Development of certain aminoquinazoline scaffolds as potential multitarget anticancer agents with apoptotic and anti-proliferative effects: Design, synthesis and biological evaluation.

Newly designed 4 - aminoquinazoline derivatives (5a-f, 6a, b, 7, 8, 9, 10a-c, 11a, b, 12a, b and 13a, b) have been synthesized and evaluated for their potential multitarget anticancer activities, apoptotic and anti-proliferative effects. Thereupon, in vitro cytotoxic activities of all the synthesized compounds were screened against NCI 60 human cancer cell lines (nine subpanels) at NCI, USA. Successfully, 2-morpholino-N-(quinazolin-4-yl) acetohydrazide 5e was granted an NSC code, owing to its significant potency and broad spectrum of activity against various cancer cell lines; leukemia K-562, non-small cell lung cancer NCI-H522 cells, colon cancer SW-620, melanoma LOX IMVI, MALME-3M, renal cancer RXF 393, ACHN and breast cancer MDA-MB231/ATCC (GI% = 99.6, 161, 126.03, 90.22, 174.47, 139.7, 191 and 97, respectively). Compound 5e showed the best inhibitory activity (GI50 = 1.3 µM) against melanoma LOX IMVI, when tested at five doses against NCI 60 cell lines. Furthermore, compound 5e showed comparable EGFR and CDK2 inhibitory activity results (IC50 = 0.093 ± 0.006 µM and 0.143 ± 0.008 µM, respectively) to those of lapatinib and ribociclib (IC50 = 0.03 ± 0.002 µM and 0.067 ± 0.004 µM, respectively). Western blotting analysis of compound 5e against melanoma LOX IMVI marked out significant reduced EGFR and CDK2 protein expression percentages, up to 32.97% and 34.09%, respectively, if compared to lapatinib (31.18%) and ribociclib (29.66%). Moreover, compound 5e caused clear cell cycle arrests at S phase of renal UO-31 cells and at G1 phase of both breast cancer MCF7 and ovarian cancer IGROV1, associated with remarkable increase of DNA content of the controls. In accordance, it demonstrated promising anti- proliferative and apoptotic activities, showing a significant increase in total apoptotic percentages of renal cancer UO-31, breast cancer MCF7 and ovarian IGROV1 cancer cell lines, if compared to the control untreated cells (from 1.79% to 46.72%, 2.19% to 39.02% and 1.66 to 42.51%, respectively). Molecular modelling and dynamic simulation study results supported the main objectives of the present work.

Design, synthesis, crystal structure, and in vitro antibacterial activities of sulfonamide derivatives bearing the 4-aminoquinazoline moiety.

A total of 66 sulfonamide derivatives bearing the 4-aminoquinazoline moiety were designed and synthesized, and their structures were fully characterized by 1H NMR, 13C NMR, and HRMS techniques. Among them, the structures of compounds 5A10 and 5B11 were further confirmed through X-ray single-crystal diffraction analyses. The bioassay results indicated that some of the target compounds displayed higher inhibition activities in vitro against the tested phytopathogenic bacteria. For example, compound 5A26 exhibited a strong anti-Xanthomonas oryzae pv. oryzicola (Xoc) efficacy with an EC50 (half-maximal effective concentration) value of 30.6 µg/mL, over twofold more active than control agent bismerthiazol (BMT). Additionally, compound 5B14 had a good antibacterial effect against the phytopathogen Xanthomonas axonopodis pv. citric (Xac) with EC50 = 34.5 µg/mL, significantly better than control agent BMT (71.5 µg/mL). The anti-Xoc mechanistic studies showed that compound 5A26 exerted its antibacterial efficacy by increasing the permeability of bacterial membrane, decreasing the content of extracellular polysaccharides, and triggering morphological changes of bacterial cells.

Design, synthesis and evaluation of anti-proliferative activity of 2-aryl-4-aminoquinazoline derivatives as EGFR inhibitors.

