Quinazolines and thiazolidine-2,4-dions as SARS-CoV-2 inhibitors: repurposing, in silico molecular docking and dynamics simulation.

This paper presents an extensive analysis of COVID-19 with a specific focus on VEGFR-2 inhibitors as potential treatments. The investigation includes an overview of computational methodologies employed in drug repurposing and highlights in silico research aimed at developing treatments for SARS-CoV-2. The study explores the possible effects of twenty-eight established VEGFR-2 inhibitors, which include amide and urea linkers, against SARS-CoV-2. Among these, nine inhibitors exhibit highly promising in silico outcomes (designated as 3-6, 11, 24, 26, 27, and sorafenib) and are subjected to extensive molecular dynamics (MD) simulations to evaluate the binding modes and affinities of these inhibitors to the SARS-CoV-2 Mpro across a 100 ns timeframe. Additionally, MD simulations are conducted to ascertain the binding free energy of the most compelling ligand-pocket complexes identified through docking studies. The findings provide valuable understanding regarding the dynamic and thermodynamic properties of the interactions between ligands and pockets, reinforcing the outcomes of the docking studies and presenting promising prospects for the creation of therapeutic treatments targeting COVID-19.

Anticancer evaluations of iodoquinazoline substituted with allyl and/or benzyl as dual inhibitors of EGFRWT and EGFRT790M: design, synthesis, ADMET and molecular docking.

Fifteen new iodoquinazoline derivatives, 5a,b to 18, are reported in this study and their anticancer evaluation as dual inhibitors of EGFRWT and EGFRT790M. The new derivatives were designed according to the target of structural requirements of receptors. Cytotoxicity of our compounds was evaluated against MCF-7, A549, HCT116 and HepG2 cell lines using MTT assay. Compounds 18, 17 and 14b showed the highest anticancer effects with IC50 = 5.25, 6.46, 5.68 and 5.24 µM, 5.55, 6.85, 5.40 and 5.11 µM and 5.86, 7.03, 6.15 and 5.77 µM against HepG2, MCF-7, HCT116 and A549 cell lines, respectively. The eight highly effective compounds 10, 13, 14a, 14b, 15, 16, 17 and 18 were inspected against VERO normal cell lines to evaluate their cytotoxicity. Our conclusion was that compounds 10, 13, 14a, 14b, 15, 16, 17 and 18 possessed low toxicity against VERO normal cells with IC50 increasing from 43.44 to 52.11 µM. All compounds were additionally assessed for their EGFRWT and EGFRT790M inhibitory activities. Additionally, their ability to bind with EGFRWT and EGFR receptors was confirmed by molecular docking. Compound 17 exhibited the same inhibitory activity as erlotinib. Compounds 10, 13, 14b, 16 and 18 excellently inhibited VEGFR-2 activity with IC50 ranging from 0.17 to 0.50 µM. Moreover, compounds 18, 17, 14b and 16 remarkably inhibited EGFRT790M activity with IC50 = 0.25, 0.30, 0.36 and 0.40 µM respectively. As planned, compounds 18, 17 and 14b showed excellent dual EGFRWT/EGFRT790M inhibitory activities. Finally, our compounds 18, 17 and 14b displayed good in silico ADMET calculated profiles.

2-Thioxo-3,4-dihydropyrimidine and thiourea endowed with sulfonamide moieties as dual EGFRT790M and VEGFR-2 inhibitors: Design, synthesis, docking, and anticancer evaluations.

