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Background: In this study, two novel hybrid series of artemisinin and quinazolinones were synthesized and evaluated in vitro cytotoxicity against two human cancer cell lines, including SKLu-1 (lung cancer), MCF- 7 (breast cancer). The bio-assay results indicated that most of the target compounds exhibited cytotoxic activities against both human cancer cell lines tested and seemed to be more cytotoxic toward the breast (MCF-7) cancer cells than lung (SKLu-1) cancer cells. Among the synthesized artemisinin hybrids, the compound 13d containing a quinazolinone conjugated system exhibited the most potent cytotoxicity against the SKLu-1 and MCF-7 cell lines with IC50 values of 1.62 and 0.77 μM, respectively. Objective: This study aims at developing novel hybrids of artemisinin and quinazolinones as anticancer agents. Method: A series of novel hybrids were designed, synthesized, and evaluated for cytotoxicity against two human cancer cell lines, including SKLu-1 and MCF-7, using the SRB method. Results: All thirteen hybrids of artemisinin with quinazolinone exhibited cytotoxic activity against two tested cancer cell lines, in which the compound 13d exhibited the most potent cytotoxicity against the SKLu-1 and MCF-7 cell lines with IC50 values of 1.62 and 0.77 μM, respectively. Conclusion: The research results suggest that some compounds could be considered as leads for future design of hybrids and have the potential for further studies in the field of anti-cancer agent development.

An efficient iodine-mediated electrochemical C(sp3)-H cyclization was developed under mild condition. A variety of functionalized quinazolinone-fused N-heterocycles can be obtained with good to excellent yields by virtue of this method. The reaction features broad substrate scope, scalability, metal-free and chemical oxidant-free.

A series of unreported novel dithioacetal derivatives containing a 4(3H)-quinazolinone pyrimidine ring were synthesized, and their antiviral activities were evaluated against tomato spotted wilt virus (TSWV). A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was established, and compound D32 was designed and synthesized according to the analysis results of the CoMFA and CoMSIA models. The bioassay results showed that compound D32 exhibited excellent inactivation activity against TSWV, with EC50 values of 144 μg/mL, which was better than those of ningnanmycin (149 μg/mL) and the lead compound xiangcaoliusuobingmi (525 μg/mL). The binding ability of compound D32 to TSWV CP was tested by microscale thermophoresis (MST), and the binding constant value was 4.4 μM, which was better than those of ningnanmycin (6.2 μM) and xiangcaoliusuobingmi (59.1 μM). Therefore, this study indicates that novel dithioacetal derivatives containing a 4(3H)-quinazolinone pyrimidine ring may be applied as new antiviral agents.

Compared with the well-developed C–C and C–N axial chirality, the asymmetric synthesis of N–N axial chirality remains elusive and challenging. Herein we report the first atroposelective N-acylation reaction of quinazolinone type benzamides with cinnamic anhydrides for the direct catalytic synthesis of optically active atropisomeric quinazolinone derivatives. This reaction features mild conditions and a broad substrate scope and produces N–N axially chiral compounds with high yields and very good enantioselectivities. Besides, the synthetic utility of the protocol was proved by a large scale reaction, transformation of the product and the utilization of the product as an acylation kinetic resolution reagent. Moreover, DFT calculations provide convincing evidence for the interpretation of stereoselection., A highly efficient atroposelective N-acylation reaction of quinazolinone type benzamides with cinnamic anhydrides for the direct catalytic synthesis of optically active atropisomeric quinazolinone derivatives was developed.

Plant bacteria such as Xanthomonas axonopodispv. citri (Xac), Pseudomonas syringaepv. actinidiae (Psa), Xanthomonas oryzaepv. oryzae (Xoo), and tobacco mosaic virus (TMV) have created huge obstacles to the global trade of food and economic crops. However, traditional chemical agents used to control these plant diseases have gradually become disadvantageous due to long-term irregular use. Therefore, finding new and efficient antibacterial and antiviral agents is becoming imperative. In this study, a series of myricetin derivatives containing a quinazolinone moiety were designed and synthesized, and the antibacterial and antiviral activities of these compounds were evaluated. The bioassay results showed that some target compounds exhibited good antibacterial activities in vitro and antiviral activities in vivo. Among them, the median effective concentration (EC50) value of compound L18 against Xac was 16.9 μg/mL, which was better than those of the control drugs bismerthiazol (BT) (62.2 μg/mL) and thiodiazole copper (TC) (97.5 μg/mL). Scanning electron microscopy (SEM) results confirmed that compound L18 inhibited the growth of Xac by affecting the morphology of cells. Microscale thermophoresis (MST) test results indicated that the dissociation constant (Kd) value of compound L11 against TMV-CP was 0.012 μM, which was better than that of the control agent ningnanmycin (2.726 μM). This study reveals that myricetin derivatives containing a quinazolinone moiety are potential antibacterial and antiviral agents.

