Quinazoline Core Research Articles

Development of diaminoquinazoline histone lysine methyltransferase inhibitors as potent blood-stage antimalarial compounds.

Modulating epigenetic mechanisms in malarial parasites is an emerging avenue for the discovery of novel antimalarial drugs. Previously we demonstrated the potent in vitro and in vivo antimalarial activity of (1-benzyl-4-piperidyl)[6,7-dimethoxy-2-(4-methyl-1,4-diazepin-1-yl)-4-quinazolinyl]amine (BIX01294; 1), a known human G9a inhibitor, together with its dose-dependent effects on histone methylation in the malarial parasite. This work describes our initial medicinal chemistry efforts to optimise the diaminoquinazoline chemotype for antimalarial activity. A variety of analogues were designed by substituting the 2 and 4 positions of the quinazoline core, and these molecules were tested against Plasmodium falciparum (3D7 strain). Several analogues with IC50 values as low as 18.5 nM and with low mammalian cell toxicity (HepG2) were identified. Certain pharmacophoric features required for antimalarial activity were found to be analogous to the previously published SAR of these analogues for G9a inhibition, thereby suggesting potential similarities between the malarial and human HKMT targets of this chemotype. Physiochemical, in vitro activity, and in vitro metabolism studies were also performed for a select set of potent analogues to evaluate their potential as antimalarial leads.

Emission tuning of fluorescent kinase inhibitors: conjugation length and substituent effects.

Fluorescent N-phenyl-4-aminoquinazoline probes targeting the ATP-binding pocket of the ERBB family of receptor tyrosine kinases are reported. Extension of the aromatic quinazoline core with fluorophore “arms” through substitution at the 6- position of the quinazoline core with phenyl, styryl, and phenylbutadienyl moieties was predicted by means of TD-DFT calculations to produce probes with tunable photoexcitation energies and excited states possessing charge-transfer character. Optical spectroscopy identified several synthesized probes that are nonemissive in aqueous solutions and exhibit emission enhancements in solvents of low polarity, suggesting good performance as turn-on fluorophores. Ligand-induced ERBB2 phosphorylation assays demonstrate that despite chemical modification to the quinazoline core these probes still function as ERBB2 inhibitors in MCF7 cells. Two probes were found to exhibit ERBB2-induced fluorescence, demonstrating the utility of these probes as turn-on, fluoroescent kinase inhibitors.

Inhibition of tumor cell growth and angiogenesis by 7-Aminoalkoxy-4-aryloxy-quinazoline ureas, a novel series of multi-tyrosine kinase inhibitors

Several regulatory and signaling molecules governing angiogenesis are targets of interest for the development of drugs in the cancer, including growth factors such as Vascular Endothelial Growth Factor (VEGF) and Platelet-Derived Growth Factor (PDGF). A series of 4-aryloxy-6,7-dimethoxyquinazolines, previously synthesized in our laboratory, has shown a nanomolar inhibition of kinase enzymatic activity of VEGFR, PDGFR and c-Kit. We have therefore studied the impact of the variation in the 7-position substitution of the quinazoline core. Substitution by aminoalkoxy chains led to new highly potent ATP-competitive inhibitors of VEGFR, PDGFR and c-Kit enzyme with IC50 values in the nanomolar range and this substitution has increased greatly antiproliferative activity on cancer cell lines (PC3, MCF7, HT29) and HUVEC (human umbilical vein endothelial cells). One of the most promising compounds (36) was assessed for its ability to limit the induction of web like network of capillary tubes by the human umbilical vascular endothelial cells (HUVEC) and for its ability to inhibit invasion.

The Design and Synthesis of a New Class of RTK/HDAC Dual-Targeted Inhibitors

Over the years, the development of targeted medicines has made significant achievements. As a typical example, receptor tyrosine kinases (RTK) inhibitors have become important chemotherapy drugs for a variety of cancers. However, the effectiveness of these agents is always hindered by poor response rates and acquired drug resistance. In order to overcome these limitations, several dual-targeted inhibitors with quinazoline core were designed and synthesized. Though these compounds can simultaneously inhibit histone deacetylases (HDAC) as well as RTK, the structure-activity relationship (SAR) is still not clear enough. To further explore this type of dual-targeted inhibitors, a new class of quinazoline derivatives were designed and synthesized. Their activity evaluations include in vitro inhibitory activity of HDAC, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). The SAR study indicated that the introduction of polar group such as hydroxamate on the 4-position of the quinazoline core is more likely to provide a potent HDACi/HER2i hybrid rather than HDACi/EGFRi molecule.

Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase-1 in Cells

Methionine aminopeptidases (MetAPs), which remove the initiator methionine from nascent peptides, are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (1-4), but all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 1-4 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells.

