Synthesis and Evaluation of Some New (1,2,4) Triazolo(4,3‐a)Quinoxalin‐4(5H)‐one Derivatives as AMPA Receptor Antagonists

The anticancer activity of novel thiazolidine‐2,4‐diones was evaluated against HepG2, HCT‐116, and MCF‐7 cells. Among the tested cancer cell lines, HCT‐116 was the most sensitive one to the cytotoxic effect of the new derivatives. In particular, compounds 18, 11, and 10 were found to be the most potent derivatives among all the tested compounds against the HepG2, HCT‐116, and MCF‐7 cancer cell lines, with IC50 values ranging from 38.76 to 53.99 µM. The most active antiproliferative derivatives (7–14 and 15–19) were subjected to further biological studies to evaluate their inhibitory potentials against VEGFR‐2. The tested compounds displayed a good‐to‐medium inhibitory activity, with IC50 values ranging from 0.26 to 0.72 µM. Among them, compounds 18, 11, and 10 potently inhibited VEGFR‐2 at IC50 values in the range of 0.26–0.29 µM, which are nearly three times that of the sorafenib IC50 value (0.10 µM). Although our derivatives showed lower activities than the reference drug, they could be useful as a template for future design, optimization, adaptation, and investigation to produce more potent and selective VEGFR‐2 inhibitors with higher anticancer analogs. The ADMET profile showed that compounds 18, 11, and 10 do not violate any of Lipinski's rules and have a comparable intestinal absorptivity in humans. Also, the new derivatives could not inhibit cytochrome P3A4. Unlike sorafenib and doxorubicin, compounds 18, 11, and 10 are expected to have prolonged dosing intervals. Moreover, compounds 10 and 18 displayed a wide therapeutic index and higher selectivity against cancer cells as compared with their cytotoxicity against normal cells.

Section: Resultsmentioning

confidence: 99%

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

El‐Adl

Sakr

El‐Hddad

et al. 2021

“…However, the 4‐nitro derivative 4a was reduced to the corresponding 4‐amino derivative 5 by heating with SnCl 2 as a reducing agent in the presence of hydrochloric acid following the reported procedure. [ 45 ] The produced amino derivative 5 was allowed to react with benzoic acid, the appropriate isocyanates, namely, phenyl and cyclohexyl isocyanates, and/or the appropriate isothiocyanates, namely, propyl, butyl, and cyclohexyl isothiocyanates, to afford the corresponding amide derivative 6 , urea 7a,b , and/or thiourea 8a–c derivatives, respectively (Scheme 2). Finally, the acid derivative 4b was reacted with the appropriate amine, namely, aniline, 4‐chloroaniline, and/or 4‐methylaniline, following the mixed anhydride method to give the corresponding acid amide derivatives 9a−c , respectively (Scheme 3).…”

Section: Resultsmentioning

confidence: 99%

N‐Substituted‐4‐phenylphthalazin‐1‐amine‐derived VEGFR‐2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluation studies

El‐Adl

Ibrahim

Khedr

et al. 2020

In accordance with the significant impetus of the discovery of potent vascular endothelial growth factor receptor 2 (VEGFR‐2) inhibitors, herein, we report the design, synthesis, and anticancer evaluation of 12 new N‐substituted‐4‐phenylphthalazin‐1‐amine derivatives against HepG2, HCT‐116, and MCF‐7 cells as VEGFR‐2 inhibitors. The results of the cytotoxicity investigation indicated that HCT‐116 and MCF‐7 were the most sensitive cell lines to the influence of the newly synthesized derivatives. In particular, compound 7a was found to be the most potent derivative among all the tested compounds against the three cancer cell lines, HepG2, HCT116, and MCF‐7, with IC50 = 13.67 ± 1.2, 5.48 ± 0.4, and 7.34 ± 0.6 µM, respectively, which is nearly equipotent to that of sorafenib (IC50 = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively). All synthesized derivatives, 4a,b−8a−c, were evaluated for their inhibitory activities against VEGFR‐2. The tested compounds displayed high to low inhibitory activity, with IC50 values ranging from 0.14 ± 0.02 to 9.54 ± 0.85 µM. Among them, compound 7a was found to be the most potent derivative that inhibited VEGFR‐2 at an IC50 value of 0.14 ± 0.02 µM, which is nearly 72% of that of the sorafenib IC50 value (0.10 ± 0.02 µM). Compounds 7b, 8c, 8b, and 8a exhibited very good activity with IC50 values of 0.18 ± 0.02, 0.21 ± 0.03, 0.24 ± 0.02, and 0.35 ± 0.04 µM, respectively. Molecular modeling studies were carried out for all compounds against the VEGFR‐2 active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling studies. However, these modifications led to new phthalazine derivatives with higher VEGFR‐2 inhibitory activities than vatalanib and which are nearly equipotent to sorafenib.

“…[ 23,24 ] Final target quinolines of the current work were achieved by the electrophilic substitution of starting 2‐mercapto‐6‐methylquinoline‐3‐carbonitrile with different electrophiles including the above‐prepared 2‐chloro‐ N ‐arylacetamide, 3‐chloro‐ N ‐arylpropanamide, α‐chloroactate, and α‐chloropropionate ester derivatives in the presence of potassium carbonate to neutralize the effect of HCl side product. [ 25,26 ]…”

Section: Resultsmentioning

confidence: 99%

“…[23,24] Final target quinolines of the current work above-prepared 2-chloro-N-arylacetamide, 3-chloro-N-arylpropanamide, α-chloroactate, and α-chloropropionate ester derivatives in the presence of potassium carbonate to neutralize the effect of HCl side product. [25,26] The progress of the chemical reactions was validated by thin-layer chromatography (TLC) methodology and the final products were purified by the column chromatography method. Structures and purities of new derivatives were confirmed on the basis of their IR, liquid chromatography-mass spectrometry, 1 H nuclear magnetic resonance (NMR), and 13 C NMR spectral data.…”

Section: Chemistrymentioning

confidence: 99%

“…After the reaction was completed (monitored by TLC), the mixture allowed to stand overnight. Later, after adding distilled cold water (100 ml), the obtained solid products were collected through filtration, washed with three repetitive portions of cold water (100 ml each) to remove the side salt product triethylammonium chloride, dried, crystallized from ethanol, and finally purified by using column chromatography technique using hexane ethyl acetate as an eluent to afford the pure amide derivatives(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) in reasonable yields.…”

mentioning

confidence: 99%

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

El-Shershaby

El‐Gamal

Bayoumi

et al. 2020

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.