Quinazoline Analogues Research Articles

Light-driven photoswitching of quinazoline analogues of combretastatin A-4 as an effective approach for targeting skin cancer cells.

A novel quinazoline series of photoswitchable combretastatin A-4 (CA-4) analogues were synthesized and their photochemical properties and antiproliferative activity against A431 epidermoid carcinoma cells were studied. It was found that quinazoline analogues, in contrast to the majority of the known CA-4, exhibit high antiproliferative activity in the E-form as well. Photoswitching of the E-form to the Z-form resulted in a multiple (9-fold) increase in antiproliferative activity. 1H NMR monitoring showed that these compounds are very resistant to UV (λ = 365 nm) or sunlight irradiation and do not undergo photodegradation with a loss of antiproliferative activity that is inherent in heterocyclic analogues of CA-4. Similar photoswitching and an increase in antiproliferative activity are observed on exposure to sunlight. A selected compound (1a-Z51) in sub-micromolar concentrations induced apoptosis in A431 cells, while rad50/ATM/p53 were not involved in cell death. The growth of A431 cells was significantly inhibited after combination treatment with compound 1a-Z51 and chemotherapy drugs (cisplatin or 5-fluorouracil). In summary, the quinazoline analogues of CA-4 represent a promising strategy to achieve a photoswitchable potency for the treatment of cancers, including the development of combination therapies.

Design, synthesis and biological evaluation of new bivalent quinazoline analogues as IAP antagonists

We recently reported the biological evaluations of monovalent IAP antagonist 7 with good potency (MDA-MB-231, IC50 = 19 nM). In an effort to increase cellular activity and improve favorable drug-like properties, we newly designed and synthesized bivalent analogues based on quinazoline structure of 7. Optimization of cellular potency and CYP inhibition led to the identification of 27, which showed dramatic increase of over 100-fold (IC50 = 0.14 nM) and caused substantial tumor regressions in MDA-MB-231 xenograft model. These results strongly support 27 as a promising bivalent antagonist for the development of an effective anti-tumor approaches.

Biological activity of quinazoline analogues and molecular modeling of their interactions with G-quadruplexes

BackgroundQuinazolines 1 to 6, with an aromatic or aryl-vinyl substituent in position 2 are selected with the aim to compare their structures and biological activity. The selection includes a natural alkaloid, schizocommunin, and the synthetic 2-(2′-quinolyl)-3H-quinazolin-4-one, known to interact with guanine-quadruplex dependent enzymes, respectively telomerase and topoisomerase. MethodsBreast cancer cells of the MDA cell line have been used to study the bioactivity of the tested compounds by the method of Comet Assay and FACS analyses. We model observed effects assuming stacking interactions of studied heterocycles with a naked skeleton of G-quadruplex, consisting of guanine quartet layers and potassium ions. Interaction energies are computed using a dispersion corrected density functional theory method, and an electron-correlated molecular orbital theory method. ResultsSelected compounds do not remarkably delay nor change the dynamics of cellular progression through the cell cycle phases, while changing significantly cell morphology. Our computational models quantify structural effects on heterocyclic G4-complex stabilization energies, which directly correlate with observed biological activity. ConclusionOur computational model of G-quadruplexes is an acceptable tool for the study of interaction energies of G-quadruplexes and heterocyclic ligands, predicting, and allowing design of novel structures. General significanceGenotoxicity of quinazolin-4-one analogues on human breast cancer cells is not related to molecular metabolism but rather to their interference with G-quadruplex regulatory mechanisms. Computed stabilization energies of heterocyclic ligand complexes of G-quadruplexes might be useful in the prediction of novel telomerase / helicase, topoisomerase and NA polymerase dependent drugs.

Discovery and SAR of Novel Disubstituted Quinazolines as Dual PI3Kalpha/mTOR Inhibitors Targeting Breast Cancer.