Survey of Recent Literature Related to the Biologically Active 4(3H)-Quinazolinones Containing Fused Heterocycles

The present review focuses on the synthesis and biological evaluation of polycyclic 4(3H)-quinazolinones containing fused aromatic or heteroaromatic rings. The first part of the review is related to compounds with ring fused to the pyrimidine part of the quinazoline core. Most of the quinazolinone alkaloids belong to this class of molecules. The second part presents molecules bearing extra ring(s) fused to the benzo moiety of the quinazolinone skeleton. Their structural diversity opens new fields in the search of active molecules.

Structure-based design and synthesis of novel pseudosaccharine derivatives as antiproliferative agents and kinase inhibitors

This study is concerned with the implementation of structure-based techniques for the design of new heterocyclic compounds based on pseudosaccharine scaffold with protein kinase inhibition activity. This nucleus was exploited based on the well-known quinazoline core and its interactions with several protein kinases. Two series of compounds employing this new scaffold were synthesized and evaluated at enzymatic and cellular levels. Compound 9b displayed broad spectrum antiproliferative activity on NCI 60-cell lines panel with mean GI50 of 5.4 μM. Investigation of the molecular mechanism showed probable inhibitory activity against Src kinase.

Recent Developments of Small Molecule EGFR Inhibitors Based on the Quinazoline Core Scaffolds

Progress in identifying and understanding the molecular and cellular causes of cancer has led to the discovery of anomalies that characterize cancer cells and that represent targets for the development of cancer therapeutics. One such target is the epidermal growth factor receptor (EGFR), a transmembrane protein that is frequently dysregulated in cancer cells and associated with the development, progression and aggressiveness of a number of malignancies. Inhibition of EGFR signaling has thus been identified as an attractive strategy in control of tumor proliferation, and over a decade of intense activity in the field has culminated in the discoveries and subsequent approvals of gefitinib and erlotinib for the treatment of non-small cell lung cancer. However, the drug's resistance to gefitinib and erlotinib has been clinically observed. Therefore, intensive efforts have been made in the discovery of novel potent and selective EGFR inhibitors. This review will focus on the developments of small molecule EGFR inhibitors based on the quinazoline core scaffolds in recent 5 years. Diverse EGFR inhibitors are classified as 4-anilinoquinazolines and 4-nonanilininoquinazolines, their biological data are described, and the structure-activity relationships (SARs) are discussed.

De novo design of quinazoline derivatives as CDK2 inhibitors: 3D-QSAR, molecular fragment replacement and Volsurf predictions

Cyclin-dependent kinase 2 (CDK2) has appeared as an important drug target over the years with a multitude of therapeutic potentials. To design compounds with enhanced inhibitory potencies against CDK2, 3D-QSAR and molecular fragment replacement studies were performed on the pyrazolo[4,3-h]quinazoline derivatives, a class of potent CDK2 inhibitors. The contours of 3D-QSAR model revealed important structural features of the inhibitors related to the active site of CDK2. Based on the pyrazolo[4,3-h]quinazoline core, the different substituents at three important points were replaced with diverse molecular fragments. The compounds resulting from fragments assembly with pyrazolo[4,3-h]quinazoline core were then scored with the robust 3D-QSAR model. Furthermore, the absorption, distribution, metabolism and excretion properties of these compounds were predicted by Volsurf to eliminate inappropriate compounds. Thirty-one new potential compounds were finally obtained. These results initiated us to further optimise and design new potential inhibitors.

Impact of aryloxy-linked quinazolines: A novel series of selective VEGFR-2 receptor tyrosine kinase inhibitors

Three series of 6,7-dimethoxyquinazoline derivatives substituted in the 4-position by aniline, N-methylaniline and aryloxy entities, targeting EGFR and VEGFR-2 tyrosine kinases, were designed and synthesized. Pharmacological activities of these compounds have been evaluated for their enzymatic inhibition of VEGFR-2 and EGFR and for their antiproliferative activities on various cancer cell lines. We have studied the impact of the variation in the 4-position substitution of the quinazoline core. Substitution by aryloxy groups led to new compounds which are selective inhibitors of VEGFR-2 enzyme with IC(50) values in the nanomolar range in vitro.

Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity.

Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.

Synthesis and biological evaluation of 4-quinazolinones as Rho kinase inhibitors

Rho kinase (ROCK) is an attractive therapeutic target for various diseases including glaucoma, hypertension, and spinal cord injury. Herein, we report the development of a series of ROCK-II inhibitors based on 4-quinazolinone and quinazoline scaffolds. SAR studies at three positions of the quinazoline core led to the identification of analogs with high potency against ROCK-II and good selectivity over protein kinase A (PKA).

