1-Benzyl-5-bromo-3-hydrazonoindolin-2-ones as Novel Anticancer Agents: Synthesis, Biological Evaluation and Molecular Modeling Insights.

Human health is experiencing several obstacles in the modern medical era, particularly cancer. As a result, the cancer therapeutic arsenal should be continually expanded with innovative small molecules that preferentially target tumour cells. In this study, we describe the development of two small molecule series (7a-d and 12a-e) based on the 1-benzyl-5-bromoindolin-2-one scaffold that connected through a hydrazone linker to a 4-arylthiazole (7a-d) or 4-methyl-5-(aryldiazenyl)thiazole (12a-e) moiety. The anticancer activity of all the reported indolin-2-one derivatives was assessed against breast (MCF-7) and lung (A-549) cancer cell lines. The 4-arylthiazole-bearing derivatives 7c and 7d revealed the best anticancer activity toward MCF-7 cells (IC50 = 7.17 ± 0.94 and 2.93 ± 0.47, respectively). Furthermore, the VEGFR-2 inhibitory activity for 7c and 7d was evaluated. Both molecules disclosed good inhibitory activity, and their IC50 values were equal to 0.728 µM and 0.503 µM, respectively. Additionally, the impacts of 7d on the cell cycle phases as well as on the levels of different apoptotic markers (caspase-3, caspase-9, Bax, and Bcl-2) were assessed. Molecular docking and dynamic simulations are carried out to explore the binding mode of 7d within the VEGFR-2 active site.

Design, synthesis, and anti-proliferative evaluation of new quinazolin-4(3H)-ones as potential VEGFR-2 inhibitors.

Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Thus, nineteen new quinazoline-4(3H)-one derivatives were designed and synthesized. Preliminary cytotoxicity studies of the synthesized compounds were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Five compounds were found to have promising cytotoxic activities against all cell lines. Compound 16f, containing a 2-chloro-5-nitrophenyl group, has emerged as the most active member. It was approximately 4.39-, 5.73- and 1.96-fold more active than doxorubicin and 3.88-, 5.59- and 1.84-fold more active than sorafenib against HepG2, HCT-116 and MCF-7 cells, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities. The results of in vitro VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Molecular docking of these compounds into the kinase domain, moreover, supported the results.

Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer.

In the current work, a new set of carbohydrazide linked benzofuran-isatin conjugates (5a-e and 7a-i) was designed and synthesised. The anticancer activity for compounds (5b-d, 7a, 7b, 7d and 7g) was measured against NCI-55 human cancer cell lines. Compound 5d was the most efficient, and thus subjected to the five-dose screen where it showed excellent broad activity against almost all tested cancer subpanels. Furthermore, all conjugates (5a-e and 7a-i) showed a good anti-proliferative activity towards colorectal cancer SW-620 and HT-29 cell lines, with an excellent inhibitory effect for compounds 5a and 5d (IC50 = 8.7 and 9.4 µM (5a), and 6.5 and 9.8 µM for (5d), respectively). Both compounds displayed selective cytotoxicity with good safety profile. In addition, both compounds provoked apoptosis in a dose dependent manner in SW-620 cells. Also, they significantly inhibited the anti-apoptotic Bcl2 protein expression and increased the cleaved PARP level that resulted in SW-620 cells apoptosis.

Development of 2-oindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells.

Mitochondrial anti-apoptotic Bcl2 and BclxL proteins, are overexpressed in multiple tumour types, and has been involved in the progression and survival of malignant cells. Therefore, inhibition of such proteins has become a validated and attractive target for anticancer drug discovery. In this manner, the present studies developed a series of novel isatin-indole conjugates (7a-j and 9a-e) as potential anticancer Bcl2 and BclxL inhibitors. The progression of the two examined colorectal cancer cell lines was significantly inhibited by all of the prepared compounds with IC50 ranges132-611 nM compared to IC50 = 4.6 µM for 5FU, against HT-29 and IC50 ranges 37-468 nM compared to IC50 = 1.5 µM for 5FU, against SW-620. Thereafter, compounds 7c and 7g were selected for further investigations. Interestingly, both compounds exhibited selective cytotoxicity against both cell lines with high safety to normal fibroblast (HFF-1). In addition, both compounds 7c and 7g induced apoptosis and inhibited Bcl2 and BclxL expression in a dose-dependent manner. Collectively, the high potency and selective cytotoxicity suggested that conjugates 7c and 7g could be a starting point for further optimisation to develop novel pro-apoptotic and antitumor agents towards colon cancer.