The dual PI3Kα/ m TOR inhibitors represent a promising molecularly targeted therapy for cancer. Here, we documented the discovery of new 2,4-disubstituted quinazoline analogs as potent dual PI3Kα/sm TOR inhibitors. Our structure based chemistry endeavor yielded six excellent compounds 9e, 9f, 9g, 9k, 9m, and 9o with single/double digit nanomolar IC50 values against both enzymes and acceptable aqueous solubility and stability to oxidative metabolism. One of those analogs, 9m, possessed a sulfonamide substituent, which has not been described for this chemical scaffold before. The short direct synthetic routes, structure-activity relationship, in vitro 2D cell culture viability assays against normal fibroblasts and 3 breast cancer cell lines, and in vitro 3D culture viability assay against MCF7 cells for this series are described.

Synthesis, characterization and evaluation of 68Ga labelled monomeric and dimeric quinazoline derivatives of the HBED-CC chelator targeting the epidermal growth factor receptor

Tyrosine kinase (TK) receptors including epidermal growth factor receptors (EGFRs) are known to be overexpressed in a wide variety of solid tumors associated with poor prognosis. The HBED-CC chelator N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid 1 was coupled via one or both its propionic acid moieties with the quinazoline EGFR-TK inhibiting pharmacophore 4-amino-N-(4-((3-bromophenyl)amino)quinazolin-6-yl)butanamide 3 resulting in either a monomeric 4 or a dimeric 5 species. Ligands 4 and 5 reacted with Ga3+ generating the corresponding complexes Ga4 and Ga5. Both ligands and complexes were characterized with mass spectrometry and NMR spectroscopy and evaluated in vitro with MTT assays in A431 cells, where they showed IC50 values in the range 51.6 to 68.8μM. Labeling of ligands 4 and 5 with the PET radionuclide 68Ga was quantitative and resulted in tracers [68Ga]Ga4 and [68Ga]Ga5 with radiochemical purities greater than 98%, which were also characterised by comparative RP-HPLC studies with Ga4 and Ga5 respectively. Radiotracers [68Ga]Ga4 and [68Ga]Ga5 were stable (intact tracer over 98%) in the reaction mixture (120min) and in human serum (30min). Both tracers were evaluated in vivo with biodistribution experiments in SCID mice bearing A431 tumors presenting tumor uptake of 1.34 for [68Ga]Ga4 and 1.01 %ID/g for [68Ga]Ga5 at 5min, which was slightly decreased at 60min p.i. and then remained stable until 120min p.i. To the best of our knowledge, this is the first report of monomeric and dimeric quinazoline conjugates with the chelator HBED-CC, which can serve as a basis for further development of EGFR-TKI targeting tracers.

Synthesis, antibacterial and free radical scavenging activity of some newer N-((10-nitro-1H-indolo [1, 2-c]quinazolin-12-yl)methylene)benzenamines

AbstractPresent research is oriented on the synthesis of some novel 12-(N-arylmethaniminyl)indolo[1,2-c]quinazoline analogs (4b1-4b11) and their characterization by 1H NMR, 13C NMR, FTIR and mass spectrophotometry. Their free radical scavenging activity and antibacterial potential were also evaluated. Many derivatives have shown a marked free radical scavenging capacity in all the concentrations but specifically compounds 4b7, 4b8 and 4b11 have shown good antioxidant potential with an IC50 value of 25.18 μmol/L, 28.09 μmol/L ---amp--- 44.22 μmol/L, respectively (DPPH method) and 39.46 μmol/L, 44.47 μmol/L ---amp--- 35.61 μmol/L, respectively (H2O2 method). The antibacterial evaluation was carried out against B. subtilis and E. coli by agar well diffusion method and it revealed that all the compounds in the series were having marked antibacterial activity but compounds 4b9 and 4b11 have shown best antibacterial potential. Then, it was concluded that the derivatives which were containing substituted anilines (4-Nitro, 4-Fluoro, 4-Bromo ---amp--- 4-Chloro-2-nitro) on the carbon attached on the 12th position of indoloquinazoline moiety were having marked potential as an antibacterial and free radical scavenger.

Investigation of some benzoquinazoline and quinazoline derivatives as novel inhibitors of HCV-NS3/4A protease: biological, molecular docking and QSAR studies.