The effectiveness of a new series of thiopyrimidine and thiourea containing sulfonamides moieties was tested on HCT-116, MCF-7, HepG2, and A549. HepG2 cell line was the one that all the new derivatives affected the most. The greatest potent compounds against the four HepG2, HCT116, MCF-7, and A549 cell lines were 8f and 8g with IC50 = 4.13, 6.64, 5.74, 6.85 µM and 4.09, 4.36, 4.22, 7.25 µM correspondingly. Compound 8g exhibited higher activity than sorafenib against HCT116 and MCF-7 but exhibited lower activity against HepG2 and A549. Moreover, compounds 8f and 8g exhibited higher activities than erlotinib on HepG2, HCT116, and MCF-7 but demonstrated lower activity on A549. The most potent cytotoxic derivatives 6f, 6g, 8c, 8d, 8e, 8f, and 8g were examined on normal VERO cell lines. Our derivatives have low toxicity on VERO cells with IC50 values ranging from 32.05 to 53.15 µM. Additionally, all compounds were assessed for dual VEGFR-2 and EGFRT790M inhibition effects. Compounds 8f and 8g were the most potent derivatives inhibited VEGFR-2 at IC50 value of 0.88 and 0.90 µM, correspondingly. As well, derivatives 8f and 8g could inhibit EGFRT790M demonstrating strongest effects with IC50 = 0.32 and 0.33 µM sequentially. Additionally, the greatest active derivatives ADMET profile was evaluated in relationship with sorafenib and erlotinib as reference agents. The data attained from docking were greatly related to that achieved from the biological testing.

Iodoquinazoline-derived VEGFR-2 and EGFRT790M dual inhibitors: Design, synthesis, molecular docking and anticancer evaluations.

Herein, we report the synthesis of a series of new fourteen iodoquinazoline derivatives 7a-c to 13a-e and their evaluation as potential anticancer agents via dual targeting of EGFRT790M and VEGFR-2. The new derivatives were designed according to the target receptors structural requirements. The compounds were evaluated for their cytotoxicity against HepG2, MCF-7, HCT116 and A549 cancer cell lines using MTT assay. Compound 13e showed the highest anticancer activities with IC50 = 5.70, 7.15, 5.76 and 6.50 µM against HepG2, MCF-7, HCT116 and A549 cell lines correspondingly. Compounds 7c, 9b and 13a-d exhibited very good anticancer effects against the tested cancer cell lines. The highly effective six derivatives 7c, 10, 13b, 13c, 13d and 13e were examined against VERO normal cell lines to estimate their cytotoxic capabilities. Our conclusion revealed that compounds 7c, 10, 13b, 13c, 13d and 13e possessed low toxicity against VERO normal cells with IC50 prolonging from 41.66 to 53.99 µM. Also compounds 7a-c to 13a-e were further evaluated for their inhibitory activity against EGFRT790M and VEGFR-2. Also, their ability to bind with both EGFR and VEGFR-2 receptors was examined by molecular modeling. Compounds 13e, 13d, 7c and 13c excellently inhibited VEGFR-2 activity with IC50 = 0.90, 1.00, 1.25 and 1.50 µM respectively. Moreover, Compounds 13e, 7c, 10 and 13d excellently inhibited EGFRT790M activity with IC50 = 0.30, 0.35, 0.45 and 0.47 µM respectively. Finally, our derivatives 7b, 13d and 13e showed good in silico calculated ADMET profile.

Five and six membered heterocyclic rings endowed with azobenzene as dual EGFRT790M and VEGFR-2 inhibitors: design, synthesis, in silico ADMET profile, molecular docking, dynamic simulation and anticancer evaluations.

Novel azobenzene scaffold-joined heterocyclic isoxazole, pyrazole, triazole, and/or triazine moieties have been developed and synthesized utilizing microwave and traditional methods. Our compounds were tested for growth inhibition of A549, MCF-7, HCT-116, and HepG2 tumors by dual targeting the VEGFR-2 and EGFRT790M enzymes. The suggested compound's manner of binding with EGFRT790M and VEGFR-2 active sites was explored through molecular design and MD modeling. The information from the results of the biological screening and the docking studies was highly correlated. The A549 cell line was the one that responded to the novel compound's effects most effectively. Having IC50 values of 5.15, 6.37, 8.44 and 6.23 µM, respectively, 14 was the most effective derivative on the four A549, MCF-7, HCT116 and HepG2 cancer cells. It had greater activity than erlotinib and slightly inferior activities on the tested cell lines than sorafenib, respectively. The cytotoxicity of the most effective derivatives, 5, 6, 10 and 14, was evaluated against typical VERO cell lines. Having IC50 values ranging from 42.32 to 55.20 µM, the results showed that the investigated drugs have modest toxicity against VERO normal cells. Additionally all derivatives were assessed for their dual VEGFR-2 and EGFRT790M inhibitory effects. Among them, derivatives 14, 5 and 10 were established as the greatest inhibitors of VEGFR-2 at IC50 values of 0.95, 1.25 and 1.50 µM correspondingly. As well, derivatives 14, 6, 5 and 10 could inhibit EGFRT790M activity demonstrating strongest effects with IC50 = 0.25, 0.35, 0.40 and 0.50 µM respectively. Furthermore, the ADMET profile was evaluated for compounds 5, 6, 10 and 14 in contrast to reference drugs sorafenib and erlotinib.

