Quinazoline Compounds Research Articles

Molecular Dynamics Study of Quinazoline Compounds Complexed with Filamenting Temperature-Sensitive Z Protein and Gyrase Subunit B as Potential Antibacterials

Molecular Dynamics Study of Quinazoline Compounds Complexed with Filamenting Temperature-Sensitive Z Protein and Gyrase Subunit B as Potential Antibacterials

Anti-colorectal Cancer Activity of Quinazoline Derivatives: A Comprehensive Review

Introduction and Objective: The identification of a bioactive template (or lead) is one of the important features of modern drug discovery. Natural products, synthetic and biotechnological sources, serve as important templates for the development of novel bioactive molecules. Quinazoline is one of the heterocyclic templates present in many natural and synthetic drugs and exhibits various biological activities, including anticancer, by blocking the pharmacological pathway of different targets. Methodology: In this study, the data was collected from the literature and patents to examine the anticolorectal cancer efficacy of quinazoline compounds and their mechanism of actions. According to the published literature and patents, the benzene and/or pyrimidine rings of the quinazoline have been substituted with amino groups or substituted amino groups to develop novel analogues endowed with anticancer properties. The anti-colorectal cancer activity of quinazolines was due to the flexible chain containing terminal phenyl and/or heterocyclic rings (thiazole, pyrazole, piperidine, piperazine, etc.). Results: These quinazoline derivatives were found to inhibit the growth of colorectal cancer cells by modulating the expression of specific genes and proteins involved in cancer progression, such as receptor tyrosine kinases, epidermal growth factor receptors, dihydrofolate reductase, topoisomerases, histone deacetylase, and apoptotic proteins. Conclusion: These findings suggest that the quinazoline nucleus may be exploited to identify new anticolorectal cancer agents with suitable pharmacokinetic profiles.

Anti-Inflammatory Activity of Pyrazolo[1,5-a]quinazolines.

Chronic inflammation contributes to a number of diseases. Therefore, control of the inflammatory response is an important therapeutic goal. To identify novel anti-inflammatory compounds, we synthesized and screened a library of 80 pyrazolo[1,5-a]quinazoline compounds and related derivatives. Screening of these compounds for their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor κB (NF-κB) transcriptional activity in human THP-1Blue monocytic cells identified 13 compounds with anti-inflammatory activity (IC50 < 50 µM) in a cell-based test system, with two of the most potent being compounds 13i (5-[(4-sulfamoylbenzyl)oxy]pyrazolo[1,5-a]quinazoline-3-carboxamide) and 16 (5-[(4-(methylsulfinyl)benzyloxy]pyrazolo[1,5-a]quinazoline-3-carboxamide). Pharmacophore mapping of potential targets predicted that 13i and 16 may be ligands for three mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 2 (ERK2), p38α, and c-Jun N-terminal kinase 3 (JNK3). Indeed, molecular modeling supported that these compounds could effectively bind to ERK2, p38α, and JNK3, with the highest complementarity to JNK3. The key residues of JNK3 important for this binding were identified. Moreover, compounds 13i and 16 exhibited micromolar binding affinities for JNK1, JNK2, and JNK3. Thus, our results demonstrate the potential for developing lead anti-inflammatory drugs based on the pyrazolo[1,5-a]quinazoline and related scaffolds that are targeted toward MAPKs.

Preparation, Agricultural Bioactivity Evaluation, Structure-Activity Relationships Estimation, and Molecular Docking of Some Quinazoline Compounds.