Angiotensin receptor blockers (ARBs) are a group of drugs primarily used in the treatment of cardiovascular disease. Multiple quantitative structural activity relationship (QSAR) models established for prediction of angiotensin II type 1a (AT-1a) receptor blocking activity of quinazolinone derivatives to investigate the structural attributes that have significant correlation with biological activity. The genetic algorithm (GA) approach was used to generate a highly predictive models using easily interpretable Py, OEstate and Padel descriptors. OECD principles have been followed to develop statistically robust QSAR models (R2tr = 0.8055 – 0.8625) with good external predictivity (CCCex = 0.7528-0.8450). The multiple QSAR models successfully identified that increase in surface area of negatively charge carbon atom within four bonds from N atom, presence of tetrazole substituents and sp3 N atoms governs the AT-1a receptor blocking activity. The validated QSAR models of present study might be helpful for evaluation AT-1a receptor blocking activity to identify novel hits.

Tomato spotted wilt virus (TSWV) is a plant virus with strong infectivity and destructive power. Given the lack of effective control agents, TSWV causes significant economic damage to several vegetables and ornamental plants worldwide. In this study, we designed and synthesized a series of novel quinazolinone derivatives containing a dithioacetal moiety and evaluated their antiviral activity in vitro and in vivo against TSWV. Some candidate compounds showed good anti-TSWV activity. Compound 6n shows excellent anti-TSWV activity in vivo, and the EC50 value is 188 mg/L, which is notably better than that observed for ribavirin (642 mg/L), xiangcaoliusuobingmi (420 mg/L), and ningnanmycin (257 mg/L). In addition, compound 6n interacts with TSWV coat protein at sites ARG94 and ARG95 forming four π-alkyl interactions. Compound 6n (9.4 μM) shows a better binding affinity with TSWV coat protein than ribavirin (67.8 μM), xiangcaoliusuobingmi (33.8 μM), and ningnanmycin (24.3 μM). Therefore, compound 6n can serve as a lead compound for the discovery of new antiviral agents for the management of TSWV.

Epidermal growth factor receptor (EGFR) acting very important part in cell growth regulation, one of the most significant consideration studied targets of tyrosine kinases (TK) inhibitors. A number of TKs take component in the role cell proliferation, differentiation and metastasis, survival and tolerant activation by mechanisms for instance point mutation might show the way to huge proportion of clinical cancers. EGFR is in excess articulated within many tumors, as well as ovarian, breast and bladder, head, brain, prostate, lung tumors. based in the field of literature study found that the invention of quinazolin 4(3H) one derivatives of structural modifications which produce their potential of cytotoxic properties. By inhibit the EGFR-TKs enzyme. In this, we introduced newly synthesized quinazolinones compounds to systematically investigate binding affinity and drug likeliness property against EGFR-TKs. the interaction of newly synthesized molecules QOC1-QOC6 against 1M17 Protein five derivatives of quinazolinone an induced fit docking analysis indicated are involved in binding affinity. The present study aimed at studies showed with the systematic analysis, the newly synthesized potential quinazolinone are recommended so as to these molecules would provide the same as enhanced show the way lead moiety for cytotoxic activity.