Design, synthesis, docking, ADMET and anticancer evaluations of N-alkyl substituted iodoquinazoline derivatives as dual VEGFR-2 and EGFR inhibitors.

Fifteen new 1-alkyl-6-iodoquinazoline derivatives 5a-d to 9a-e were designed and synthesized and their anticancer activities were evaluated against HepG2, MCF-7, HCT116 and A549 cancer cell lines via dual targeting of EGFR and VEGFR-2. The newly synthesized compounds were designed based on the structure requirements of the target receptors and were confirmed using spectral data. Compound 9c showed the highest anticancer activities with EC50 = 5.00, 6.00, 5.17 and 5.25 µM against HepG2, MCF-7, HCT116 and A549 cell lines correspondingly. Moreover, compounds 5d, 8b, 9a, 9b, 9d, and 9e exhibited very good anticancer effects against the tested cancer cell lines. The highly effective seven derivatives 5d, 8b, 9a-e were examined against VERO normal cell lines to estimate their cytotoxic capabilities. Compounds 9c, 9b, 9d, 9a, 9e and 5d excellently inhibited VEGFR-2 activity with IC50 = 0.85, 0.90, 0.90, 1.00, 1.20 and 1.25 µM respectively. Moreover, compounds 9c, 9d, 9e, 5d, 8b and 9b excellently inhibited EGFRT790M activity with IC50 = 0.22, 0.26, 0.30, 0.40, 0.45 and 0.50 µM respectively. Also, compounds 9c, 9d and 9e excellently inhibited EGFRWT activity with IC50 = 0.15, 0.20 and 0.25 µM respectively. As planned, compound 9c showed excellent dual EGFR/VEGFR-2 inhibitory activities. Consonantly, ADMET study was calculated in silico for the supreme three worthwhile compounds 9b, 9c and 9e in contrast to sorafenib and erlotinib as reference drugs. The obtained results concluded that, our compounds might be useful as prototype for design, optimization, adaptation and investigation to have more powerful and selective dual VEGFR-2/EGFRT790M inhibitors with higher antitumor activity.

New quinazoline sulfonamide derivatives as potential anticancer agents: Identifying a promising hit with dual EGFR/VEGFR-2 inhibitory and radiosensitizing activity.

Herein, we report the synthesis of a series of new quinazoline sulfonamide conjugates 2-16 and their evaluation as potential anticancer agents via dual targeting of EGFRT790M and VEGFR-2. The newly synthesized compounds were designed based on the structure requirements of the target receptors and were confirmed using spectral data. The compounds were evaluated for their cytotoxicity against four cancer cell lines (HepG2, MCF-7, HCT116 and A549) using MTT assay. The most active compounds were further evaluated for their inhibitory activity against EGFRT790M and VEGFR-2. Compound 15 showed the most significant cytotoxic activity with IC50 = 0.0977 µM against MCF-7 and the most potent inhibitory activity against both EGFR and VEGFR with IC50 = 0.0728 and 0.0523 µM, respectively. Compound 15 was able to induce apoptosis in MCF-7 cells and cell cycle arrest at the G2/M phase. The relative safety profile of 15 was assessed using HEK-293 normal cell line and an ADMET profile was carried out. Radiosensitizing evaluation of 15 proved its significant ability to sensitize the cancer cell to the effect of radiation after being subjected to a single dose of 8 Gy gamma irradiation. Molecular docking studies revealed that 15 could bind to the ATP-binding site of EGF and VEGF receptors, inhibiting their activity.