Discovery of novel triazolophthalazine derivatives as DNA intercalators and topoisomerase II inhibitors.

A new series of triazolophthalazine derivatives was designed and synthesized as topoisomerase II (Topo II) inhibitors and DNA intercalators. The synthesized derivatives were evaluated in vitro for their cytotoxic activities against three human cancer cell lines: HepG2, MCF-7, and HCT-116 cells. Compound IXb was the most potent counterpart with IC50 values of 5.39 ± 0.4, 3.81 ± 0.2, and 4.38 ± 0.3 µM, as it was about 1.47, 1.77, and 1.19 times more active than doxorubicin (IC50 = 7.94 ± 0.6, 6.75 ± 0.4, and 5.23 ± 0.3 µM) against HepG2, MCF-7, and HCT-116 cells, respectively. Additionally, the binding affinity of the synthesized compounds toward the DNA molecule was assessed using the DNA/methyl green assay. Compound IXb showed an excellent DNA binding affinity with an IC50 value of 27.16 ± 1.2 µM, which was better than that of the reference drug doxorubicin (IC50 = 31.02 ± 1.80 µM). Moreover, compound IXb was the most potent member among the tested compounds when investigated for their Topo II inhibitory activity. Furthermore, compound IXb induced apoptosis in HepG2 cells and arrested the cell cycle at the G2/M phase. Additionally, compound IXb showed Topo II poisoning effects at 2.5 µM and Topo II catalytic inhibitory effects at 5 and 10 µM. Finally, molecular docking studies were carried out against the DNA-Topo II complex and DNA, to investigate the binding patterns of the designed compounds.

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.

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).

Design, synthesis, molecular modeling, in vivo studies and anticancer activity evaluation of new phthalazine derivatives as potential DNA intercalators and topoisomerase II inhibitors.

Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism for the anticancer activity. Compounds 15h, 23c, 32a, 32b, and 33 exhibited the highest activities against Topo II with IC50 ranging from 5.44 to 8.90 µM, while compounds 27 and 32a were found to be the most potent DNA binders at IC50 values of 36.02 and 48.30 µM, respectively. Moreover, compound 32a induced apoptosis in HepG-2 cells and arrested the cell cycle at the G2/M phase. Besides, compound 32a showed Topo II poisoning effect at concentrations of 2.5 and 5 µM, and Topo II catalytic inhibitory effect at a concentration of10 µM. In addition, compound 32b showed in vivo a significant tumor growth inhibition effect. Furthermore, molecular docking studies were carried out against DNA-Topo II complex and DNA to investigate the binding patterns of the designed compounds.

Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole-Indole Conjugates as Anticancer CDK Inhibitors.

On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole-indole conjugates (6a-i and 9a-f) and carbocycle-indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole-indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05-21.40 ± 1.58 µM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04-22.54 ± 1.67 µM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a-h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s equal 1.82 and 1.26 µM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.

Phthalazine-1,4-dione derivatives as non-competitive AMPA receptor antagonists: design, synthesis, anticonvulsant evaluation, ADMET profile and molecular docking.

In view of the anticonvulsant activity reported for phthalazine derivatives as non-competitive AMPA receptor antagonists, a new series of phthalazine-1,4-diones (2-12) were designed and synthesized. The neurotoxicity was assessed using rotarod test. The molecular docking was performed for the synthesized compounds to assess their binding affinities toward AMPA receptor as non-competitive antagonists. The molecular modeling data were strongly interrelated to biological screening data. Compounds 8, 7b, 7a, 10 and 3a exhibited the highest binding affinities as non-competitive AMPA receptor antagonists and also showed the highest relative potencies of 1.78, 1.66, 1.60, 1.59 and 1.29, respectively, as anticonvulsants in comparison with diazepam. The most active compounds 8, 7b, 7a, 10 and 3a were further tested against maximal electroshock seizure (MES). Compounds 8 and 7b and 3a showed 100% protection at a dose level of 125 µgm/kg, while compounds 7a and 10 exhibited 83.33% protection at the same dose level. These agents exerted low neurotoxicity and high safety margin in comparison with valproate as a reference drug. Most of our designed compounds exhibited good ADMET profile.