Quinazolin-4(3H)-one derivatives exhibiting a wide spectrum of a pharmacological activity, represent a promising class of substances used to obtain antibacterial agents, which is especially important in the context of the emergence of pathogenic microorganisms’ resistance to drugs used in medicine. It has been proved that compounds having a naphthyl radical in the molecule, as well as an amide group bound to the benzene ring as quinazolinone substituents, are characterized by a pronounced antimicrobial activity againstStaphylococcus aureusandStreptococcus pneumoniae.The aimof the research is a primary microbiological screening of thein vitroantimicrobial activity of new quinazolin-4(3H)-one derivatives againstStaphylococcus aureusandStreptococcus pneumoniae, as well as the assessment of the relationship between the pharmacological effect and the structural transformation of the substance molecule, lipophilicity and the possibility of forming resistance to them.Materials and methods.The experimental studies have been carried out using well-known nosocomial pathogens of infectious and inflammatory diseasesStaphylococcus aureusandStreptococcus pneumoniaeby a serial dilution method.Results.A compound containing a naphthyl radical in its structure, which contributes to an increase in the hydrophobicity of the substance and its solubility in the membrane of a bacterial cell, has a bacteriostatic effect against bothStaphylococcus aureusandStreptococcus pneumoniae.A similar pharmacological effect is exhibited by a derivative with an amide group as a substituent of the quinazolinone nucleus linked to a phenyl radical, which probably contributes to an increase in the degree of binding to active sites of enzymes involved in the DNA replication, and protein synthesis. Obviously, the increased lipophilicity, which promotes better binding to the efflux protein, cannot serve as objective characteristics of the emergence possibility of the pathogen’s resistance to this substance.Conclusion.Among the synthesized compounds, the leading substances that exhibit an antimicrobial activity againstStaphylococcus aureusandStreptococcus pneumonia,have been identified.The assessment of the chemical structure made it possible to substantiate their pharmacological action and draw conclusions about the possibility of developing resistance to it in microbial cells.

In recent years, tankyrase inhibition has gained a great focus as an anti-cancer strategy due to their modulatory effect on WNT/β-catenin pathway implicated in many malignancies, including colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). Based on the structural homology in the catalytic domain of PARP enzymes, bis-quinazolinone 5 (Cpd 5) was designed to be a potent selective tankyrase inhibitor. In this study, we employed molecular dynamics simulations and binding energy analysis to decipher the underlying mechanism of TNK-1 inhibition by Cpd 5 in comparison with a known selective tankyrase, IWR-1. The Cpd 5 had a relatively higher ΔGbind than IWR-1 from the thermodynamics analysis, revealing the better inhibitory activity of Cpd 5 compared to IWR-1. High involvement of solvation energy (ΔGsol) and the van der Waals energy (ΔEvdW) potentiated the affinity of Cpd 5 at TNK-1 active site. Interestingly, the keto group and the N3 atom of the quinazolinone nucleus of Cpd 5, occupying the NAM subsite, was able to form H-bond with Gly1185, thereby favoring the better stability and higher inhibitory efficacy of Cpd 5 relative to IWR-1. Our analysis proved that the firm binding of Cpd 5 was achieved by the quinazolinone groups via the hydrophobic interactions with the side chains of key site residues at the two subsite regions: His1201, Phe1188, Ala1191, and Ile1192 at the AD subsite and Tyr1224, Tyr1213, and Ala1215 at the NAM subsite. Thus, Cpd 5 is dominantly bound through π-π stacked interactions and other hydrophobic interactions. We believe that findings from this study would provide an important rationale towards the structure-based design of improved selective tankyrase inhibitors in cancer therapy.

A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure-activity relationship studies led to identification of a potent inhibitor 19f, 95-fold more potent than the original hit compound, active against laboratory-resistant strains of malaria. Profiling of 19f suggested a fast in vitro killing profile. In vivo activity in a murine model of human malaria in a dose-dependent manner constitutes a concomitant benefit.

In the report, we described the ruthenium(II)-catalyzed C–H activation/cyclization of 2-arylquinazolinones with vinyl carbonate for the synthesis of different fused quinazolinones. Through this strategy, the 6-hydroxy-5,6-dihydro-8H-isoquinolino[1,2-b]quinazolin-8-one and 8H-isoquino[1,2-b] quinazolin-8-one have been obtained, respectively, under different temperatures. Additionally, the reaction features broad substrate scope and good yields, only producing carbon dioxide as byproduct. Moreover, we performed preliminary mechanistic studies of this reaction and proposed a possible mechanism.