Quinazoline compounds have gained significant attention in the fields of agriculture and chemistry due to their diverse activities. In this study, we focused on a series of quinazoline derivatives (4a-l). The objectives involved multiple aspects, including preparation, evaluation of their agricultural bioactivity against the maize aphid (Rhopalosiphum maidis), estimation of the structure-activity relationships (SAR), and conducting molecular docking analysis. The results of the agricultural bioactivities revealed that compound (4b) possesses the highest insecticidal activity, and the other compounds have good potential as insecticidal agents. We conducted the SARs and also molecular docking investigation to elucidate the binding modes and interactions of these compounds with target proteins relevant to the agricultural bioactivity. The docking results provided valuable information on the binding affinities and molecular interactions, aiding in the rationalization of the observed bioactivity trends. The enzyme, acetylcholinesterase (AChE), was docked with the 12 synthetic compounds (4a-l). Among these compounds, (4b), (4i), and (4e)exhibited the highest binding affinity, with docking scores (S) of -7.96, -7.83, and -7.73 kcal/mol, respectively. They were followed by compounds (4d) (S = -7.57 kcal/mol), (4c) (S = -7.53 kcal/mol), (4g) (S = -7.34 kcal/mol), (4f) (S = -7.23 kcal/mol), (4h) (S = -7.14 kcal/mol), (4k) (S = -6.61 kcal/mol), (4j) (S = -6.57 kcal/mol), (4a) (S = -6.28 kcal/mol), and finally (4l) (S = -6.01 kcal/mol). These compounds were shown to have a variety of binding interactions within the 2ACE active site, as evidenced by protein-ligand docking configurations. This study gives evidence that those compounds have AChE-inhibitory capabilities and, hence, may be used for AChE-targeting development. Also, the findings in this study highlight the potential of these compounds as agricultural agents and provide valuable insights for the design and development of some quinazoline derivatives with enhanced bioactivity for crop protection.

Photocatalytic synthesis of 2,4‐substituted quinazolines via a one‐pot, three‐component reaction under catalyst‐free conditions

AbstractA novel, catalyst‐free photoinduced synthesis of 2,4‐substituted quinazoline using 2‐amino‐aryl ketone, an aldehyde, and ammonium acetate was developed. A series of 2,4‐substituted quinazoline compounds were obtained via irradiating the reactants with a light‐emitting diode light (18 W) at room temperature. The broad substrate range and excellent gram‐scale experimental results demonstrate the versatility of the reaction. To the best of our knowledge, the synthesis of 2,4‐substituted quinazoline using ammonium acetate as the nitrogen source under photocatalysis has not been reported thus far. This method utilizes visible light oxidation to eliminate the use of oxidants in the reaction and is complementary to previous methods.

Pyrazolo[4,3-H]quinazolines as Cyclin-dependent Kinase Inhibitors for Treating Cancer.

The application describes the synthesis of 1H-pyrazolo[4,3-H]quinazoline compounds for treating cell proliferation dysfunction and is a broad-spectrum and strongly-active inhibitor for a cell cyclin-dependent kinase (CDK).

Design, synthesis, and antiproliferative activities of novel substitutedhydrazone/triazolo-linked quinazoline derivatives

A series of novel hydrazonoquinazolines and triazoloquinazolines analogues of Erlotinib were synthesized and evaluated for their antiproliferative as well as EGFR kinase inhibitory activities. Most of the quinazoline compounds showed significant antiproliferative against different cancer cells. Among these, both compounds 4b and 5b were the best members of all the tested cancer cell lines with IC50 in the range 1.25–4.92 μM and 1.95–7.60 μM, respectively (c.f. erlotinib (IC50 7.52–16.02 μM) and inhibited EGFR with IC50 0.80 and 0.66 μM, sequentially. Additionally, these two compounds effectively induced cell cycle arrest and triggered apoptosis in HL-60 cancer cells by regulating the pro-apoptotic protein BAX and anti-apoptotic protein Bcl-2 expression. The docking studies revealed that there are interactions like that of erlotinib at the EGFR active site. In conclusion, the synthesized quinazoline compounds 4b and 5b effectively inhibit EGFR. Such a finding can be sited as a good starting point for the development of novel antitumor compounds targeting EGFR kinase.