A class of 2-aryl-4-aminoquinazoline derivatives (7a-7j, 8a-8h, 9a-9h and 10a-10k) were designed, synthesized and evaluated as EGFR inhibitors. The anti-proliferative activity of compounds in vitro showed that compound 9e was considered to be a promising derivative. Compared with the lead compound Angew2017-7634-1, 9e exhibited excellent inhibitory activity against A549, NCI-H460 and H1975 cell lines, with IC50 values of 14.33 ± 1.16 µM, 17.81 ± 1.25 µM and 13.41 ± 1.14 µM, respectively. Moreover, 9e could effectively inhibit against Ba/F3-EGFRDel19/T790M/C797S cell lines. In the kinase experiment, the most promising compound 9e exhibited excellent enzymatic inhibitory activity and selectivity for EGFRL858R/T790M, with an IC50 value of 0.74 µM. Further activity studies showed that 9e could not only induce remarkable cell-apoptosis of A549, but also block A549 cell lines in S-phase in a concentration-dependent manner. Furthermore, molecular docking study revealed the binding mode of 9e. All in all, we analyzed the structure-activity relationship of the target compounds, and explored their mechanism of action.

Identification of 4-anilino-6-aminoquinazoline derivatives as potential MERS-CoV inhibitors.

New therapies for treating coronaviruses are urgently needed. A series of 4-anilino-6-aminoquinazoline derivatives were synthesized and evaluated to show high anti-MERS-CoV activities. N4-(3-Chloro-4-fluorophenyl)-N6-(3-methoxybenzyl)quinazoline-4,6-diamine (1) has been identified in a random screen as a hit compound for inhibiting MERS-CoV infection. Throughout optimization process, compound 20 was found to exhibit high inhibitory effect (IC50 = 0.157 µM, SI = 25) with no cytotoxicity and moderate in vivo PK properties.

Octanol-water partition coefficient measurements for the SAMPL6 blind prediction challenge.

Partition coefficients describe the equilibrium partitioning of a single, defined charge state of a solute between two liquid phases in contact, typically a neutral solute. Octanol-water partition coefficients ([Formula: see text]), or their logarithms (log P), are frequently used as a measure of lipophilicity in drug discovery. The partition coefficient is a physicochemical property that captures the thermodynamics of relative solvation between aqueous and nonpolar phases, and therefore provides an excellent test for physics-based computational models that predict properties of pharmaceutical relevance such as protein-ligand binding affinities or hydration/solvation free energies. The SAMPL6 Part II octanol-water partition coefficient prediction challenge used a subset of kinase inhibitor fragment-like compounds from the SAMPL6 [Formula: see text] prediction challenge in a blind experimental benchmark. Following experimental data collection, the partition coefficient dataset was kept blinded until all predictions were collected from participating computational chemistry groups. A total of 91 submissions were received from 27 participating research groups. This paper presents the octanol-water log P dataset for this SAMPL6 Part II partition coefficient challenge, which consisted of 11 compounds (six 4-aminoquinazolines, two benzimidazole, one pyrazolo[3,4-d]pyrimidine, one pyridine, one 2-oxoquinoline substructure containing compounds) with log P values in the range of 1.95-4.09. We describe the potentiometric log P measurement protocol used to collect this dataset using a Sirius T3, discuss the limitations of this experimental approach, and share suggestions for future log P data collection efforts for the evaluation of computational methods.

Exploring MDR-TB Inhibitory Potential of 4-Aminoquinazolines as Mycobacterium tuberculosis N-Acetylglucosamine-1-Phosphate Uridyltransferase (GlmUMTB ) Inhibitors.

Drug resistance tuberculosis is one of the challenging tasks that dictates the desperate need for the development of new antitubercular agents which operate via novel modes of action. Here, we are reporting on 4-aminoquinazolines as M. tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase (GlmUMTB ) inhibitors to overcome the problem of the MDR-TB. Amongst the synthesized compounds, two of them were observed to be the effective compounds of the series (IC50 =6.4 µM (H37Rv), MIC=25 µM (MDR-TB) and IC50 =2.9 µM (H37Rv), MIC=6.25 µM (MDR-TB), respectively).

A Novel Conjugate of Bis[((4-bromophenyl)amino)quinazoline], a EGFR-TK Ligand, with a Fluorescent Ru(II)-Bipyridine Complex Exhibits Specific Subcellular Localization in Mitochondria.