Background: Antioxidants are small molecules that prevent or delay the process of oxidations caused by highly reactive free radicals. These molecules are known for their ability to protect various cellular architecture and other biomolecules from oxidative stress and free radicals. Thus, antioxidants play a key role in the prevention of oxidative damages caused by highly reactive free radicals. Methods: In the present study, a series of previously synthesized heterocyclic 2-aryl-4(3H)- quinazolinone derivatives 1-25 were screened for antioxidant activity by employing in vitro DPPH and superoxide anion radical scavenging activities. ROS inhibitory activities were also evaluated by serum-opsonized zymosan activated whole blood phagocytes and isolated neutrophils. Cytotoxicity studies were carried out by employing an MTT assay against the 3T3 cell line. Results: Most of the 2-aryl-4(3H)-quinazolinone derivatives showed potent antioxidant activities in superoxide anion radical scavenging assay with IC50 value ranging between 0.57 μM - 48.93 μM, as compared to positive control quercetin dihydrate (IC50 = 94.1 ± 1.1 μM ). Compounds 5, 6, and 14 showed excellent activity in DPPH assay. Compounds 5-8, 12-15, 17, and 20 showed promising activities in the ROS inhibition assay. All compounds were found to be non-cytotoxic against the 3T3 cell line. Structure antioxidant activity has been established. Conclusion: It can be concluded that most of the heterocyclic 2-aryl-4(3H)-quinazolinone derivatives 1-25 are identified as promising antioxidant agents that are capable of fighting against free radicals and oxidative stress. Thus, they can serve as a lead towards treating oxidative stress and related pathologies.

An expedient route to enantiopure, diastereomeric pyrrolopyrazinoquinazolinones was developed following the discovery of a domino quinazolinone rearrangement-intramolecular cyclization of N-H benzamidines. A Ugi-Mumm-Staudinger sequence employing an optically pure proline derivative gave quinazolinones that, upon N-Boc deprotection, rearranged to tautomeric Z-benzamidines. Subsequent spontaneous cyclization afforded 15 diastereomeric pyrazinoquinazolinone pairs in up to 83% overall yield and 89:11 d.r which were separated easily via routine chromatographic purification – the only one required in the entire process.

For the first time, the sequential reaction of peroxyoxindole that involves base-promoted oxidative fragmentation to isocyanate formation and primary amine or amino alcohol accelerated skeletal rearrangement to synthesize exo-olefinic-substituted quinazolinone or oxazoloquinazolinone is reported. The advantages of this new reaction include a broad substrate scope and transition-metal-free and room-temperature conditions. The formation of the isocyanate as a key intermediate that accelerates oxidative skeletal rearrangement has been confirmed by trapping experiments and spectroscopic evidence.

The effect of an organo-aqueous solvent on the yields of 12-oxo-6,12-dihydroazepino[2,1-b]quinazoline-6-carboxylic acid methyl ester and 3H-azepine-2(1H)-one-3-carboxylic acid methyl ester has been evaluated. It has been found that at low concentrations, water competes with 2-aminobenzoic acid ethyl ester in the nucleophilic addition reaction, reducing the yields of azepino[2,1-b]quinazolinone and increasing the yields of 3H-azepinone. At a water concentration of more than 20 wt %, the nucleophilicity of substituted aniline increases, contributing to an increase in the yields of azepino[2,1-b]quinazolinone and a decrease in the yields of 3H-azepinone.

A series of new quinazolinones and related compounds has been conveniently synthesized via reaction of (E)-3-(1,3-diphenyl-1H-pyrazol-4-yl)-2-(6-iodo-4-oxo-4H-benzo[d] [1,3] oxazin-2-yl)acrylonitri...

Electrochemistry has recently emerged as a sustainable approach for efficiently generating radical intermediates utilizing eco-friendly electric energy. An electrochemical process was developed to transform 1,2,4-oxadiazolines under mild conditions. The electrochemical N-O bond cleavage at a controlled oxidation potential led to the selective synthesis of quinazolinone derivatives that could not be obtained by photocatalytic radical processes, indicating complementary reactivities in radical processes. The electrochemical reaction pathways were fully revealed by density functional theory-based investigations.

