We report herein, the design and synthesis of thiazolidine-2,4-diones derivatives as new inhibitors for VEGFR-2. The designed members were assessed for their in vitro anticancer activity against four ...cancer cell lines; A549, Caco-2, HepG-2 and MDA-MB-231. Compound 14a showed the most potent effects against Caco-2, and HepG-2 cell lines (IC.sub.50 = of 1.5 and 31.5 muM, respectively). Next, the in vitro VEGFR-2 inhibitory activity, safety profiles and selectivity indices were examined for all the synthesized members against the normal Vero cell line. Compound 14a (the safest member against Caco-2 cell line) was further investigated for its ability to inhibit Caco-2 cells migration and healing. Moreover, the apoptotic induction of compound 14a against Caco-2 cell line was investigated by assessing against four apoptotic genes (Bcl2, Bcl-xl, TGF, and Survivin). The results revealed that compound 14a can exert apoptosis through significant reduction of Bcl2, Survivin, and TGF gene expression levels. Finally, deep computational studies including molecular docking, ADMET, toxicity studies, and MD simulation were carried out. Also, the DFT calculations were performed and discussed, and the results confirmed the inhibitory reactivity of 14a against VEGFR-2. Compound 14a is expected to be used as a potential lead in the development of new VEGFR-2 inhibitors with increased potency.
A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against ...VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound 12a was found to be the most potent candidate against the investigated cell lines with IC
50
values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested in vitro for their VEGFR-2 inhibitory activity showing strong inhibition. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. Compound 12a was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound 12a against VEGFR-2.
The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the “COVID-19” disease that has been declared by WHO as a global emergency. The pandemic, which emerged in China and widespread ...all over the world, has no specific treatment till now. The reported antiviral activities of isoflavonoids encouraged us to find out its in silico anti-SARS-CoV-2 activity. In this work, molecular docking studies were carried out to investigate the interaction of fifty-nine isoflavonoids against hACE2 and viral Mpro. Several other in silico studies including physicochemical properties, ADMET and toxicity have been preceded. The results revealed that the examined isoflavonoids bound perfectly the hACE-2 with free binding energies ranging from −24.02 to −39.33 kcal mol−1, compared to the co-crystallized ligand (−21.39 kcal mol–1). Furthermore, such compounds bound the Mpro with unique binding modes showing free binding energies ranging from −32.19 to −50.79 kcal mol–1, comparing to the co-crystallized ligand (binding energy = −62.84 kcal mol–1). Compounds 33 and 56 showed the most acceptable affinities against hACE2. Compounds 30 and 53 showed the best docking results against Mpro. In silico ADMET studies suggest that most compounds possess drug-likeness properties.
Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of ...anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives
and
were better than the co-crystallized ligand while derivatives
,
,
,
,
,
,
,
, and
exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives
,
, and
have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of
,
, and
against the co-crystallized ligand in a DFT study indicated that
is the most promising candidate to interact with the target receptor (PLpro).
A new semisynthetic derivative of the natural alkaloid, theobromine, has been designed as a lead antiangiogenic compound targeting the EGFR protein. The designed compound is an (m-tolyl)acetamide ...theobromine derivative, (T-1-MTA). Molecular Docking studies have shown a great potential for T-1-MTA to bind to EGFR. MD studies (100 ns) verified the proposed binding. By MM-GBSA analysis, the exact binding with optimal energy of T-1-MTA was also identified. Then, DFT calculations were performed to identify the stability, reactivity, electrostatic potential, and total electron density of T-1-MTA. Furthermore, ADMET analysis indicated the T-1-MTA's general likeness and safety. Accordingly, T-1-MTA has been synthesized to be examined in vitro. Intriguingly, T-1-MTA inhibited the EGFR protein with an IC50 value of 22.89 nM and demonstrated cytotoxic activities against the two cancer cell lines, A549, and HCT-116, with IC50 values of 22.49, and 24.97 μM, respectively. Interestingly, T-1-MTA's IC50 against the normal cell lines, WI-38, was very high (55.14 μM) indicating high selectivity degrees of 2.4 and 2.2, respectively. Furthermore, the flow cytometry analysis of A549 treated with T-1-MTA showed significantly increased ratios of early apoptosis (from 0.07% to 21.24%) as well as late apoptosis (from 0.73% to 37.97%).