Novel promising benzoxazole/benzothiazole-derived immunomodulatory agents: Design, synthesis, anticancer evaluation, and in silico ADMET analysis.

Eleven novel benzoxazole/benzothiazole-based thalidomide analogs were designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against HepG-2, HCT-116, PC3, and MCF-7 cells. Generally, the open analogs with semicarbazide and thiosemicarbazide moieties (10, 13a-c, 14, and 17a,b) exhibited higher cytotoxic activities than derivatives with closed glutarimide moiety (8a-d). In particular, compound 13a (IC50 = 6.14, 5.79, 10.26, and 4.71 µM against HepG-2, HCT-116, PC3, and MCF-7, respectively) and 14 (IC50 = 7.93, 8.23, 12.37, and 5.43 µM, respectively) exhibited the highest anticancer activities against the four tested cell lines. The most active compounds 13a and 14 were further evaluated for their in vitro immunomodulatory activities on tumor necrosis factor-alpha (TNF-α), caspase-8 (CASP8), vascular endothelial growth factor (VEGF), and nuclear factor kappa-B p65 (NF-κB p65) in HCT-116 cells. Compounds 13a and 14 showed a remarkable and significant reduction in TNF-α. Furthermore, they showed significant elevation in CASP8 levels. Also, they significantly inhibited VEGF. In addition, compound 13a showed significant decreases in the level of NF-κB p65 while compound 14 demonstrated an insignificant decrease with respect to thalidomide. Moreover, our derivatives exhibited good in silico absorption, distribution, metabolism, elimination, toxicity (ADMET) profiles.

Design, synthesis, and docking of novel thiazolidine-2,4-dione multitarget scaffold as new approach for cancer treatment.

Novel thiazolidine-2,4-diones have been developed and estimated as conjoint inhibitors of EGFRT790M and VEGFR-2 against HCT-116, MCF-7, A549, and HepG2 cells. Compounds 6a, 6b, and 6c were known to be the dominant advantageous congeners against HCT116 (IC50 = 15.22, 8.65, and 8.80 µM), A549 (IC50 = 7.10, 6.55, and 8.11 µM), MCF-7 (IC50 = 14.56, 6.65, and 7.09 µM) and HepG2 (IC50 = 11.90, 5.35, and 5.60 µM) mass cell lines, correspondingly. Although compounds 6a, 6b, and 6c disclosed poorer effects than sorafenib (IC50 = 4.00, 4.04, 5.58, and 5.05 µM) against the tested cell sets, congeners 6b and 6c demonstrated higher actions than erlotinib (IC50 = 7.73, 5.49, 8.20, and 13.91 µM) against HCT116, MCF-7 and HepG2 cells, yet lesser performance on A549 cells. The hugely effective derivatives 4e-i and 6a-c were inspected versus VERO normal cell strains. Compounds 6b, 6c, 6a, and 4i were found to be the most effective derivatives, which suppressed VEGFR-2 by IC50 = 0.85, 0.90, 1.50, and 1.80 µM, respectively. Moreover, compounds 6b, 6a, 6c, and 6i could interfere with the EGFRT790M performing strongest effects with IC50 = 0.30, 0.35, 0.50, and 1.00 µM, respectively. What is more, 6a, 6b, and 6c represented satisfactory in silico computed ADMET profile.

Design, synthesis, anticancer evaluation, in silico docking and ADMET analysis of novel indole-based thalidomide analogs as promising immunomodulatory agents.