4-(6,7-Disubstituted quinazolin-4-ylamino)phenyl] carbamic acid esters: a novel series of dual EGFR/VEGFR-2 tyrosine kinase inhibitors

Investigating a series of anilinoquinazoline derivatives substituted by carbamic acid esters, we have established the importance of the carbamate functional group and the substitution on the arylamino ring by a donor/acceptor group such as halide or methyl. All the newly-synthesized compounds described were evaluated for both their in vitroEGFR and VEGFR-2 kinase inhibition and antiproliferative activities against various cancer cells. These novel compounds were effective tyrosine kinase inhibitors (TKIs) for these two enzymes with in vitro IC50 values in the submicromolar range, but showed a moderated inhibitory activity on cancer cells. Modification of the ether linkage at the 6- or 7- position of the quinazoline core with a basic or aliphatic side chain (70–80) was investigated and it was demonstrated that introduction of aminoalkyl substituents such as morpholinoethoxy is a key modification that increases antiproliferative activity.

The discovery of the potent aurora inhibitor MK-0457 (VX-680)

The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) containing the T315I mutation.

ChemInform Abstract: A Facile Route to the Synthesis of Pyrimido[2,1‐b]quinazoline Core from the Primary Allyl Amines Afforded from Baylis—Hillman Adducts.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Three-point variation of a gefinitib quinazoline core

A versatile four-step process describing the controlled systematic variation of a key quinazoline core from one intermediate is highlighted.

A facile route to the synthesis of pyrimido[2,1- b]quinazoline core from the primary allyl amines afforded from Baylis–Hillman adducts

A highly simplified approach for the generation of substituted pyrimido[2,1- b]quinazoline core from the primary allyl amines afforded from the Baylis–Hillman adducts is described. Sequential reductive alkylation of the primary allyl amine with 2-nitrobenzaldehyde, reduction of the aromatic nitro group with In, CNBr-promoted intramolecular cyclization followed by NaOMe-mediated another intramolecular cyclization furnish the title compounds.

Discovery of 2-Chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (EP128265, MPI-0441138) as a Potent Inducer of Apoptosis with High In Vivo Activity

Using a live cell, high-throughput caspase-3 activator assay, we have identified a novel series of 4-anilinoquinazolines as inducers of apoptosis. In this report, we discuss the discovery of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine, compound 2b (EP128265, MPI-0441138) as a highly active inducer of apoptosis (EC50 for caspase activation of 2 nM) and as a potent inhibitor of cell proliferation (GI50 of 2 nM) in T47D cells. Compound 2b inhibited tubulin polymerization, was effective in cells overexpressing ABC transporter Pgp-1, and was efficacious in the MX-1 human breast and PC-3 prostate cancer mouse models. In contrast to the SAR of 4-anilinoquinazolines as EGFR kinase inhibitors, the methyl group on the nitrogen linker was essential for the apoptosis-inducing activity of 4-anilinoquinazolines and substitution in the 6- and 7-positions of the quinazoline core structure decreased potency.

Structure-guided development of affinity probes for tyrosine kinases using chemical genetics

As key components in nearly every signal transduction pathway, protein kinases are attractive targets for the regulation of cellular signaling by small-molecule inhibitors. We report the structure-guided development of 6-acrylamido-4-anilinoquinazoline irreversible kinase inhibitors that potently and selectively target rationally designed kinases bearing two selectivity elements that are not found together in any wild-type kinase: an electrophile-targeted cysteine residue and a glycine gatekeeper residue. Cocrystal structures of two irreversible quinazoline inhibitors bound to either epidermal growth factor receptor (EGFR) or engineered c-Src show covalent inhibitor binding to the targeted cysteine (Cys797 in EGFR and Cys345 in engineered c-Src). To accommodate the new covalent bond, the quinazoline core adopts positions that are different from those seen in kinase structures with reversible quinazoline inhibitors. Based on these structures, we developed a fluorescent 6-acrylamido-4-anilinoquinazoline affinity probe to report the fraction of kinase necessary for cellular signaling, and we used these reagents to quantitate the relationship between EGFR stimulation by EGF and its downstream outputs-Akt, Erk1 and Erk2.

A novel structural class of potent inhibitors of NF-κB activation: structure–activity relationships and biological effects of 6-aminoquinazoline derivatives

In this study, we have investigated the roles of substituents on the terminal phenyl ring at the C(4)-position of the quinazoline core to complete the structure–activity relationships (SARs) of our NF-κB activation inhibitors. Among them, compound 12j afforded highly potent inhibitory activity toward NF-κB transcriptional activation with IC 50 value of 2 nM, along with an excellent in vivo efficacy by reducing the edema formation seen in carrageenin-induced inflammation of the rat hind paw.