Synthesis, antimicrobial evaluation, DNA gyrase inhibition, and in silico pharmacokinetic studies of novel quinoline derivatives

Abstract

Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was assessed against a panel of pathogenic microbes including Gram‐positive bacteria (Streptococcus pneumoniae and Bacillus subtilis), Gram‐negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds that revealed the best activity were subjected to further biological studies to determine their minimum inhibitory concentrations (MICs) against the selected pathogens as well as their in vitro activity against the E. coli DNA gyrase, to realize whether their antimicrobial action is mediated via inhibition of this enzyme. Four of the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent antimicrobial activity with MIC values in the range of 0.66–5.29 μg/ml. Among them, compound 14 exhibited a particularly potent broad‐spectrum antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 0.66–3.98 μg/ml. A subsequent in vitro investigation against the bacterial DNA gyrase target enzyme revealed a significant potent inhibitory activity of quinoline derivative 14, which can be observed from its IC50 value (3.39 μM). Also, a molecular docking study of the most active compounds was carried out to explore the binding affinity of the new ligands toward the active site of DNA gyrase enzyme as a proposed target of their activity. Furthermore, the ADMET profiles of the most highly effective derivatives were analyzed to evaluate their potentials to be developed as good drug candidates.

Synthesis and potential antimicrobial activity of novel α-aminophosphonates derivatives bearing substituted quinoline or quinolone and thiazole moieties

“…Quinoline belongs to a biologically active class of compounds as they show quite diverse biological activities [ 6 ]. Many scientific reports revealed that natural and synthetic quinolines are drawn considerable attention in medicinal chemistry [ 7 , 8 ]. The great attention paid by researchers to the study of quinoline derivatives is explained by their broad range of biological activities, such as anti-Alzheimer [ 9 ], antidiabetic [ 10 ], anti-inflammatory [ 11 ], antituberculosis [ 12 ], anticancer [ 13 ], antioxidant [ 14 ], and as inhibitors of SARS‐CoV‐2 (COVID-19) virus [ 15 – 17 ].…”

Design, synthesis, docking, ADMET profile, and anticancer evaluations of novel thiazolidine‐2,4‐dione derivatives as VEGFR‐2 inhibitors

“…The ester derivatives ( 4 – 6 ) were readily obtained by reacting the potassium salt 3 a under reflux with the appropriate α‐chloroester derivative. [ 49–54 ] However, α‐chloroacetyl chloride was allowed to react with a variety of aromatic amines to obtain the corresponding α‐chloro‐ N ‐arylamides. [ 35,55 ] Treating the potassium salt of 3 a with the freshly prepared α‐chloro‐ N ‐arylamides furnished the corresponding amide derivatives 7 – 14 .…”

In vivo‐ and in silico‐driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors

“…[35][36][37] The resulting N 1 -ethylbenzene-1,2-diamine was utilized for the preparation of 1-ethylquinoxaline-2,3(1H,4H)-dione through condensation with diethyl oxalate. [38] Treatment of the latter with hydrazine hydrate in refluxing ethanol [39,40] readily afforded 1-ethyl-3hydrazinylquinoxalin-2(1H)-one (17). [34] As depicted in Schemes 2 and 3, compound 17 was used as a starting material for the synthesis of both new sets of target compounds.…”