Design, synthesis, in silico ADMET profile and GABA-A docking of novel phthalazines as potent anticonvulsants.

A new series of 2-substituted-2,3-dihydrophthalazine-1,4-diones (2- 9) were designed and synthesized to evaluate their anticonvulsant activity. The neurotoxicity was assessed using the rotarod test. Molecular docking was performed for the synthesized compounds to assess their binding affinities as γ-aminobutyric acid A (GABA-A) receptor agonists as a possible mechanism of their anticonvulsant action, to rationalize their anticonvulsant activity in a qualitative way. The data obtained from the molecular modeling was strongly matched with that obtained from the biological screening, which revealed that compounds 5a , 9b , and 9h showed the highest binding affinities toward the GABA-A receptor and also showed the highest anticonvulsant activities with relative potencies of 1.66, 1.63, and 1.61, respectively, compared with diazepam. The most active compounds 5a , 9b , and 9h were further tested against maximal electroshock seizures. Compounds 5a and 9b showed 100% protection at a dose level of 125 µg/kg, while compound 9h exhibited 83.33% protection at the same dose level. A GABA enzymatic assay was performed for these highly active compounds to confirm the obtained results and to explain the possible mechanism for their anticonvulsant action. These agents exerted low neurotoxicity and a high safety margin compared with valproate as a reference drug. Most of our designed compounds exhibited a good ADMET profile.

Discovery and antiproliferative evaluation of new quinoxalines as potential DNA intercalators and topoisomerase II inhibitors.

In continuation of our previous work on the design and synthesis of topoisomerase II (Topo II) inhibitors and DNA intercalators, a new series of quinoxaline derivatives were designed and synthesized. The synthesized compounds were evaluated for their cytotoxic activities against a panel of three cancer cell lines (Hep G-2, Hep-2, and Caco-2). Compounds 18b, 19b, 23, 25b, and 26 showed strong potencies against all tested cell lines with IC50 values ranging from 0.26 ± 0.1 to 2.91 ± 0.1 µM, comparable with those of doxorubicin (IC50 values ranging from 0.65 ± 0.1 to 0.81 ± 0.1 µM). The most active compounds were further evaluated for their Topo II inhibitory activities and DNA intercalating affinities. Compounds 19b and 19c exhibited high activities against Topo II (IC50 = 0.97 ± 0.1 and 1.10 ± 0.1 µM, respectively) and bound the DNA at concentrations of 43.51 ± 2.0 and 49.11 ± 1.8 µM, respectively, whereas compound 28b exhibited a significant affinity to bind the DNA with an IC50 value of 37.06 ± 1.8 µM. Moreover, apoptosis and cell-cycle tests of the most promising compound 19b were carried out. It was found that 19b can significantly induce apoptosis in Hep G-2 cells. It has revealed cell-cycle arrest at the G2/M phase. Moreover, compound 19b downregulated the Bcl-2 levels, indicating its potential to enhance apoptosis. Furthermore, molecular docking studies were carried out against the DNA-Topo II complex to examine the binding patterns of the synthesized compounds.

Design, Synthesis, Molecular Docking, and Anticancer Activity of Phthalazine Derivatives as VEGFR-2 Inhibitors.

