Design, synthesis, molecular docking, anticancer evaluations, and in silico pharmacokinetic studies of novel 5‐[(4‐chloro/2,4‐dichloro)benzylidene]thiazolidine‐2,4‐dione derivatives as VEGFR‐2 inhibitors

Abstract

The anticancer activity of novel thiazolidine‐2,4‐diones was evaluated against HepG2, HCT‐116, and MCF‐7 cells. MCF‐7 was the most sensitive cell line to the cytotoxicity of the new derivatives. In particular, compounds 18, 12, 17, and 16 were found to be the most potent derivatives over all the tested compounds against the cancer cell lines HepG2, HCT116, and MCF‐7, with IC50 = 9.16 ± 0.9, 8.98 ± 0.7, 5.49 ± 0.5 µM; 9.19 ± 0.5, 8.40 ± 0.7, 6.10 ± 0.4 µM; 10.78 ± 1.2, 8.87 ± 1.5, 7.08 ± 1.6 µM; and 10.87 ± 0.8, 9.05 ± 0.7, 7.32 ± 0.4 µM, respectively. Compounds 18 and 12 have nearly the same activities as sorafenib (IC50 = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively), against HepG2 cells, but slightly lower activity against HCT116 cells and slightly higher activity against the MCF‐7 cancer cell line. Also, these compounds displayed lower activities than doxorubicin against HepG2 and HCT‐116 cells but higher activity against MCF‐7 cells (IC50 = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 µM, respectively). In contrast, compounds 17 and 16 exhibited lower activities than sorafenib against HepG2 and HCT116 cells, but nearly equipotent activity against the MCF‐7 cancer cell line. Also, these compounds displayed lower activities than doxorubicin against the three cell lines. All the synthesized derivatives 7–18 were evaluated for their inhibitory activities against VEGFR‐2. The tested compounds displayed high to medium inhibitory activity, with IC50 values ranging from 0.17 ± 0.02 to 0.27 ± 0.03 µM. Compounds 18, 12, 17, and 16 potently inhibited VEGFR‐2 at IC50 values of 0.17 ± 0.02, 0.17 ± 0.02, 0.18 ± 0.02, and 0.18 ± 0.02 µM, respectively, which are nearly more than half of that of the IC50 value for sorafenib (0.10 ± 0.02 µM).

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

“…As depicted in Scheme 2, our convergent synthesis approach to the final compounds started with the preparation of N ‐aryl‐2‐chloroacetamides and N ‐aryl‐3‐chloropropionamides by the reaction of substituted anilines with 2‐chloroacetyl chloride or 3‐chloropropionyl chloride in the presence of triethylamine. [ 20,21,22 ] Similarly, α‐chloroacetate and α‐chloropropionate esters were obtained by the action of α‐chloroacetyl chloride or α‐chloropropionyl chloride against the appropriate alcohol. [ 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.…”

“…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.…”

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

“…Condensation of 17 with one-carbon synthons, namely acetyl chloride, tetrabromophthalic anhydride, and carbon disulfide, in refluxing glacial acetic acid furnished the 1,2, 4-triazolo [4,3-a]quinoxalin-4(5H)-one derivatives 23-25. [45,46] The IR allowed to react with previously prepared α-chloroacetanilide derivatives [47] in the presence of potassium carbonate in dimethylformamide (DMF) to produce the corresponding acetamides 27-34. The structures assigned to this set of acetamide products were established on the basis of their elemental analysis, infrared (IR), mass spectrometry, and 1 H NMR spectral data.…”

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

“…Shah et al [ 9 ] reported that TZD derivative ciglitazone ( I ) (Figure 1) significantly decreased the VEGF production in human granulosa cells in an in vitro model. Extensive studies were reported on the synthesis of several 5‐benzylidenethiazolidine‐2,4‐dione derivatives as potent anticancer agents [ 10–13 ] and potent VEGFR‐2 inhibitors, for example, compound II . [ 9 ] Numerous reports on VEGFR‐2 inhibitors, including the commercialized sunitinib ( III ) (Figure 1), have been published.…”

“…In view of the abovementioned findings and based on our continuous efforts to develop new anticancer agents,[ 70,34–39 ] especially VEGFR‐2 inhibitors, [ 12,13,40–44 ] the goal of our work was to synthesize new agents with the same essential pharmacophoric features of the reported and clinically used VEGFR‐2 inhibitors (e.g., sorafenib). The main core of our molecular design rationale comprised bioisosteric modification strategies of VEGFR‐2 inhibitors at four different positions (Figure 3).…”