Design of new molecules against cervical cancer using DFT, theoretical spectroscopy, 2D/3D-QSAR, molecular docking, pharmacophore and ADMET investigations

Cervical cancer is a major health problem of women. Hormone therapy, via aromatase inhibition, has been proposed as a promising way of blocking estrogen production as well as treating the progression of estrogen-dependent cancer. To overcome the challenging complexities of costly drug design, in-silico strategy, integrating Structure-Based Drug Design (SBDD) and Ligand-Based Drug Design (LBDD), was applied to large representative databases of 39 quinazoline and thioquinazolinone compound derivatives. Quantum chemical and physicochemical descriptors have been investigated using density functional theory (DFT) and MM2 force fields, respectively, to develop 2D-QSAR models, while CoMSIA and CoMFA descriptors were used to build 3D-QSAR models. The robustness and predictive power of the reliable models were verified, via several validation methods, leading to the design of 6 new drug-candidates. Afterwards, 2 ligands were carefully selected using virtual screening methods, taking into account the applicability domain, synthetic accessibility, and Lipinski's criteria. Molecular docking and pharmacophore modelling studies were performed to examine potential interactions with aromatase (PDB ID: 3EQM). Finally, the ADMET properties were investigated in order to select potential drug-candidates against cervical cancer for experimental in vitro and in vivo testing.

Exploring Substituted Tetrazoloquinazoline: Biological Activities, Molecular Docking Analysis, and Anti-Breast Cancer MCF7/HER2 Effects.

Breast cancer is a condition where breast tissue cells grow uncontrollably. Various natural and synthesized compounds, such as quinazoline, have been studied for their potential as anticancer agents. Quinazoline derivatives have shown diverse bioactivities, including antimalarial, antifungal, antimicrobial, and anticancer properties. This research aims to synthesize substituted tetrazoloquinazoline and evaluate its potential as an anticancer agent using molecular docking studies with the Molecular Operating Environment (MOE) software. Furthermore, molecular dynamic was also performed to analyze the binding stability of this protein-ligand complex. Additionally, the physicochemical and pharmacokinetic properties of quinazoline compounds were assessed using the website https://www.swissadme.ch. The cytotoxic activity of the compounds was evaluated using the MTT assay. The docking results revealed that substituted tetrazoloquinazoline exhibited a significantly different range of binding free energy compared to the positive control. Moreover, the substituted tetrazoloquinazoline compounds comply with Lipinski's Rule of Five (Ro5), indicating that they are easily absorbable and have good permeability. The cytotoxic activity of the compounds was found to have an IC50 value of >1000 ppm, classifying them as noncytotoxic. It therefore paved the way for the discovery of promising next-generation drugs against breast cancer.

New validated liquid chromatography‐tandem mass spectrometry method for the determination of Dacomitinib in human plasma and its application to a pharmacokinetic study

AbstractDacomitinib, a quinazoline compound, exhibits antineoplastic activity against brain metastasis activities in non‐small cell lung cancer and the central nervous system. In this study, the liquid–liquid extraction method with high‐performance liquid chromatography and tandem mass spectrometry detection method was established and validated for the determination of Dacomitinib in human plasma. Plasma samples were prepared and chromatographic separation was achieved on analytical column Discovery C18 (10 cm × 4.6 mm, 5 μm) with gradient elutes at a flow rate of 0.8 mL/min, using a mobile phase consisting of acetonitrile and ammonium formate. Dacomitinib and dacomitinib D10 (internal standard) were detected by multiple reactions. The method was fully validated according to the United States Food and Drug Administration guidelines. The calibration curve was linear with an excellent correlation coefficient (r2 ˂ 0.99). The method validation steps such as carry‐over, matrix effect, extraction recovery, dilution effect, intra‐inter accuracy, and precision were found within acceptable limits. The method was then applied to a pharmacokinetic study in human plasma. After oral administration, the plasma concentration in different volunteers reached 0.5–250.01 ng/mL. The result established can be applied to the estimation of drugs in human plasma.