As a continuation of our earlier work against SARS-CoV-2, seven FDA-approved drugs were designated as the best SARS-CoV-2 nsp16-nsp10 2'-
-methyltransferase (2'OMTase) inhibitors through 3009 ...compounds. The in silico inhibitory potential of the examined compounds against SARS-CoV-2 nsp16-nsp10 2'-
-methyltransferase (PDB ID: (6W4H) was conducted through a multi-step screening approach. At the beginning, molecular fingerprints experiment with
(
-Adenosylmethionine), the co-crystallized ligand of the targeted enzyme, unveiled the resemblance of 147 drugs. Then, a structural similarity experiment recommended 26 compounds. Therefore, the 26 compounds were docked against 2'OMTase to reveal the potential inhibitory effect of seven promising compounds (Protirelin, (
), Calcium folinate (
), Raltegravir (
), Regadenoson (
), Ertapenem (
), Methylergometrine (
), and Thiamine pyrophosphate hydrochloride (
)). Out of the docked ligands, Ertapenem (
) showed an ideal binding mode like that of the co-crystallized ligand (
). It occupied all sub-pockets of the active site and bound the crucial amino acids. Accordingly, some MD simulation experiments (RMSD, RMSF, R
, SASA, and H-bonding) have been conducted for the 2'OMTase-Ertapenem complex over 100 ns. The performed MD experiments verified the correct binding mode of Ertapenem against 2'OMTase exhibiting low energy and optimal dynamics. Finally, MM-PBSA studies indicated that Ertapenem bonded advantageously to the targeted protein with a free energy value of -43 KJ/mol. Furthermore, the binding free energy analysis revealed the essential amino acids of 2'OMTase that served positively to the binding. The achieved results bring hope to find a treatment for COVID-19 via in vitro and in vivo studies for the pointed compounds.
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•Twenty compounds of novel quinazolin-4(3H)-ones bearing sulfonylurea derivatives were designed and synthesized.•Molecular docking, pharmacophore, QSAR and ADMET studies were carried ...out.•In vivo anti-hyperglycemic activity, in vitro PPARγ binding affinity and insulin-secreting ability were carried out.•Some of the synthesized compounds showed promising anti-hyperglycemic activities.
Peroxisome proliferator-activated receptor gamma (PPARγ) and sulfonylurea receptor (SUR) play crucial roles in management of type-2 diabetes mellitus. In this study, a series of novel quinazoline-4(3H)-one-sulfonylurea hybrids were designed and synthesized as dual PPARγ and SUR agonists. The synthesized compounds were evaluated for their in vivo anti-hyperglycemic activities against STZ-induced hyperglycemic rats. Four compounds (19a, 19d, 19f and 25g) demonstrated potent activities with reduction in blood glucose levels of 40.43, 46.42, 41.23 and 42.50 %, respectively. The most active ten compounds were further evaluated in vitro for their PPARγ binding affinities and insulin-secreting abilities. Compounds 19b, 19d, 19f, 25f and 25g exhibited the highest affinities against PPARγ with IC50 values of 0.371, 0.350, 0.369, 0.408 and 0.353µM, respectively. In addition, compounds 19d, 19f, and 25d showed the highest insulin-secreting activities with EC50 values of 0.97, 1.01 and 1.15µM, respectively. Furthermore, molecular docking and pharmacophore generation techniques were carried out to investigate binding patterns and fit values of the designed compounds with PPARγ and SUR, respectively. Also, two QSAR models were generated to explore the structural requirements controlling the different biological activities of the synthesized compounds against PPARγ and SUR.