In the present work, novel 16 indole-based thalidomide analogs were designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against HepG-2, HCT-116, PC3 and MCF-7 cell lines. Generally, the opened analogs of glutarimide ring exhibited higher activities than the closed ones. Compounds 21a-b and 11d,g showed strong potencies against all tested cell lines with IC50 values ranging from 8.27 to 25.20 µM comparable to that of thalidomide (IC50 values ranging from 32.12 to 76.91 µM). The most active compounds were further evaluated for their in vitro immunomodulatory activities via estimation of human tumor necrosis factor alpha (TNF-α), human caspase-8 (CASP8), human vascular endothelial growth factor (VEGF), and nuclear factor kappa-B P65 (NF-κB P65) in HCT-116 cells. Thalidomide was used as a positive control. Compounds 11g, 21a and 21b showed remarkable significant reduction in TNF-α. Furthermore, compounds 11g, 21a and 21b showed significant elevation in CASP8 levels. Compounds 11g and 21a significantly inhibited VEGF. In addition, derivatives 11d, 11g and 21a showed significant decrease in level of NF-κB p65. Moreover, our derivatives exhibited good in silico docking and ADMET profile.Communicated by Ramaswamy H. Sarma.

Exploration of thiazolidine-2,4-diones as tyrosine kinase inhibitors: Design, synthesis, ADMET, docking, and antiproliferative evaluations.

As dual EGFR and VEGFR-2 inhibitors, 22 innovative thiazolidine-2,4-diones were modeled, constructed, and measured for their anticancer performance versus four human neoplasms HCT-116, MCF-7, A549, and HepG2. Molecular docking and MD simulation were performed to inspect the binding technique of the proffered congeners with the EGFR and VEGFR-2 receptors. Evidence realized thanks to the docking inquests was vastly consistent together with that detected through the biological screening. Structures 14a and 14g emerged as the most active compounds toward HCT116 (IC50 = 6.01 and 7.44 µM), MCF-7 (IC50 = 5.77 and 7.23 µM), A549 (IC50 = 5.35 and 5.47 µM) and HepG2 (IC50 = 3.55 and 3.85 µM) tumefaction cells. Compounds 14a and 14g exhibited higher events than sorafenib (IC50 = 5.05, 5.58, 4.04, and 4.00 µM) against HepG2 instead subordinate incidents concerning A549, MCF-7, and HCT116, parallelly. Nevertheless, these compounds signified weightier performance than erlotinib (IC50 = 13.91, 8.20, 5.49, 7.73, and µM), with respect to the four cell lines. Compounds having the best activity against the four cell lines, 12a-f, 13a-d, and 14a-g were chosen to appraise their in vitro VEGFR-2 and EGFRT790M inhibiting activities. The best results were for compounds 14a and 14g compared to sorafenib and erlotinib, respectively, with IC50 values of 0.74 and 0.78 µM and 0.12 and 0.14 µM, respectively. Moreover, 13d, 14a, and 14g showed an adequate in silico calculated ADMET profile. The current investigation presents novel candidates for future optimization to construct mightier and eclectic binary VEGFR-2/EGFRT790M restrainers with higher antitumor effects.

In silico molecular docking, dynamics simulation and repurposing of some VEGFR-2 inhibitors based on the SARS-CoV-2-main-protease inhibitor N3.

The global and rapid spread of the novel human coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has brought immediate urgency to the discovery of favorable targets for COVID-19 treatment. Here, we consider drug reuse as an attractive methodology for drug discovery by reusing existing drugs to treat diseases other than their initial indications. Here, we review current information concerning the global health issue of COVID-19 including VEGFR-2 inhibitors. Besides, we describe computational approaches to be used in drug repurposing and highlight examples of in silico studies of drug development efforts against SARS-CoV-2. The present study suggests the potential anti-SARS-CoV-2 activities of 35 reported VEGFR-2 inhibitors containing the amide and urea linkers. Nineteen members revealed the best in silico results and hence, were subjected to further molecular dynamics (MD) simulation for their inhibitory activities against SARS-CoV-2 Mpro across 100 ns. Furthermore, MD simulations followed by calculations of the free energy of binding were also carried out for the most promising ligand-pocket complexes from docking studies to clarify some information on their dynamic and thermodynamic properties and approve the docking results. These results we obtained probably provided an excellent lead candidate for the development of therapeutic drugs against COVID-19.Communicated by Ramaswamy H. Sarma.