Morbidity and mortality due to hepatitis C virus (HCV) is a globe health concern. Hence, there is a persistent demand to design and optimize current HCV therapy and develop novel agents. HCV NS3/A4 protease plays an essential role in HCV life cycle and replication. Thus, HCV NS3/A4 protease inhibitors are one of the best therapeutic targets for the identification of novel candidate drugs. Recent studies have shown some benzoquinazolines as potent antiviral agents and promising HAV-3C protease inhibitors. In the present study, a series of benzo[g]quinazolines (1–13) and their quinazoline analogues (14–17) were evaluated for their HCV-NS3/4A inhibitory activities using in vitro assay. Our results revealed that the target compounds inhibited the activity of the NS3/4A enzyme, (IC50 = 6.41 ± 0.12 to 78.80 ± 1.70 μM) in comparison to telaprevir (IC50 = 1.72 ± 0.03 μM) as a reference drug. Compounds 1, 2, 3, 9, 10 and 13 showed the highest activity (IC50 = 11.02 ± 0.25, 6.41 ± 0.12, 9.35 ± 0.19, 9.08 ± 0.20, 16.03 ± 0.34 and 7.21 ± 0.15 μM, respectively). Molecular docking was performed to study the binding modes of the docked-chosen benzo[g]quinazolines, hydrogen bonding, and amino acid residues at the catalytic triad of the NS3/4A enzyme of HCV. The QSAR was determined to explore the relationships between the molecular structures of the targets and their biological activities by developing prediction models among the known HCV NS3/A4 inhibitors and then to predict the inhibitory activity of the target molecules synthesized.

Synthesis, biological evaluation and molecular docking of pyrimidine and quinazoline derivatives of 1,5-benzodiazepine as potential anticancer agents

A new series of Pyrimidine (A, D and F) and quinazoline (B, C and E) analogues of 1,5-benzodiazepines were prepared via its nitrile-derived amidoximes in and nitrilium ions, respectively using one pot Domino reaction with DMAD in presence of DABCO catalyst and benzanilide in presence of Tf2O and 2-chloropyridine. The prepared molecules were examined for their biological property namely apoptotic and antiproliferative effects through cell cycle arrest using breast cancer cell line of human (MCF-7). Receptor-ligand interactions were studied on human epidermal evolution factor receptor (HER-2) with the help of molecular docking using Autodock 4.2.6 molecular modeling software. All the compounds demonstrated inhibitory effects on cell proliferation in a concentration dependent fashion (20–100 μg/mL). Notably, compound C exhibited highest inhibitory activity and caused inhibition of S and G2 phase in cell cycle arrest via caspase dependent apoptotic pathway in MCF-7 cells lines.

Tubulin Inhibitors Binding to Colchicine-Site: A Review from 2015 to 2019.

Due to the three domains of the colchicine-site which is conducive to the combination with small molecule compounds, colchicine-site on the tubulin has become a common target for antitumor drug development, and accordingly, a large number of tubulin inhibitors binding to the colchicine-site have been reported and evaluated over the past years. In this study, tubulin inhibitors targeting the colchicine-site and their application as antitumor agents were reviewed based on the literature from 2015 to 2019. Tubulin inhibitors were classified into ten categories according to the structural features, including colchicine derivatives, CA-4 analogs, chalcone analogs, coumarin analogs, indole hybrids, quinoline and quinazoline analogs, lignan and podophyllotoxin derivatives, phenothiazine analogs, N-heterocycle hybrids and others. Most of them displayed potent antitumor activity, including antiproliferative effects against Multi-Drug-Resistant (MDR) cell lines and antivascular properties, both in vitro and in vivo. In this review, the design, synthesis and the analysis of the structure-activity relationship of tubulin inhibitors targeting the colchicine-site were described in detail. In addition, multi-target inhibitors, anti-MDR compounds, and inhibitors bearing antitumor activity in vivo are further listed in tables to present a clear picture of potent tubulin inhibitors, which could be beneficial for medicinal chemistry researchers.