Novel series of phthalazine derivatives 6-11 were designed, synthesized, and evaluated for their anticancer activity against two human tumor cell lines, HCT-116 human colon adenocarcinoma and MCF-7 breast cancer cells, targeting the VEGFR-2 enzyme. Compounds 7a,b and 8b,c showed the highest anticancer activities against both HCT116 human colon adenocarcinoma cells with IC50 of 6.04 ± 0.30, 13.22 ± 0.22, 18 ± 0.20, and 35 ± 0.45 µM, respectively, and MCF-7 breast cancer cells with IC50 of 8.8 ± 0.45, 17.9 ± 0.50, 25.2 ± 0.55, and 44.3 ± 0.49 µM, respectively, in comparison to sorafenib as reference drug with IC50 of 5.47 ± 0.3 and 7.26 ± 0.3 µM, respectively. Eleven compounds in this series were further evaluated for their inhibitory activity against VEGFR-2, where compounds 7a, 7b, 8c, and 8b also showed the highest VEGFR-2 inhibition with IC50 of 0.11 ± 0.01, 0.31 ± 0.03, 0.72 ± 0.08, and 0.91 ± 0.08 µM, respectively, in comparison to sorafenib as reference ligand with IC50 of 0.1 ± 0.02. Furthermore, molecular docking studies were performed for all synthesized compounds to predict their binding pattern and affinity towards the VEGFR-2 active site, in order to rationalize their anticancer activity in a qualitative way.

Inhibition of carbonic anhydrase isoforms I, II, IV, VII and XII with carboxylates and sulfonamides incorporating phthalimide/phthalic anhydride scaffolds.

We report a panel of carboxylates and sulfonamides incorporating phthalic anhydride and phthalimide moieties in their structure and their interaction with the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). They were synthesized from substituted anthranilic acids and trimellitic anhydride chloride, followed by reaction with primary amines and were tested for the inhibition of five physiologically relevant CA isoforms, the human (h) hCA I, II, IV, VII and XII, some of which are involved in serious pathologies (CA II, IV and XII in glaucoma; CA VII in epilepsy; CA XII in some solid tumors). The carboxylic acids were generally poor inhibitors of isoforms hCA I, II and IV but were highly effective, low nanomolar inhibitors of hCA VII and XII. The sulfonamides inhibited all isoforms significantly, and some of them were sub-nanomolar hCA VII inhibitors, although their isoform selectivity was lower compared to the carboxylates. This study proves that carboxylic acids incorporating a phthalic anhydride/phthalimide based scaffold may lead to isoform-selective inhibitors by applying the tail approach, mostly used up until now for obtaining sulfonamide, sulfamide and sulfamate CA inhibitors.

Synthesis, antitumor and antimicrobial activity of some new 6-methyl-3-phenyl-4(3H)-quinazolinone analogues: in silico studies.

Some new derivatives of substituted-4(3H)-quinazolinones were synthesized and evaluated for their in vitro antitumor and antimicrobial activities. The results of this study demonstrated that compound 5 yielded selective activities toward NSC Lung Cancer EKVX cell line, Colon Cancer HCT-15 cell line and Breast Cancer MDA-MB-231/ATCC cell line, while NSC Lung Cancer EKVX cell line and CNS Cancer SF-295 cell line were sensitive to compound 8. Additionally, compounds 12 and 13 showed moderate effectiveness toward numerous cell lines belonging to different tumor subpanels. On the other hand, the results of antimicrobial screening revealed that compounds 1, 9 and 14 are the most active against Staphylococcus aureus ATCC 29213 with minimum inhibitory concentration (MIC) of 16, 32 and 32 µg/mL respectively, while compound 14 possessed antimicrobial activities against all tested strains with the lowest MIC compared with other tested compounds. In silico study, ADME-Tox prediction and molecular docking methodology were used to study the antitumor activity and to identify the structural features required for antitumor activity.

Synthesis, antitumor activity and molecular docking study of some novel 3-benzyl-4(3H)quinazolinone analogues.

A novel series of 3-benzyl-substituted-4(3H)-quinazolinones were designed, synthesized and evaluated for their in vitro antitumor activity. The results of this study demonstrated that 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide, 2-(3-benzyl-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide and 3-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)-propanamide have shown amazing broad spectrum antitumor activity with mean GI(50) (10.47, 7.24 and 14.12 µM. respectively), and are nearly 1.5-3.0-fold more potent compared with the positive control 5-FU with mean GI50, 22.60 µM. On the other hand, compounds 6 and 10 yielded selective activities toward CNS, renal and breast cancer cell lines, whereas compound 9 showed selective activities towards leukemia cell lines. Molecular docking methodology was performed for compounds 7 and 8 into ATP binding site of EGFR-TK which showed similar binding mode to erlotinib, while compound 11 into ATP binding site of B-RAF kinase inhibited the growth of melanoma cell lines through inhibition of B-RAF kinase, similar to PLX4032.

Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies.

The potential antitumor activities of a series of 7-(4-substituted piperazin-1-yl)fluoroquinolone derivatives (1-14a,b) using ciprofloxacin and norfloxacin as scaffolds are described. These compounds exhibit potent and broad spectrum antitumor activities using 60 human cell lines in addition to the inherent antibacterial activity. Compounds 1a, 2a, 3b, 6b and 7a were found to be the most potent, while 2b, 5b, and 6a were found to have an average activity. The results of this study demonstrated that compounds 1a, 2a, 3b, 6b and 7a (mean GI50; 2.63-3.09 µM) are nearly 7-fold more potent compared with the positive control 5-fluorouracil (mean GI50; 22.60 µM). More interestingly, compounds 1a, 2a, 3b, 6b and 7a have an almost antitumor activity similar to gefitinib (mean GI50; 3.24 µM) and are nearly 2-fold more potent compared to erlotinib (mean GI50; 7.29 µM). In silico study and ADME-Tox prediction methodology were used to study the antitumor activity of the most active compounds and to identify the structural features required for antitumor activity.

Design, Synthesis, In Vitro Anti-cancer Activity, ADMET Profile and Molecular Docking of Novel Triazolo[3,4-a]phthalazine Derivatives Targeting VEGFR-2 Enzyme.

BACKGROUND: Extensive studies were reported in the synthesis of several phthalazine derivatives as promising anticancer agents as potent VEGFR-2 inhibitors. Vatalanib (PTK787) was the first anilinophthalazine published derivative as a potent inhibitor of VEGFR. The discovery of vatalanib as a clinical candidate led to the design and synthesis of different anilinophthalazine derivatives as potent inhibitors for VEGFR-2. The objective of present research work is the synthesis of new agents with the same essential pharmacophoric features of the reported and clinically used VEGFR-2 inhibitors (e.g vatalanib and sorafenib). The main core of our molecular design rationale comprised bioisosteric modification strategies of VEGFR-2 inhibitors at four different positions. MATERIAL AND METHODS: A correlation between structure and biological activity of our designed phthalazines was established using molecular docking and VEGFR-2 kinase assay. RESULTS AND DISCUSSION: In view of their expected anticancer activity, novel triazolo[3,4-a]phthalazine derivatives 5-6a-o and 3-substituted-bis([1,2,4]triazolo)[3,4-a:4',3'-c]phthalazines 9a-b were designed, synthesized and evaluated for their anti-proliferative activity against two human tumor cell lines HCT-116 human colon adenocarcinoma and MCF-7 breast cancer. It was found that, compound 6o the most potent derivative against both HCT116 and MCF-7 cancer cell lines. Compounds 6o, 6m, 6d and 9b showed the highest anticancer activities against HCT116 human colon adenocarcinoma with IC50 of 7±0.06, 13±0.11, 15±0.14 and 23±0.22 µM respectively while compounds 6o, 6d, 6a and 6n showed the highest anticancer activities against MCF-7 breast cancer with IC50 of 16.98±0.15, 18.2±0.17, 57.54±0.53 and 66.45±0.67 µM respectively. Sorafenib as a highly potent VEGFR-2 inhibitor was used as a reference drug with IC50 of 5.47±0.3 and 7.26±0.3 µM respectively. Nine compounds were further evaluated for their VEGFR-2 inhibitory activity. Compounds 6o, 6m, 6d and 9b emerged as the most active counterparts against VEGFR-2 with IC50 values of 0.1±0.01, 0.15±0.02, 0.28±0.03 and 0.38±0.04 µM, respectively comparable to that of sorafenib (IC50 = 0.1±0.02) µM. Furthermore, molecular docking studies were carried out for all synthesized compounds to investigate their binding pattern and predict their binding affinities towards VEGFR-2 active site. In silico ADMET studies were calculated for the tested compounds. Most of our designed compounds exhibited good ADMET profile. CONCLUSION: The obtained results showed that, the most active compounds 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.