Discovery and development of quinazoline compounds as irreversible pan-fibroblast growth factor receptor inhibitors with potent antitumor activities

Abnormal activation of fibroblast growth factor receptors (FGFRs) results in the development and progression of multiple cancer types. Therefore, it is an attractive target for tumor therapy, and many efforts have been directed to the discovery of irreversible FGFR inhibitors over the last decade. Using a quinazoline scaffold, we used structure-based drug design to obtain a series of novel covalent pan-FGFR inhibitors. One of the representative compounds, I-11, showed remarkable enzymatic activity toward FGFR1–4 (FGFR1/2/3/4, IC50 = 5.6/2.2/8.5/4.6 nM) and strongly suppressed the proliferation of Huh7 HCC cells (IC50 = 6.35 nM). Further, I-11 exhibited reasonable PK profiles (F = 57.5 %) and showed significant antitumor effects in the Huh-7 xenograft model without obvious changes in body weight. Overall, I-11 was identified as a potential pan-FGFR inhibitor for cancer therapy and deserved further research.

Spectrophotometric and infra-red analyses of azo reactive dyes derived from 2-methyl-3-(2’- methylphenyl)-6-arylazo-4- oxoquinazoline

Ultraviolet-visible and infrared spectroscopic techniques were used to determine the possible composition and functional groups present in a series of quinazoline based mono azo reactive dyes (DM1-5) which was prepared by coupling 2-methyl-3-(2’- methylphenyl)-6-arylazo-4-oxoquinazoline diazonium solution with five (5) cyanurated coupling components . The result of visible absorption spectra showed that the λmax obtained for each dye depends on the coupling component used and that the λmax tend to shift to the shorter wavelength (hypsochromic shift) as the auxochromes appear to have influence on the absorption peak of the dyes... The IR spectral showed all the characteristics and representative of azo reactive dyes, with characteristic band in the range of 3400 - 3309 cm-1 indicating the presence of -OH and –NH stretching vibration, 1382 - 1049 cm-1 for the presence of –C-N, 1141-1010 cm-3 for –S=0 and 925 - 56 cm-1 for the presence of - C-Cl . The azo band occurred in the region of 1458 - 1411 cm-1 which is due to stretching vibration of the -N=N- group. A strong band at 1643 - 1604 cm-1 is due to the stretching vibration of -C=O group of the quinazoline compound. However, the IR spectrum did not actually reveal the chemical structure of the reactive dyes being studied. Further studies could be conducted using GCMS and NMR spectroscopy to confirm the structure of the dyes.

Combining enzyme and photoredox catalysis for the synthesis of quinazolines

Herein, a novel one-pot strategy combining an enzyme and visible-light catalysis for the synthesis of quinazoline derivatives from 2-aminobenzylamine and methyl benzoylformate is described for the first time. The reaction comprises enzyme-catalyzed hydrolysis, visible-light-activated decarboxylation, and oxidation cyclization. A series of reactions between 2-aminobenzylamine and different methyl benzoylformates afforded the corresponding products. This strategy was successfully applied to the reaction of 2-aminobenzamide and o-phenylenediamine with methyl benzoylformate. This method has the advantages of not requiring additional additives or transition metals, providing an efficient and environmentally friendly approach for synthesizing quinazoline compounds.

Design, Synthesis, and Activity Evaluation of Novel Dual-Target Inhibitors with Antifungal and Immunoregulatory Properties.

Dual-target (CYP51/PD-L1) plays an important role in the process of fungal proliferation and immune suppression. A series of novel quinazoline compounds with dual-target inhibition function was constructed using the skeleton growth method, and their structures were synthesized, characterized, and evaluated. Among them, the perfected compounds (L11, L20, L21) were selected for further study, which exhibited remarkable biological activity against different fungal strains (MIC50, 0.25-2.0 μg/mL) in vitro. On the one hand, these compounds inhibited CYP51 activity, induced ROS aggregation, and mitochondrial damage; this ultimately caused fungal lysis and death. On the other hand, they also effectively activated the body's immune ability by blocking the interaction between PD-L1 and PD-1, slowed down the inflammatory reaction, and accelerated the recovery process of fungal infections.

