experimental‐computational analysis

“…The rigid aromatic system that present in the structure of benzimidazole gives rise to specific spectroscopic which makes it an active probe for nucleic acids. Recently, benzimidazole and its derivatives have attained considerable attention due to their potential applications as antiulcer (omeprazole), tubulin polymerization inhibitor, antihypertensive, antifungal, anticancer, anthelmintic, antibacterial, cytotoxicity, antimicrobial, anti‐inflammatory, antitumor, Trypanosomacruzi (Tc) infection, histamine‐H3 antagonist, antioxidant, gastro protective and anti‐parasitic, DNA binding and DNA‐encoded library (DEL) technology, enzyme inhibition, Alzheimer disease (AD) and HIV‐1 induced inhibitor for cytopathic activity. Furthermore, these derivatives have been employed as organic ligands, corrosion science, functional materials, catalysis, chemosensing, fluorescence signaling, self‐aggregation and dye sensitized solar cells (DSSCs) …”