The epidermal growth factor receptor (EGFR) is a key target in anticancer research, whose aberrant function in malignancies has been linked to severe irregularities in critical cellular processes, including cell cycle progression, proliferation, differentiation, and survival. EGFR mutant variants, either transmembrane or translocated to the mitochondria and/or the nucleus, often exhibit resistance to EGFR inhibitors. The ability to noninvasively image and quantify EGFR provides novel approaches in the detection, monitoring, and treatment of EGFR-related malignancies. The current study aimed to deliver a new theranostic agent that combines fluorescence imaging properties with EGFR inhibition. This was achieved via conjugation of an in-house-developed ((4-bromophenyl)amino)quinazoline inhibitor of mutant EGFR-TK, selected from a focused aminoquinazoline library, with a [Ru(bipyridine)3]2+ fluorophore. A triethyleneglycol-derived diamino linker featuring (+)-ionizable sites was employed to link the two functional moieties, affording two unprecedented Ru conjugates with 1:1 and 2:1 stoichiometry of aminoquinazoline to the Ru complex (mono-quinazoline-Ru-conjugate and bis-quinazoline-Ru-conjugate, respectively). The bis-quinazoline-Ru-conjugate, which retains an essential inhibitory activity, was found by fluorescence imaging to be effectively uptaken by Uppsala 87 malignant glioma (grade IV malignant glioma) cells. The fluorescence imaging study and a time-resolved fluorescence resonance energy transfer study indicated a specific subcellular distribution of the conjugate that coincides with that of a mitochondria-targeted dye, suggesting mitochondrial localization of the conjugate and potential association with mitochondria-translocated forms of EGFR. Mitochondrial localization was further documented by the specific concentration of the bis-quinazoline-Ru-conjugate in a mitochondrial isolation assay.

Novel 4-aminoquinazoline derivatives induce growth inhibition, cell cycle arrest and apoptosis via PI3Kα inhibition.

Phosphatidylinositol 3-kinase (PI3K) signaling pathway has diverse functions, including the regulation of cellular survival, proliferation, cell cycle, migration, angiogenesis and apoptosis. Among class I PI3Ks (PI3Kα, ß, γ, δ), the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in a large portion of human cancers. Therefore, the inhibition of PI3Kα has been considered as a promising target for the development of a therapeutic treatment of cancer. In this study, we designed and synthesized a series of 4-aminoquinazoline derivatives and evaluated their antiproliferative activities against six cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638, A549 and MCF-7. Compound 6b with the most potent antiproliferative activity and without obvious cytotoxicity to human normal cells was selected for further biological evaluation. PI3K kinase assay showed that 6b has selectivity for PI3Kα distinguished from other isoforms. The western blot assay and PI3K kinase assay indicated that 6b effectively inhibited cell proliferation via suppression of PI3Kα kinase activity with an IC50 of 13.6 nM and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 6b caused G1 cell cycle arrest owing to the inhibition of PI3K signaling and induced apoptosis via mitochondrial dependent apoptotic pathway. Our findings suggested that 6b has a therapeutic value as an anticancer agent via PI3Kα inhibition.

Discovery of aminoquinazoline derivatives as human A(2A) adenosine receptor antagonists.

Novel bicyclic adenosine A(2A) antagonists with an aminoquinazoline moiety were designed and synthesized. The optimization of the initial lead compound based on in vitro and in vivo activity has led to the discovery of a potent and selective class of adenosine A(2A) antagonists. The structure-activity relationships of this novel series of bicyclic aminoquinazoline derivatives as adenosine A(2A) antagonists are described in detail.

NAD(P)H: quinone oxidoreductase 1 inducer activity of novel 4-aminoquinazoline derivatives.

Fourteen novel 4-aminoquinazoline derivatives 2-15 were designed and synthesized. The structure of the newly synthesized compounds was established on the basis of elemental analyses, IR, (1)H-NMR, (13)C-NMR, and mass spectral data. The compounds were evaluated for their potential cytoprotective activity in murine Hepa1c1c7 cells. All of the synthesized compounds showed concentration-dependent ability to induce the cytoprotective enzyme NAD(P)H: quinone oxidoreductase (NQO1) with potencies in the low- to sub-micromolar range. This approach offers an encouraging framework which may lead to the discovery of potent cytoprotective agents.