Synthesis and Some Reactions of 1-aryl-4-acetyl-5-methyl-1,2,3-triazole Derivatives with Anticonvulsant Activity.

The triazoles 3a-d underwent condensation reactions with 4-(piperidin-1-yl)-benzaldehyde to afford the chalcones 5a-d. Chalcone derivatives 5a-d were reacted with 2,3-diaminomaleonitrile, thiourea and hydrazine hydrate to afford the novel diazepine-dicarbonitrile derivatives 7a-d, the pyrimidine-2-thiol derivatives 9a-d and hydrazino-pyrimidines 10a-d respectively. Structures of the prepared compounds were elucidated by physical and spectral data like FT-IR, (1)H NMR, (13)C NMR, and mass spectroscopy. Some of the synthesized compounds were screened for their anticonvulsant activity and SAR.

Synthesis, anti-inflammatory, analgesic, COX-1/2 inhibitory activities and molecular docking studies of substituted 2-mercapto-4(3H)-quinazolinones.

A new series of 2-substituted mercapto-4(3H)-quinazolinone 1-26 were synthesized and assessed for in vivo anti-inflammatory and analgesic activities and in vitro inhibition of cyclooxygenase COX-1/COX-2. A new series of 2-substituted mercapto-4(3H)-quinazolinone 1-26 were synthesized and assessed for in vivo anti-inflammatory and analgesic activities. The potent anti-inflammatory compounds were subjected to in vitro cyclooxygenase COX-1/COX-2 inhibition assays. Compounds 1, 3, 5, 11, 12, 13, 15, 17, and 25 exhibited potent anti-inflammatory effects, with half-maximal effective dose (ED50) values of 65.7-102.4 mg/kg, (0.16-0.36 mmol/kg), and strong analgesic activities, with ED50 values of 33.3-104.6 mg/kg, (0.07-0.34 mmol/kg). These values were compared with those of diclofenac sodium [ED50 values: 112.2 and 100.4 mg/kg, (0.35 and 0.31 mmol/kg)], and celecoxib [ED50 values: 84.3 and 71.6 mg/kg (0.22 and 0.19 mmol/kg)], respectively as reference drugs. Compounds 1, 11, 12, 13, 15, 17, and 25 exhibited effective COX-2 inhibitory activity, with half-maximal inhibitor concentration (IC50) values of 0.70-2.0 µM and selectivity index (SI) values of more than 50-142.9 compared with celecoxib as reference drugs (IC50 = 0.30 µM and COX-2 SI: >333). Potent COX-2 inhibitors, i.e., compounds 15, 11, and 17 were docked into the binding site pockets of COX-1 and COX-2. These compounds exhibited strong interactions at the COX-2 binding site and poor interactions at COX-1 active site pocket.

Synthesis and antitumor evaluation of trimethoxyanilides based on 4(3H)-quinazolinone scaffolds.

A novel series of 2-[(3-substituted-4(3H)-quinazolin-2-yl)thio]-N-(3,4,5-trimethoxyphenyl)acetamide (15-21) and 3-[(3-substituted-4(3H)-quinazolin-2-yl)thio])-N-(3,4,5-trimethoxyphenyl)propanamide (23-29) were designed, prepared and estimated for their anticancer activity in a solo dose 10 µM of the test compounds in the NCI 57 cell lines panel assay. Compounds 20, 23, 26, 27 and 28 revealed extensive-spectrum antitumor efficiency to numerous cell lines that belong to various tumor subpanels, while compounds 15, 16 and 19 possessed perceptive activity toward A498 and UO-31 renal cancer cell lines, and compound 17 showed selective effectiveness against NSC lung cancer NCI-H522 cell line. Additionally, compound 18 showed advanced activity against SR leukemia cell line, NSC lung cancer HOP-92 and renal cancer UO-31 cell lines.