Guided by molecular docking, a commonly used open-chain linker was cyclized into a five-membered pyrrolidine to lock the overall conformation of the propeller-shaped molecule. Different substituents were introduced into the pyrrolidine moiety to block oxidative metabolism. Surprisingly, it was found that a small methyl substituent could be used to alleviate the oxidative metabolism of pyrrolidine while maintaining or enhancing potency, which could be described as a "magic methyl". Further optimization around the "3rd blade" of the propeller led to identification of a series of potent and selective PI3Kδ inhibitors. Among them, compound 50 afforded an optimum balance of PK profiles and potency. Oral administration of 50 attenuated the arthritis severity in a dose-dependent manner in a collagen-induced arthritis model without obvious toxicity. Furthermore, 50 demonstrated excellent pharmacokinetic properties with high bioavailability, suggesting that 50 might be an acceptable candidate for treatment of inflammatory diseases.

Aim: A series of novel quinazolinone derivates was synthesized and assessed for their ability to inhibitory action on pancreatic lipase. The cyclization of quinazolinone-4(3H)-one derivatives was achieved, whereas carbon-carbon cross coupling reactions were carried out on cyclized quinazolinone-4(3H)-one. This synthesis method afforded corresponding 2, 3 and 6 substituted quinazolin-4(3H)-ones (3a to 3m) with moderate to high yields. Methods: Benzamide derivatives (1a-1b) were synthesized from anthranilic acid using acid-amine reaction, followed by cyclization using catalytic p-toluene sulfonic acid and oxidation using (diacetoxyiodo)benzene to give bromo substituted quinazolin-4(3H)-ones (2a-2b), which were cross coupled to suitable boronic acid using Suzuki-Miyaura condition to obtain desired compound (3a-3m). All synthesized compounds were characterized by FTIR, proton NMR, LC-MS analysis, checked for their drug likeness, absorption and evaluated for in vitro pancreatic lipase inhibition activity. Results: Analytical interpretation of all compounds with infrared, proton NMR and LC-MS spectroscopy confirmed their correct structure. All compounds (3a-3m) show good absorption and have reasonably good molecular properties except 3c and 3m which violate two criteria for Lipinski’s rule. Whereas, Compounds 3l and 3m showed IC50 value of 13.13±0.84 µg/mL and 13.80±1.27 µg/mL respectively comparable to the Orlistat (12.72±0.97µg/mL), a US FDA approved drug for the treatment of obesity. Conclusion: Pancreatic lipase is an important lipolytic enzyme, synthesized and secreted through pancreas, plays an important role in dietary trigycerol absorption and metabolism. Therefore, reducing fat absorption through pancreatic lipase inhibition is a promising strategy to treat obesity. Based upon our findings, compounds 3l and 3m can be further developed as potent anti-obesity agents.

Specific features of the molecular and crystal structures of two substituted benzoxazinones (I and II) and their structural analog quinazolinone (III) have been analyzed by the XRD method. Compound I exists in two crystalline modifications. All investigated molecules are nonplanar; however, the character of their nonplanarity is different. In molecules I and II, the intramolecular hydrogen bond N–H⋅⋅⋅N rather than the potentially possible bond N–H⋅⋅⋅О is closed. Molecule III also contains the similar hydrogen bond. The occurrence of weak directional interactions in the crystal packings (π–π interactions in I and II and intermolecular hydrogen bonds N–Н⋅⋅⋅O in III) leads to the formation of isolated dimer structures rather than infinite formations.