Nanogel-mediated drug delivery system for anticancer agent: pH stimuli responsive poly(ethylene glycol/acrylic acid) nanogel prepared by gamma irradiation.

The popularity of nanogel as nano drug carrier lies in its adjustable physical properties, and the ability to encapsulate drug particles with improved properties is being developed to meet the diverse pH-sensitive nanogel for anticancer agent. Monitoring pH has been identified as an important diagnostic element during the treatment process. A pH-sensitive nanogel consisting of (PEG/PMAc) in the ratio of (50:50%) hasbeen cross-linkedby γ-irradiation techniques at an irradiation dose of 5 kGy. Compound 4 and its nanogel 5 were synthesized and assessed for their anticancer effects against HepG2, A549, MCF-7 and HCT-116 as dual VEGFR-2 and EGFR tyrosine kinases inhibitors. The molecular design was performed to investigate the binding mode of compound 4 with VEGFR-2 and EGFR receptors. Our compound 5 in nanogel showed enhanced anticancer activities against the four tested cancer cell lines and also showed higher inhibition activities against VEGFR-2 and EGFRT790M kinases than the derivative 4. Finally, our derivative 4 showed good in silico calculated ADMET profile. It was expected to show good GIT absorption in human, lower CNS side effects, no hepatotoxic actions and higher acute and oral chronic toxic doses in comparing to sorafenib and erlotinib. The obtained results showed that, our compound could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective dual VEGFR-2/EGFRT790M inhibitors with higher anticancer activity.

Design, synthesis, in silico docking, ADMET and anticancer evaluations of thiazolidine-2,4-diones bearing heterocyclic rings as dual VEGFR-2/EGFRT790M tyrosine kinase inhibitors.

Fourteen recent thiazolidine-2,4-diones bearing furan and/or thiophene heterocyclic rings have been designed, synthesized and assessed for their anticancer activities against four human tumor cell lines HepG2, A549, MCF-7 and HCT-116 targeting both VEGFR-2 and EGFR tyrosine kinases. Molecular design was carried out to investigate the binding mode of the proposed compounds with VEGFR-2 and EGFR receptors. HepG2 was the most susceptible cell line to the influence of our derivatives. Compounds 5g and 4g revealed the highest activities against HepG2 (IC50 = 3.86 and 6.22 µM), A549 (IC50 = 7.55 and 12.92 µM), MCF-7 (IC50 = 10.65 and 10.66 µM) and HCT116 (IC50 = 9.04 and 11.17 µM) tumor cell lines. Sorafenib (IC50 = 4.00, 4.04, 5.58 and 5.05 µM) and elotinib (IC50 = 7.73, 5.49, 8.20 and 13.91 µM) were used as reference standards. Furthermore, the most active cytotoxic compounds 4d, 4e, 4f, 4g, 5d, 5e, 5f and 5g were selected to assess their VEGFR-2 inhibitory effects. Derivatives 5g, 4g and 4f were observed to be the highest effective derivatives that inhibited VEGFR-2 at the submicromolar level (IC50 = 0.080, 0.083 and 0.095 µM respectively) in comparison to sorafenib (IC50 = 0.084 µM). As well, compounds 4d, 4e, 4f, 4g, 5d, 5e, 5f and 5g were additionally assessed for their inhibitory activities against mutant EGFRT790M. Compounds 5g and 4g could interfere with the EGFRT790M activity exhibiting stronger activities than elotinib with IC50 = 0.14 and 0.23 µM respectively. Finally, our derivatives 4g, 5f and 5g showed a good in silico calculated ADMET profile. The obtained results showed that our compounds could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective dual VEGFR-2/EGFRT790M inhibitors with higher anticancer activity.

Triazoloquinoxalines-based DNA intercalators-Topo II inhibitors: design, synthesis, docking, ADMET and anti-proliferative evaluations.