Design, Synthesis and Antitumor Activity of Quinazoline Derivatives Bearing 2,3-Dihydro-indole or 1,2,3,4-Tetrahydroquinoline

Background: Cancer continues to pose a great problem and burden on society despite new treatment options. While surgery, radiotherapy, and chemotherapy have led to major improvements in patient prognosis, newer treatments are needed to more effectively manage this disease in its advanced stage. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK), which is catalytically active and under tight regulatory control. Dysregulation of its activity is strongly associated with tumorigenesis and cancer patients with altered EGFR activity tend to have a more aggressive disease, associated with a poor clinical prognosis. The family of EGFR has been intensively studied due to its strong influence on the formulation and deterioration of carcinoma. Thus, it is a good strategy that design anticancer agents by inhibiting the EGFR pathway. Methods: We group to obtain the six series compounds (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d). Hence we disclosed the design, synthesis and antitumor activity of novel quinazoline analogues against EGFR overexpression cancer cells A549 (human lung cancer), HepG-2 (human liver cancer), MCF-7 (human breast cancer) and PC-3 (human prostate cancer) and as well as the inhibitory on EGFR kinase. Moreover, apoptosis by acridine orange single staining and docking studies were presented in this paper as well. Results: Six series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d) were designed, synthesized and evaluated for the half maximal inhibitory concentration (IC50) values against four cancer cell lines (A549, HepG-2, MCF-7 and PC-3). Thirty target compounds showed moderate to excellent (1.49 - 50 µM) cytotoxicity activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, HepG- 2, MCF-7 and PC-3 cancer cell lines, with the IC50 values of 1.49 ± 0.17 µM, 2.90 ± 0.24 µM, 1.85 ± 0.19 µM, 3.30 ± 0.22 µM, respectively. What’s more, the secondary amines were introduced to the target compounds to improve the water-soluble. The results showed that the compounds were beneficial to the cytotoxicity activity. Furthermore, the results prompted us that this series of compounds may be a kind of potential epidermal growth factor receptor (EGFR) kinase inhibitors. Conclusion: Six series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4- tetrahydroquinoline moiety (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d) were designed, synthesized and evaluated for the IC50 values of cytotoxicity against four cancer cell lines (A549, HepG-2, MCF-7 and PC-3). Thirty synthesized compounds showed moderate to excellent cytotoxicity activity against the different cancer cells. Especially, the compound 13a exerted antitumor effects in a dosage-dependent manner and the IC50 values of compound 13a were 1.49 µM, 2.90 µM, 1.85 µM and 3.30 µM against A549, HepG-2, MCF-7 and PC-3, respectively. From the antitumor activity data show that the compounds possessed selectivity for A549 and MCF-7 cancer cell lines. It meant that the compounds had better treatment effect on lung cancer and breast cancer. On the whole, the compounds substituted by 1,2,3,4-tetrahydroquinoline at C-4 position of quinazoline and (S)-tetrahydrofuran-3-ol at C-8 position of quinazoline were beneficial to the cytotoxicity activity. From the result of acridine orange (AO) single staining which indicated the compound 13a could induce apoptosis of A549 cells. From the result of Docking Studies, we hypothesized that the C-4 position of quinazoline were substituted by 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline with the equal influence of the cytotoxicity activity. Overall, the results prompted us that this series of compounds may be a kind of potential EGFR kinase inhibitors.

Targeting the CaVα-CaVβ interaction yields an antagonist of the N-type CaV2.2 channel with broad antinociceptive efficacy.