Background: Although exhaustive efforts to prevent and treat tuberculosis (TB) have been made, the problem still continues due to multi-drug-resistant (MDR) and extensively drugresistant TB (XDR-TB). It clearly highlights the urgent need to develop novel “druggable” molecules for the co-infection treatment and strains of MDR-TB and XDR-TB. Objective: In this approach, a hybrid molecule was created by merging two or more pharmacophores. The active site of targets may be addressed by each of the pharmacophores and proffers the opportunity for selectivity. In addition, it also reduces undesirable side effects and drug-resistance. Methods: In this study, a novel quinazolinone analog was designed and synthesized by substituting thiourea nucleus and phenyl ring at N-3 and C-2 position of quinazoline ring, respectively. All title compounds were tested for antitubercular activity by in vitro M. tuberculosis and anti-human immunodeficiency virus (HIV) activity by MT-4 cell assay method. The agar dilution method was used to test the antibacterial potency of entire prepared derivatives against various strains of grampositive and gram-negative microorganisms. Results: The title compounds, 1-(substituted)-2-methyl-3-(4-oxo-2-phenyl quinazolin-3(4H)-yl) isothioureas (QTS1 – QTS15) were synthesized by the reaction between key intermediate 3-amino- 2-phenylquinazolin-4(3H)-one with various alkyl/aryl isothiocyanates followed by methylation with dimethyl sulphate. Among the series, compound 1-(3-chlorophenyl)-2-methyl-3-(4-oxo-2-phenyl quinazolin- 3(4H)-yl) isothioureas (QTS14) showed the highest potency against B. subtilis, K. pneumonia and S. aureus at 1.6 μg/mL. The compound QTS14 exhibited the most potent antitubercular activity at the MIC of 0.78 μg/mL and anti-HIV activity at 0.97 μg/mL against HIV1 and HIV2. Conclusion: The results obtained from this study confirm that the synthesized and biologically evaluated quinazolines showed promising antimicrobial, antitubercular and anti-HIV activities. The new scaffolds proffer a plausible lead for further development and optimization of novel antitubercular and anti-HIV drugs.

Background: Quinazoline and quinazolinone scaffolds represent an important class of biologically active nitrogen heterocyclic compounds. Many marketed drugs are based on these moieties. A diverse range of molecules with quinazoline/quinazolinone moieties have been reported to exhibit broad spectrum of biological activities Objective: This study is aimed at the synthesis of these quinazolinone derivatives, quinazolin-4(3H)-One, 2-Methyl-4(3H)-quinazolinone and 2–Phenyl-4(3H)-quinazolin-4(3H)–one and evaluate them for their antibacterial activities. Method: The consolidation of 2-amino-methyl-4-methoxybenzoate with acetic anhydride produced the cyclic compound 2-methyl-4, 5-disubstituted-1, 3-benzo-oxazine-4-one which also produce a novel 2,3-disubstituted quinazolin-4 ones via the reaction with hydrazine hydrate. The quinazolinone derivatives quinazolin-4(3H)-One, 2-Methyl-4(3H)-quinazolinone and 2–Phenyl-4(3H)-quinazolin-4(3H)–one were evaluated pharmacologically for their in vivo analgesic activities by acetic acid induced writhing in mice. The compounds synthesized were assuredly validated by means of Infrared, Nuclear Magnetic Resonance (1H and 13C), Gas Chromatography Mass Spectrophotometer and Elemental analysis. The synthesized compounds were tested for their antibacterial activity.Compounds 1,2 and 3 showed significant antibacterial activities. Discussion: Compound 1 was identified by the absence of methyl group and the presence of methyl group for compound 2. The test analysed compounds exhibited significant antibacterial activities. The compounds synthesized exhibited promising antibacterial activities against the tested organisms. Conclusion: The compounds have high antibacterial activities. Compound 2 has a higher activity compared to Compound 1 and 3. Compound 2 has a higher antibacterial against Escherichia coli, Klebsiella pneumonia and Pseudomonas aeuriginosa

Background: Mutations that cause high expression of epidermal growth factor can lead to cancer. Therefore, this factor serves as a potential molecular target for cancer treatment, and inhibitors of this enzyme are of particular importance in the treatment of cancer. This study aimed to investigate the bioinformatics of inhibition of EGFR enzyme by a number of quinazolinone derivatives. Materials and Methods: This study was conducted based on a descriptive-analytical method. To investigate how quinazolinone derivatives bind to the active site of the enzyme, the chemical structure of the compounds was first plotted using ChemBioDrawUltra software (version 14). It was then transferred to Hyperchem software for energy optimization. Docking studies were performed using AutoDock software (version 4.2), and in the final stage, the results were analyzed using three programs, including AutoDockTools, DS Visualizer, and Ligplot. Results: Based on the results of docking studies, the most important bonds involved in drug-receptor binding are hydrophobic and hydrogen bonds. Among all the studied compounds, the best docking results are related to compound number 3. This compound with the most negative binding energy level (ΔGbind=-7.53 Kcal/mol) has a greater tendency to bind to key amino acids at the active site of the EGFR. Conclusion: In the end, due to the high effectiveness and docking results, it can be conclude that compound number 3 can be considered an effective erlotinib EGFR inhibitor.