Regarding the crucial role of deubiquitinase (DUB) enzymes in many viruses, in particular, Adenovirus, HSV-1, coxsackievirus, and SARS-CoV-2, DUB inhibition was reported as an effective new approach ...to find new effective antiviral agents. In the present study, a new wave of 4-(2-nitrophenoxy)benzamide derivatives was designed and synthesized to fulfill the basic pharmacophoric features of DUB inhibitors. The molecular docking of the designed compounds against deubiquitinase enzymes of the aforementioned viruses was carried out. Significant molecular docking results directed us to conduct in vitro antiviral screening against the aforementioned viruses. The biological data showed very strong to strong antiviral activities with IC 50 values ranging from 10.22 to 44.68 μM against Adenovirus, HSV-1, and coxsackievirus. Compounds 8c, 8d, 10b, and 8a were found to be the most potent against Adenovirus, HSV-1, coxsackievirus, and SAR-CoV-2, respectively. Also, the CC 50 values of the examined compounds ranged from 72.93 to 120.50 μM. Finally, the in silico ADMET and toxicity studies demonstrated that the tested members have a good profile of drug-like properties. Furthermore, we concluded the structure–activity relationship (SAR) of the newly designed and synthesized compounds regarding their in vitro results, which may help medicinal chemists in further optimization to obtain more potential antiviral candidates in the near future as well.
A new series of 1,2,4‐triazolo4,3‐cquinazoline derivatives was designed and synthesized as Topo II inhibitors and DNA intercalators. The cytotoxic effect of the new members was evaluated in vitro ...against a group of cancer cell lines including HCT‐116, HepG‐2, and MCF‐7. Compounds 14c, 14d, 14e, 14e, 15b, 18b, 18c, and 19b exhibited the highest activities with IC50 values ranging from 5.22 to 24.24 µM. Furthermore, Topo II inhibitory activities and DNA intercalating affinities of the most promising candidates were evaluated as a possible mechanism for the antiproliferative effect. The results of the Topo II inhibition and DNA binding tests were coherent with that of in vitro cytotoxicity. Additionally, the most promising compound 18c was analyzed in HepG‐2 cells for its apoptotic effect and cell cycle arrest. It was found that 18c can induce apoptosis and arrest the cell cycle at the G2–M phase. Finally, molecular docking studies were carried out for the designed compounds against the crystal structure of the DNA−Topo II complex as a potential target to explore their binding modes. On the basis of these studies, it was hypothesized that the DNA binding and/or Topo II inhibition would participate in the noted cytotoxicity of the synthesized compounds.
A new series of 1,2,4‐triazolo4,3‐cquinazoline derivatives was designed and synthesized as topoisomerase II (Topo II) inhibitors and DNA intercalators, and their cytotoxic effect was evaluated in vitro. Compounds 14c, 14d, 14e, 14e, 15b, 18b, 18c, and 19b exhibited the highest activities. DNA binding and/or Topo II inhibition may contribute to the cytotoxicity of the synthesized compounds
Based on quinazoline, quinoxaline, and nitrobenzene scaffolds and on pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesised. VEGFR-2 IC
50
values ranged from ...60.00 to 123.85 nM for the new derivatives compared to 54.00 nM for sorafenib. Compounds 15
a
, 15
b
, and 15
d
showed IC
50
from 17.39 to 47.10 µM against human cancer cell lines; hepatocellular carcinoma (HepG2), prostate cancer (PC3), and breast cancer (MCF-7). Meanwhile, the first in terms of VEGFR-2 inhibition was compound 15
d
which came second with regard to antitumor assay with IC
50
= 24.10, 40.90, and 33.40 µM against aforementioned cell lines, respectively. Furthermore, Compound 15
d
increased apoptosis rate of HepG2 from 1.20 to 12.46% as it significantly increased levels of Caspase-3, BAX, and P53 from 49.6274, 40.62, and 42.84 to 561.427, 395.04, and 415.027 pg/mL, respectively. Moreover, 15
d
showed IC
50
of 253 and 381 nM against HER2 and FGFR, respectively.
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