Rational design of inhibitors of the bacterial cell wall synthetic enzyme GlmU using virtual screening and lead-hopping.

An aminoquinazoline series targeting the essential bacterial enzyme GlmU (uridyltransferase) were previously reported (Biochem. J.2012, 446, 405). In this study, we further explored SAR through a combination of traditional medicinal chemistry and structure-based drug design, resulting in a novel scaffold (benzamide) with selectivity against protein kinases. Virtual screening identified fragments that could be fused into the core scaffold, exploiting additional binding interactions and thus improving potency. These efforts resulted in a hybrid compound with target potency increased by a 1000-fold, while maintaining selectivity against selected protein kinases and an improved level of solubility and protein binding. Despite these significant improvements no significant antibacterial activity was yet observed within this class.

Design, synthesis, and antimicrobial evaluation of 2-aminothiazole derivatives bearing the 4-aminoquinazoline moiety against plant pathogenic bacteria and fungi.

BACKGROUND: To find more effective agricultural antibiotics, a class of new 2-aminothiazole derivatives containing the 4-aminoquinazoline moiety were synthesized and evaluated for their antimicrobial properties against phytopathogenic bacteria and fungi of agricultural importance. RESULTS: All the target compounds were fully characterized by 1 H NMR, 13 C NMR, and high-resolution mass spectrometry. The bioassay results showed that compound F29 with a 2-pyridinyl substituent exhibited an outstanding antibacterial effect against Xanthomonas oryzae pv. oryzicola (Xoc) in vitro, having an half-maximal effective concentration (EC50 ) value as low as 2.0 µg/mL (over 30-fold more effective than the commercialized agrobactericide bismerthiazol, with an EC50 value of 64.3 µg/mL). In addition, compound F8 with a 2-fluorophenyl group demonstrated a good inhibitory activity toward the bacterium Xanthomonas axonopodis pv. citri (Xac), around twofold more active than bismerthiazol in terms of their EC50 values (22.8 versus 71.5 µg/mL). Interestingly, this compound also demonstrated a notable fungicidal effect against Phytophthora parasitica var. nicotianae, with an EC50 value largely comparable with that of the commercialized fungicide carbendazim. Finally, mechanistic studies revealed that compound F29 exerted its antibacterial effects by increasing the permeability of bacterial membranes, reducing the release of extracellular polysaccharides, and triggering morphological changes of bacterial cells. CONCLUSION: Compound F29 has promising potential as a lead compound for developing more efficient bactericides to fight against Xoc. © 2023 Society of Chemical Industry.

Crystal structures of 6-nitro-quinazolin-4(3H)-one, 6-amino-quinazolin-4(3H)-one and 4-amino-quinazoline hemi-hydro-chloride dihydrate.

The title compounds, 6-nitro-quinazolin-4(3H)-one (C8H5N3O3; I), 6-amino-quinazolin-4(3H)-one (C8H7N3O; II) and 4-amino-quinazolin-1-ium chloride-4-amino-quinazoline-water (1/1/2), (C8H8N3 +·Cl-·C8H7N3·2H2O; III) were synthesized and their structures were determined by single-crystal X-ray analysis. In the crystals of I and II, the quinazoline mol-ecules form hydrogen-bonded dimers via N-H⋯O inter-actions. The dimers are connected by weak inter-molecular C-H⋯N and C-H⋯O hydrogen bonds, forming a layered structure in the case of I. In the crystal of II, N-H⋯N and C-H⋯O inter-actions link the dimers into a three-dimensional network structure. The asymmetric unit of III consists of two quinazoline mol-ecules, one of which is protonated, a chloride ion, and two water mol-ecules. The chloride anion and the water mol-ecules form hydrogen-bonded chains consisting of fused five-membered rings. The protonated and unprotonated quinazolin mol-ecules are linked to the chloride ions and water mol-ecules of the chain by their amino groups.

2-Styryl-4-aminoquinazoline derivatives as potent DNA-cleavage, p53-activation and in vivo effective anticancer agents.