Sixteen [1, 2, 4]triazolo[4,3-a]quinoxalines as DNA intercalators-Topo II inhibitors have been prepared and their anticancer actions evaluated towards three cancer cell lines. The new compounds affected on high percentage of MCF-7. Derivatives 7e, 7c and 7b exhibited the highest anticancer activities. Their activities were higher than that of doxorubicin. Molecular docking studies showed that the HBA present in the chromophore, the substituted distal phenyl moiety and the extended linkers enable our derivatives to act as DNA binders. Also, the pyrazoline moiety formed six H-bonds and improved affinities with DNA active site. Finally, 7e, 7c and 7b exhibited the highest DNA affinities and act as traditional intercalators of DNA. The most active derivatives 7e, 7c, 7b, 7g and 6e were subjected to evaluate their Topo II inhibition and DNA binding actions. Derivative 7e exhibited the highest binding affinity. It intercalates DNA at IC50 = 29.06 µM. Moreover, compound 7e potently intercalates DNA at an IC50 value of 31.24 µM. Finally, compound 7e demonstrated the most potent Topo II inhibitor at a value of 0.890 µM. Compound 7c exhibited an equipotent IC50 value (0.940 µM) to that of doxorubicin. Furthermore, derivatives 7b, 7c, 7e and 7g displayed a high ADMET profile.

New quinoxalin-2(1H)-one-derived VEGFR-2 inhibitors: Design, synthesis, in vitro anticancer evaluations, in silico ADMET, and docking studies.

More than 70% of cancer patients who are treated with chemotherapeutics do not show a durable response. As part of the global plan seeking new effective chemotherapeutics, here, we report the synthesis and in vitro and computational studies of new lenvatinib and sorafenib analog quinoxalines as vascular endothelial growth factor receptor II (VEGFR-2) tyrosine kinase inhibitors. The central quinolone and pyridine moieties of the Food and Drug Administration-approved anticancer agents lenvatinib and sorafenib were replaced with the versatile quinoxaline scaffold that has been exploited for developing potent cytotoxic agents. With some minor structural optimizations, all the other pharmacophoric features of lenvatinib and sorafenib were maintained. Accordingly, three new sets of quinoxalines were synthesized to evaluate their activity against liver, colorectal, and breast malignancies. The results obtained in the in vitro cytotoxicity evaluation study revealed the superior activity of three derivatives (20, 25, and 29) compared with that of doxorubicin and sorafenib. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling and docking of 20, 25, and 29 into the VEGFR-2 receptor were also performed. Results of in silico studies showed the potential of the designed compounds to bind effectively with a number of key residues. The obtained in vitro cytotoxic activity and ADMET profiles of compounds 20, 25, and 29 suggested that they should be subjected to further structural optimizations to develop new candidates in cancer treatment protocols.

Triazoloquinazoline derived classical DNA intercalators: Design, synthesis, in silico ADME profile, docking, and antiproliferative evaluations.

Thirteen novel [1,2,4]triazolo[4,3-c]quinazoline derivatives as DNA intercalators were synthesized and their anticancer activities evaluated against HepG2 and HCT-116 cells. A docking study was carried out to explore how the new derivatives bind to active sites of DNA. The docking data were highly interrelated with that of biological testing. The HCT-116 cell line was the most sensitive one to the effect of the new derivatives. Compound 7c exhibited the highest anticancer activities against both the HepG2 and HCT116 cancer cell lines. Despite this compound displaying less activity than doxorubicin, it could be useful as a template for future manipulation, optimization, and investigation to produce other analogs with potential activity. The most active derivatives, 7c , 7b , and 7a were evaluated as DNA binders. Compound 7c displayed the highest binding affinity. Furthermore, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile was calculated for the four most active compounds in comparison to doxorubicin as reference drug. Our derivatives 7a , 7b , and 7c displayed a very good calculated ADMET profile in comparison to doxorubicin.

Antiproliferative evaluations of triazoloquinazolines as classical DNA intercalators: Design, synthesis, ADMET profile, and molecular docking.

