Design, synthesis, molecular docking, and spectral studies of new class of carbazolyl polyhydroquinoline derivatives as promising antibacterial agents with noncytotoxicity towards human mononuclear cells from peripheral blood

Abstract

In the present study, we report the design and eco‐benign synthesis of new class of carbazolyl‐1,4‐dihydropyridine (1,4‐CDHP) and carbazolyl‐1,8‐dioxodecahydroacridine (CAD) derivatives via a three‐component coupling reaction of substituted carbazole aldehydes, ethyl acetoacetate/dimedone, and ammonium acetate under solvent‐free conditions at 112°C to 115°C. We also report an efficient one‐pot synthesis of new class of carbazolyl polyhydroquinoline (CPQ) derivatives via a four‐component coupling reaction of substituted ethyl acetoacetate, dimedone, ammonium acetate, and carbazole aldehydes in acetonitrile/water medium (3:1) at 73°C to 75°C in moderate yields. All the products were thoroughly characterized by 1H NMR, 13C NMR, Fourier transform infrared (FTIR), mass spectral, and CHN analysis. The synthesized heterocyclic compounds were evaluated for their in vitro antibacterial activity against pathogenic strains of both Gram‐negative and Gram‐positive bacteria. Minimum inhibitory concentration (MIC) of the active compounds was evaluated by macrodilution method. The CPQ derivative (8a) displayed superior antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhi with the MIC values of 16.0 to 32.0 μg/mL in comparison with the reference drug. The mechanism of antibacterial action of the CPQ derivatives was investigated via scanning electron microscope (SEM) studies. The molecular docking studies indicate that the CPQ derivative (8a) binds to the cell wall protein of E coli and P aeruginosa by formation of hydrogen bonds with amino acid residues (TYR328 and GLU249) of the bacterial cell wall protein. The 1,4‐CDHP, CAD, and CPQ derivatives were either noncytotoxic or exhibited minimal cytotoxicity towards human mononuclear cells from peripheral blood. All the products were evaluated for Lipinski rule of five (RO5) and were found to have good oral bioavailability.

Ultrases Destekli 9-(Substitue heteroaril) akridindion Türevlerinin Tek Basamakta Sentezi

“…For this purpose, 4-pyridine-carboxaldehyde (2b), 9-ethyl-9H-carbazole-2-carbaldehyde (2c), 2,3-dimethyl-5-oxo-1-phenyl-3-pyrazoline-4carboxaldehyde (2d), 5-methylfuran-2-carboxaldehyde (2e) and ferrocenecarboxaldehyde (2f) were treated with the mentioned conditions above. The reaction of 2b and 2c with dimedon was reported by literature [30][31][32][33] afforded 3b and 3c 83 % and 87 % respectively. We synthesized 3b and biologically active 3c compounds with higher yields in milder conditions and shorter times.…”

Synthesis, Antibacterial Activities and Theoretical Study of Polyhydroquinoline Derivatives

“…[37] Venkatapathy et al synthesized number of carbazolyl polyhydroquinoline compounds (b) and screened them against pathogenic strains of gram positive and gram negative bacteria which have superior activity against six strains of gram positive and gram negative bacteria such as Escherichia coli, Shigella dysenteriae, Pseudomonas aeruginosa, Streptococcus pneumonia, Salmonella typhi and Staphylococcus aureus. [38] In recent years, Nosrati et al synthesized number of polyhydroquinoline derivatives (c) and investigated their antimicrobial activities which exhibit good activity against gram-positive bacteria S. aures. [39] Similarly, Zainab et al reported various compounds based on PHQ nucleus, which exhibit significant antibacterial activity against Escherichia coli (gram-negative bacterium)…”

“…et al . synthesized number of carbazolyl polyhydroquinoline compounds ( b ) and screened them against pathogenic strains of gram positive and gram negative bacteria which have superior activity against six strains of gram positive and gram negative bacteria such as Escherichia coli , Shigella dysenteriae , Pseudomonas aeruginosa , Streptococcus pneumonia , Salmonella typhi and Staphylococcus aureus [38] . In recent years, Nosrati et al .…”

Novel Polyhydroquinoline-Hydrazide-Linked Schiff’s Base Derivatives: Multistep Synthesis, Antimicrobial, and Calcium-Channel-Blocking Activities

“…Exploring non-toxic, effective, and safe chemotherapeutical gents is still a very important concern due to the growth of multi-resistant bacterial strains [ 25 , 26 ]. Infectious diseases continue to attack human beings with opportunistic infectious disorders, and infection with drug-resistant microorganisms [ 27 , 28 ]. During recent years, the treatment of bacterial infections has been challenging in patients with weak immune systems or with other associated diseases [ 29 , 30 ].…”