Forty-eight analogues of CP-31398, an antitumor agent modulated the mutant p53 gene were synthesized and their cytotoxicities against four cancer cell lines with different p-53 status including bladder cell T24 (w-p53), gastric cell MGC-803 (m-p53), prostate cell DU145 (m-p53), prostate cell PC-3 (null-p53), lung cell A549 (w-p53) and normal liver cell line HL-7702 (w-p53) were examined. (E)-2-(4-Nitrostyryl)-4-(3-dimethylaminopropyl)-aminoquinazoline (10ah) was identified as the most potent compound in anti-proliferation against MGC-803 cells, with IC50 lowed to 1.73 µM, far potency than that of CP-31398. Molecular mechanism study revealed that 10ah and CP-31398 differ greatly in mechanism to exert their antitumor properties. 10ah could intercalate into DNA and resulted in significant DNA double-strand break. 10ah-treatment in MGC-803 cells increased the expression of p53, phosphorylated p53 (p-p53), CDK4, p21 to cause cell cycle arrest at G2/M phase, significantly up-regulated the levels of pro-apoptosis proteins Bak, Bax, Bim while down-regulated the anti-apoptosis proteins Bcl-2, Bcl-xL and the levels of cyclin B1, fluctuated the intracellular reactive oxygen species (ROS), Ca2+ and mitochondrial membrane potential, activated Caspase-9 and Caspase-3 to induce apoptosis. 10ah also displayed potent anticancer efficiency against MGC-803 xenograft tumors models, with tumor growth inhibition (TGI) up to 61.8% at 20 mg/kg without obvious toxicity.

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives.

Since accelerated metabolism produces much higher levels of reactive oxygen species (ROS) in cancer cells compared to ROS levels found in normal cells, human MutT homolog 1 (MTH1), which sanitizes oxidized nucleotide pools, was recently demonstrated to be crucial for the survival of cancer cells, but not required for the proliferation of normal cells. Therefore, dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells. While several inhibitors were indeed confirmed to be effective, some inhibitors failed to kill cancer cells, complicating MTH1 as a viable target for cancer eradication. In this review, we summarize the current status of developing MTH1 inhibitors as drug candidates, classify the MTH1 inhibitors based on their structures, and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1.

Recent advancements of 4-aminoquinazoline derivatives as kinase inhibitors and their applications in medicinal chemistry.

The 4-aminoquinazoline core is an interesting pharmacophore and its applications in medicinal chemistry are wide spread. The core has been used for making many kinase inhibitors in past few years. Many researcher demonstrated 4-aminoquinazoline derivatives as specific kinase inhibitors, including tyrosine kinase and serine/theronine kinases. A number of anticancer drugs with 4-aminoquinazoline core are in the market, e.g. gefitinib, erlotinib, afatinib, lapatinib, decomitinib etc. 4-aminoquinazoline derivatives are applied for target specific treatment of lung, breast, colon, prostate cancers. In this review, we discussed the current development of 4-aminoquinazoline derivatives as kinase inhibitors and their uses as anticancer agents in recent years.

Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents.

Through a structure-based molecular hybridization approach, a series of novel quinazolinyl-diaryl urea derivatives were designed, synthesized, and screened for their in vitro antiproliferative activities against three cancer cell lines (HepG2, MGC-803, and A549). Six compounds (7 g, 7 m, 7 o, 8 e, 8 g, and 8 m) showed stronger activity against a certain cell line compared with the positive reference drugs sorafenib and gefitinib. Among the six compounds, 8 g exhibited the strongest activity. In particular, compound 8 g induced A549 apoptosis, arrested cell cycle at the G0/G1 phase, elevated intracellular reactive oxygen species level, and decreased mitochondrial membrane potential. This compound can also effectively regulate the expression of apoptosis- and cell cycle-related proteins, and influence the Raf/MEK/ERK pathway. Molecular docking and structure-activity relationship analyses revealed that it can bind well to the active site of the receptor c-Raf, which was consistent with the biological data. Therefore, compound 8 g may be a potent antitumor agent, representing a promising lead for further optimization.