Inhibition of voltage-gated calcium (CaV) channels is a potential therapy for many neurological diseases including chronic pain. Neuronal CaV1/CaV2 channels are composed of α, β, γ and α2δ subunits. The β subunits of CaV channels are cytoplasmic proteins that increase the surface expression of the pore-forming α subunit of CaV. We targeted the high-affinity protein-protein interface of CaVβ's pocket within the CaVα subunit. Structure-based virtual screening of 50,000 small molecule library docked to the β subunit led to the identification of 2-(3,5-dimethylisoxazol-4-yl)-N-((4-((3-phenylpropyl)amino)quinazolin-2-yl)methyl)acetamide (IPPQ). This small molecule bound to CaVβ and inhibited its coupling with N-type voltage-gated calcium (CaV2.2) channels, leading to a reduction in CaV2.2 currents in rat dorsal root ganglion sensory neurons, decreased presynaptic localization of CaV2.2 in vivo, decreased frequency of spontaneous excitatory postsynaptic potentials and miniature excitatory postsynaptic potentials, and inhibited release of the nociceptive neurotransmitter calcitonin gene-related peptide from spinal cord. IPPQ did not target opioid receptors nor did it engage inhibitory G protein-coupled receptor signaling. IPPQ was antinociceptive in naive animals and reversed allodynia and hyperalgesia in models of acute (postsurgical) and neuropathic (spinal nerve ligation, chemotherapy- and gp120-induced peripheral neuropathy, and genome-edited neuropathy) pain. IPPQ did not cause akinesia or motor impairment, a common adverse effect of CaV2.2 targeting drugs, when injected into the brain. IPPQ, a quinazoline analog, represents a novel class of CaV2.2-targeting compounds that may serve as probes to interrogate CaVα-CaVβ function and ultimately be developed as a nonopioid therapeutic for chronic pain.

Quinazolines as inhibitors of chromatin-associated proteins in histones

It is increasing the evidence that quinazolines are inhibitors of chromatin-associated proteins in histones. Quinazolines have a broad structural diversity among the structural classes that have been designed. Herein, we review the development of selective and potent quinazolines highlighting the current state of these molecules with an emphasis on the structural requirements for the interaction within the target. Chemical synthesis and results of the biological assays in vitro or in vivo of these compounds are also discussed. There is extensive evidence that support quinazoline derivatives as inhibitors of histone methyltransferase (G9a) and G9a-like protein (GLP). There is one quinazoline analogue that inhibits an extra-terminal bromodomain motif (BET) and that is on clinical trials as potential treatment for different chronic diseases. There is also clinical evidence that quinazolines act as dual inhibitors targeting histone deacetylases (HDACs) Zn2+-dependent and kinase receptors for the potential treatment of cancer. Additional proposals of quinazoline structures are being evaluated as inhibitors targeting two or more chromatin-associated proteins simultaneously. Therefore, further improvements in synthetic methods, computational studies, and additional biological assays in vitro and in vivo remain to be addressed.

Elucidation of Vasodilation Response and Structure Activity Relationships of N²,N⁴-Disubstituted Quinazoline 2,4-Diamines in a Rat Pulmonary Artery Model.

Pulmonary arterial hypertension (PAH) is a rare and progressive disease arising from various etiologies and pathogenesis. PAH decreases life expectancy due to pulmonary vascular remodeling, elevation of mean pulmonary arterial pressure, and ultimately progresses to heart failure. While clinical treatments are available to reduce the associated symptoms, a complete cure has yet to be found. Phosphodiesterase-5 (PDE-5) inhibition has been identified as a possible intervention point in PAH treatment. The functional vasodilation response to N2,N4-diamino quinazoline analogues with differing PDE-5 inhibitory activities and varying physicochemical properties were assessed in both endothelium-intact and denuded rat pulmonary arteries to gain greater insight into their mode of action. All analogues produced vasorelaxant effects with EC50s ranging from 0.58 ± 0.22 µM to ˃30 µM. It was observed that vasodilation response in intact vessels was highly correlated with that of denuded vessels. The ~10% drop in activity is consistent with a loss of the nitric oxide mediated cyclic guanosine monophosphate (NO/cGMP) pathway in the latter case. A moderate correlation between the vasodilation response and PDE-5 inhibitory activity in the intact vessels was observed. Experimental protocol using the alpha-adrenergic (α1) receptor agonist, phenylephrine (PE), was undertaken to assess whether quinazoline derivatives showed competitive behavior similar to the α1 receptor blocker, prazosin, itself a quinazoline derivative, or to the PDE-5 inhibitor, sildenafil. Competitive experiments with the α1-adrenergic receptor agonist point to quinazoline derivatives under investigation here act via PDE-5 inhibition and not the former. The pre-incubation of pulmonary arterial rings with quinazoline test compounds (10 μM) reduced the contractile response to PE around 40–60%. The most promising compound (9) possessed ~32 folds higher selectivity in terms of vasodilation to its mammalian A549 cell cytotoxicity. This study provides experi0 0mental basis for PDE-5 inhibition as the mode of action for vasodilation by N2,N4-diamino quinazoline analogues along with their safety studies that may be beneficial in the treatment of various cardiovascular pathologies.