An Updated Overview on the Synthesis and Anticancer Evaluation of Quinazoline Derivatives

AbstractCancer, a leading global cause of death, necessitates the exploration of safer and more effective anticancer drugs due to the adverse side effects associated with current cytotoxic treatments. Quinazoline and its derivatives have emerged as a promising class of drugs with demonstrated efficacy against diverse tumor types. In light of these advancements, this comprehensive review aims to outline recent developments in the utilization of quinazoline derivatives as anticancer agents. Additionally, the article offers valuable insights into the potential for novel quinazoline derivatives to serve as future anticancer drugs. By delving into the structure‐activity relationship study, this review equips researchers with a thorough understanding necessary for designing a substantial number of impactful quinazoline compounds, which hold great potential in the treatment of various life‐threatening disorders.

In vitro and In silico Xanthine Oxidase Inhibitory Activities of 3-Aryl-2- thioxo-2,3-dihydroquinazolin-4(1H)-one Derivatives.

Hyperuricemia is associated with several disease conditions, such as atherosclerosis, arthritis, kidney stones, and many others. Xanthine oxidase (XO) is an enzyme that catalyzes the conversion of xanthine to uric acid. Hence, XO is a major therapeutic drug target in the treatment of hyperuricemia and associated disorders. The current study aimed to identify XO inhibitors based on quinazoline derivatives, with the potential to be used against gout and other hyperuricemia-associated diseases. In the current study, eighteen quinazoline derivatives 2-19 were synthesized and assessed for their in vitro xanthine Oxidase (XO) inhibitory activity. Furthermore, the most active compounds, 5 and 17, were subjected to kinetics studies, followed by computational docking. Human BJ fibroblast cells were used to measure the cytotoxicity of active compounds. Compounds 4-6, 8, 10, 13, 15-17, and 19 were found active against XO, with an IC50 values between 33.688 to 362.173μM. The obtained results showed that compounds 5 and 17 possess a significant xanthine oxidase inhibitory activity. The kinetics and molecular docking studies suggested that compounds 5 (IC50 = 39.904 ± 0.21 μM) and 17 (IC50 = 33.688 ± 0.30 μM) bind in the allosteric site of XO and exhibit a non-competitive type of inhibition. The molecular docking studies also predicted that the NH group of the pyrimidine ring binds with Ser344 residues of XO. Furthermore, all active compounds were non-cytotoxic on the human BJ fibroblasts cell line. This study identifies a series of quinazoline compounds as xanthine oxidase inhibitors, with the potential to be further investigated.

3D,2D-QSAR study and docking of novel quinazolines as potential target drugs for osteosarcoma.

Background: Quinazolines are an important class of benzopyrimidine heterocyclic compounds with a promising antitumor activity that can be used for the design and development of osteosarcoma target compounds. Objective: To predict the compound activity of quinazoline compounds by constructing 2D- and 3D-QSAR models, and to design new compounds according to the main influencing factors of compound activity in the two models. Methods: First, heuristic method and GEP (gene expression programming) algorithm were used to construct linear and non-linear 2D-QSAR models. Then a 3D-QSAR model was constructed using CoMSIA method in SYBYL software package. Finally, new compounds were designed according to molecular descriptors of 2D-QSAR model and contour maps of 3D-QSAR model. Several compounds with optimal activity were used for docking experiments with osteosarcoma related targets (FGFR4). Results: The non-linear model constructed by GEP algorithm was more stable and predictive than the linear model constructed by heuristic method. A 3D-QSAR model with high Q2 (0.63) and R 2 (0.987) values and low error values (0.05) was obtained in this study. The success of the model fully passed the external validation formula, proving that the model is very stable and has strong predictive power. 200 quinazoline derivatives were designed according to molecular descriptors and contour maps, and docking experiments were carried out for the most active compounds. Compound 19g.10 has the best compound activity with good target binding capability. Conclusion: To sum up, the two novel QSAR models constructed were very reliable. The combination of descriptors in 2D-QSAR with COMSIA contour maps provides new design ideas for future compound design in osteosarcoma.