Novel triazoloquinazolines were designed and synthesized and evaluated as anticancer agents against HepG2 and HCT-116 cells. The biological testing data corresponded well to those of the molecular docking studies. The HCT-116 cell line was most affected due to the actions of our derivatives. Derivative 7a was the most potent one against both HepG2 and HCT116 cells, with IC50 = 7.98 and 5.57 µM, respectively. This compound showed anticancer activity that was nearly equipotent to that of doxorubicin against HepG2 cells, but higher than that of doxorubicin against HCT116 cells (IC50 = 7.94 and 8.07 µM, respectively). Compounds 8, 7b , and 6f showed excellent anticancer activities against both the HCT116 and HepG2 cell lines. The highly active compounds 6f , 7a , 7b , and 8 were evaluated for their DNA-binding activities. Compounds 7a and 8 showed the highest binding activities. These derivatives potently intercalate in DNA, at IC50 values of 42.90 and 48.13 µM, respectively. Derivatives 6f and 7b showed good DNA-binding activities, with IC50 values of 54.24 and 50.56 µM, respectively. Furthermore, in silico calculated ADMET profiles were established for our four highly active derivatives, in comparison to doxorubicin. Our derivatives 6f , 7a , 7b , and 8 showed a very good ADMET profile. Compounds 6f , 7a , 7b , and 8 follow Lipinski's rules, while doxorubicin violates three of these rules.

Design, Molecular Docking, Synthesis, Anticancer and Anti-Hyperglycemic Assessments of Thiazolidine-2,4-diones Bearing Sulfonylthiourea Moieties as Potent VEGFR-2 Inhibitors and PPARγ Agonists.

Newly designed thiazolidine-2,4-diones 3-7a-c were synthesized, and their anticancer activities were screened against three cancer lines. They showed potent activities against HepG2 compared to the other HCT116 and MCF-7 tumor cell lines. Compounds 7c and 6c were detected as highly effective derivatives against MCF-7 (IC50 = 7.78 and 8.15 µM), HCT116 (IC50 = 5.77 and 7.11 µM) and HepG2 (IC50 = 8.82 and 8.99 µM). The highly effective derivatives 6a-c and 7a-c were tested against VERO normal cell lines. All derivatives were evaluated for their VEGFR-2 inhibitory actions and demonstrated high to low activities, with IC50 values varying from 0.08 to 0.93 µM. Moreover, derivatives 5a-c, 6a-c and 7a-c were assessed to verify their in vitro binding affinities to PPARγ and insulin-secreting activities. Finally, docking studies were performed to explore their affinities and binding modes toward both VEGFR-2 and PPARγ receptors.

Design, synthesis, in silico ADMET, docking, and antiproliferative evaluations of [1,2,4]triazolo[4,3-c]quinazolines as classical DNA intercalators.

Eleven novel [1,2,4]triazolo[4,3-c]quinazolines were designed, synthesized, and evaluated against HepG2 and HCT-116 cells. The molecular design was performed to investigate the binding mode of the proposed compounds with the DNA active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling. HCT-116 was found to be the most sensitive cell line to the influence of the new derivatives. In particular, compounds 6f and 6e were found to be the most potent derivatives over all the tested compounds against the two HepG2 and HCT116 cancer cell lines, with IC50 = 23.44 ± 2.9, 12.63 ± 1.2, and 25.80 ± 2.1, and 14.32 ± 1.5 µM, respectively. Although compounds 6f and 6e displayed less activity than doxorubicin (IC50 = 7.94 ± 0.6 and 8.07 ± 0.8 µM, respectively), both could be useful as a template for future design, optimization, and investigation to produce more potent anticancer analogs. The most active derivatives 6a , 6c , 6e , and 6f were evaluated for their DNA-binding activities. Compound 6f displayed the highest binding affinity. This compound potently intercalates DNA at a decreased IC50 value (54.08 µM). Compounds 6a , 6c , and 6e exhibited good DNA-binding affinities, with IC50 values of 79.35, 84.08, and 59.35 µM, respectively. Furthermore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles were calculated for the four most active compounds in comparison to doxorubicin as a reference drug. Our derivatives 6a , 6c , 6e , and 6f displayed very good in-silico-predicted ADMET profiles. Doxorubicin violates three of Lipinski's rules, our derivatives 6a , 6c , 6e , and 6f do not violate any rule.