Abstract 2377: Design, synthesis, and characterization of 4-aminopyrazole quinazolines as potent inhibitors of G protein-coupled receptor kinase GRK6 for the potential treatment of multiple myeloma

Abstract Multiple myeloma (MM) is one of the most common hematological malignancies, but current therapeutic options are limited to high-dose chemotherapy or high-risk stem-cell transplantation. In a kinome-wide RNAi study by Tiedemann and colleagues (2010), the G-protein coupled receptor kinase GRK6 was identified as a critical kinase required for survival of MM cells. This study also suggests that MM cells, but not other cell types, are dependent on GRK6; and that gene silencing by shRNA or siRNA of GRK6, but not other members of the GRK family, results in decreased survival. Through gene silencing techniques, we determined that a functional GRK6 kinase domain is required for survival of MM cells. These findings helped validate that the kinase domain of GRK6 is a promising target for MM, and therefore encouraged us to embark on an effort to identify potent small molecule kinase inhibitors of GRK6. Toward that end, by screening a focused kinase-directed library of small molecule inhibitors, compounds with moderate potency against GRK6 in biochemical assays were identified. Through this exercise, we discovered that two structurally distinct aminopyrazoles AZ-960 and ASC-082 had modest inhibition of GRK6. By combining structural features of these hits and further optimization we identified the quinazoline analogue OICR9945, a potent GRK6 inhibitor with good selectivity against a panel of diverse kinases and anti-proliferative activity against MM cell lines. Herein, we describe the design, synthesis and early pharmacological characterization of OICR9945 along with structure activity relationships (SAR) of this series against GRK6 and other kinases. Citation Format: David Uehling, Babu Joseph, Carly Griffin, Ratheesh Subramaniam, Ayome Abibi, Richard Marcellus, Michael Prakesch, Gennadiy Poda, Methvin Isaac, Chungyee Leung-Hagesteijn, Rodger Tiedemann, Rima Al-awar. Design, synthesis, and characterization of 4-aminopyrazole quinazolines as potent inhibitors of G protein-coupled receptor kinase GRK6 for the potential treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2377.

Molecular Docking and Anticonvulsant Activity of Newly Synthesized Quinazoline Derivatives.

A new series of quinazoline-4(3H)-ones are evaluated for anticonvulsant activity. After intraperitoneal (ip) injection to albino mice at a dose of 100 mg/kg body weight, synthesized quinazolin-4(3H)-ones (1–24) were examined in the maximal electroshock (MES) induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The Rotarod method was applied to determine the neurotoxicity. Most of the compounds displayed anticonvulsant activity in the scPTZ screen at a dose range of 0.204–0.376 mmol/mL. Out of twenty-four, compounds 8, 13 and 19 proved to be the most active with a remarkable protection (100%) against PTZ induced convulsions and four times more potent activity than ethosuximide. The structure-activity relationship concluded valuable pharmacophoric information, which was confirmed by the molecular docking studies using the target enzyme human carbon anhydrase II (HCA II). The studied quinazoline analogues suggested that the butyl substitution at position 3 has a significant effect on preventing the spread of seizure discharge and on raising the seizure threshold. However, benzyl substitution at position 3 has shown a strong anticonvulsant activity but with less seizure prevention compared to the butyl substitution.