Synthesis, Characterization, and Antitubercular Evaluation of Tetrahydrotetrazolo Quinazoline Derivatives

Background: Tuberculosis is a highly contagious disease that is one of the major causes of mortality worldwide and the leading infectious organism-related cause of death. Various tetrazole and quinazoline compounds have been successfully developed in the past for tuberculosis treatment. In this case, we planned to design the hybrid moieties by combining both tetrazole and quinazoline nuclei to create novel compounds with increased activity. Methods: 6, 6-dimethyl-5, 6, 7, 9–tetrahydrotetrazolo [5, 1-b] Quinazolin-8(4H) -one derivatives were synthesized, characterized by using spectral data. The antitubercular activity of the synthesized compounds was tested against the H37RV strain of Mycobacterium tuberculosis. In order to identify the interactions with the target protein Mtb Pks13 Thioesterase domain in complex with an inhibitor, docking analysis of the final compounds was performed (Protein data bank ID: 5V41). To verify their drug-like potential, the synthesized compounds were subjected to Pharmacokinetic prediction experiments. Zebrafish larvae had been used to test the teratogenicity of the synthesized compounds. Results: At 6.25 μg/mL, compounds F4 and F7 exhibited good efficacy against Mycobacterium tuberculosis strains. Docking studies aided in determining the most likely binding mode within the binding cavity of the concerned target protein. Conclusion: Compounds containing p-fluorophenyl and p-nitrophenyl groups as substituents were found to have excellent anti-tubercular activity.

The Anti-Multidrug-Resistant Acinetobacter baumannii Study on 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline Compounds

As a major public health problem, the prevalence of Acinetobacter baumannii (A. baumannii) infections in hospitals due to the pathogen's multiple-antibiotic resistance has attracted extensive attention. We previously reported a series of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline (PQZ) compounds, which were designed by targeting Escherichia coli dihydrofolate reductase (ecDHFR), and exhibited potent antibacterial activities. In the current study, based on our molecular-modeling study, it was proposed that PQZ compounds may function as potent A. baumannii DHFR (abDHFR)-inhibitors as well, which inspired us to consider their anti-A. baumannii abilities. We further found that three PQZ compounds, OYYF-171, -172, and -175, showed significant antibacterial activities against A. baumannii, including multidrug-resistant (MDR) strains, which are significantly stronger than the typical DHFR-inhibitor, trimethoprim (TMP), and superior to, or comparable to, the other tested antibacterial agents belonging to β-lactam, aminoglycoside, and quinolone. The significant synergistic effect between the representative compound OYYF-171 and the dihydropteroate synthase (DHPS)-inhibitor sulfamethoxazole (SMZ) was observed in both the microdilution-checkerboard assay and time-killing assay, which indicated that using SMZ in combination with PQZ compounds could help to reduce the required dosage and forestall resistance. Our study shows that PQZ is a promising scaffold for the further development of folate-metabolism inhibitors against MDR A. baumannii.

Medicinal Chemistry of Quinazolines as Analgesic and Anti-Inflammatory Agents

Quinazoline is an essential scaffold, known to be linked with various biological activities. Some of the prominent biological activities of this system are analgesic, anti-inflammatory, anti-hypertensive, anti-bacterial, anti-diabetic, anti-malarial, sedative–hypnotic, anti-histaminic, anti-cancer, anti-convulsant, anti-tubercular, and anti-viral activities. This diversity in the pharmacological response of the quinazoline system has encouraged medicinal chemists to study and discover this system and its multitude of potential against several biological activities. Many of these studies have successfully investigated the structure–activity relationship to explore the specific structural features of their biological targets. The developing understanding of quinazoline derivatives and their biological targets presents opportunities for the discovery of novel therapeutics. This review represents different aspects of medicinal chemistry, including drug design, structure–activity relationship, and the mode of action of some analgesic and anti-inflammatory quinazoline compounds. It pays comprehensive attention to the analgesic and anti-inflammatory activities of quinazolines from the viewpoint of drug discovery and its development.