Design, synthesis, and docking studies of quinazoline analogues bearing aryl semicarbazone scaffolds as potent EGFR inhibitors

Two series of quinazoline derivatives bearing aryl semicarbazone scaffolds (9a–o and 10a–o) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). The selected compound 9o was further evaluated for the inhibitory activity against EGFR kinases. Four of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 values in single-digit μM to nanomole range. Two of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound 9o showed the best activity against A549, HepG2, MCF-7 and PC-3 cancer cell lines and EGFR kinase, with the IC50 values of 1.32±0.38μM, 0.07±0.01μM, 0.91±0.29μM and 4.89±0.69μM, which were equal to more active than afatinib (1.40±0.83μM, 1.33±1.28μM, 2.63±1.06μM and 3.96±0.59μM), respectively. Activity of the most promising compound 9o (IC50 56nM) against EGFR kinase was slightly lower to the positive compound afatinib (IC50 1.6nM) but more active than reference staurosporine (IC50 238nM). The result of flow cytometry, with the dose of compound 9o increasing, which indicated the compound 9o could induce remarkable apoptosis of A549 and cells in a dose dependent manner. Structure–activity relationships (SARs) and docking studies indicated that replacement of the cinnamamide group by aryl semicarbazone scaffolds slightly decreased the anti-tumor activity. The results suggested that hydroxy substitution at C-4 had a significant impact on the activity and replacement of the tetrahydrofuran group by methyl moiety was not beneficial for the activity.

Quinazoline derivatives as selective CYP1B1 inhibitors

CYP1B1 is implicated to have a role in the development of breast, ovarian, renal, skin and lung carcinomas. It has been suggested that identification of potent and specific CYP1B1 inhibitors can lead to a novel treatment of cancer. Flavonoids have a compact rigid skeleton which fit precisely within the binding cavity of CYP1B1. Systematic isosteric replacement of flavonoid ‘O’ atom with ‘N’ atom led to the prediction that a ‘quinazoline’ scaffold could be the basis for designing potential CYP1B1 inhibitors. A total of 20 quinazoline analogs were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™. IC50 determinations of six compounds with capability of inhibiting CYP1B1 identified quinazolines 5c and 5h as the best candidates for CYP1B1 inhibition, with IC50 values in the nM range. Further selectivity studies with homologous CYPs, belonging to the CYP1, CYP2 and CYP3 family of enzymes, showed that the compounds are likely to be free from critical drug-drug interaction liability. Molecular modelling studies were performed to rationalize the observed enzymatic inhibitions. Further biological studies in live yeast and human cells, harboring CYP1A1 and CYP1B1 enzymes, have illustrated the most potent compounds' cellular permeability and capability of potently inhibiting CYP1B1 enzyme expressed within live cells.

Expedient Synthesis of Quinazoline Analogues through Direct Nucleophilic Arylation/Alkylation of 2-Chloroquinazoline

A practical approach was developed for the synthesis of 4-arylquinazoline compounds through a one-pot nucleophilic arylation/alkylation of 2-chloroquinazoline with aryl lithium compounds generated in situ, followed by ring oxidation. The obtained 2-chloro-4-arylquinazoline adducts were further used as versatile intermediates that undergo a variety of synthetic transformations to provide functionalized quinazoline compounds. The arylation intermediate dihydroquinazoline was also elaborated to the tricyclic dihydroimidazo[2,1-b]quinazolinone.

Synthesis of 4-phenyl-5,6-dihydrobenzo[h]quinazolines and their evaluation as growth inhibitors of carcinoma cells

The synthesis of various benzo[h]quinazoline analogs was accomplished through the reaction of chalcone with guanidine. The synthesized compounds were screened for their anticancer potential against different cancer cells.

Design, synthesis and in vivo screening of some novel quinazoline analogs as anti-hyperlipidemic and hypoglycemic agents.

A novel series of substituted quinazoline derivatives were designed, synthesized and evaluated for their hypolipidemic activity in cholesterol induced hyperlipidemic rats. In vivo screening concluded that compounds A-4, C-5 and C-6 have shown potent antihyperlipidemic activity by decreasing the plasma level of triglycerides (TG), very low density lipoprotein (VLDL), low density lipoprotein (LDL), followed by increase in level of high density lipoprotein (HDL).