Quinazolinone Derivatives Research Articles

Halogen-based quinazolin-4(3H)-one derivatives as MCF-7 breast cancer inhibitors: Current developments and structure-activity relationship.

Currently, cancer is a serious health challenge with predominance beyond restrictions. Breast cancer remains one of the major contributors to cancer-related morbidity and mortality in women. Chemotherapy continues to be crucial in the treatment of all variants of cancer. Several antitumor drugs are presently in different phases of clinical trials, whereas many more have been approved for clinical use. However, these drugs have the potential to cause adverse effects, and certain individuals may become resistant to them, which would eventually reduce the drug's efficacy. Therefore, it is essential to discover, develop, and improve newer anticancer drug molecules that could potentially inhibit proliferative pathways. In recent years, quinazolinone derivatives, more specifically halogen-substituted 4(3H)-quinazolinone, have drawn attention as a promising new class of chemotherapeutic agents. In addition, these molecules showed significant inhibition in micromolar ranges when tested in vitro against the MCF-7 cell line. Therefore, this study aims to emphasize the intriguing versatility of halogen atoms, providing an in-depth summary and highlighting recent developments in the anticancer properties of halogenated 4(3H)-quinazolinones. It also features a detailed discussion of the structure-activity relationship (SAR) of various functional groups and their interaction with amino acid residues utilizing molecular docking studies. The intent is to foster novel discoveries that can inspire innovative investigations in this domain. Hence, this study simplifies the drug design and development strategies by prolonging the array of pharmacologically active candidates.

Design, synthesis and antitumor activity of triphenylphosphonium-linked derivatives of quinazolinone

Cancer is the leading cause of human death. Quinazolinone heterocyclic compounds have a variety of biological activities and have been extensively studied in recent years, especially for their potential anticancer activity. The triphenylphosphonium moiety (TPP+) has become a very important lipophilic cation, especially concerning its application the development of anticancer agents. In this work, we designed and synthesised 24 new TPP+ -conjugated quinazolinone derivatives, which have alkylated TPP+ at the N-3 position and different small group substitutions at the C-6 position, and their antiproliferative activity was evaluated in three cancer cell lines (human alveolar adenocarcinoma cells (A549), human hepatoblastoma cells (HepG2) and human breast cancer cells (MCF-7)) and human normal liver cells (QSG-7701). The cytotoxicity screening results showed that some derivatives exhibited effective inhibitory effects in cancer cells. Among them, the compound 5k–o showed better antiproliferative activity than the positive control drug gefitinib on MCF-7 and A549 cells. The most active compounds being 5o, with IC50 values of 6.56, 14.52 and 7.51 µM in MCF-7 cells, HepG2 cells and A549 cells, respectively. Compound 5o may be a promising compound for cancer treatment worthy of further study.

Dimethyl Sulfoxide Promoted Quinazolinone Synthesis

AbstractAn efficient and one‐step synthesis of quinazolinones using 2‐aminobenzamide and benzylamine in DMSO under external catalyst‐ and base‐free conditions is reported. A broad substrate scope and environment‐benign mild reaction conditions are the major attributes of this straightforward synthesis. Moreover, the synthesized quinazolinone derivatives were used to produce pharmaceutically active rutaecarpine analogues using a two‐step reaction: N‐alkylation followed by intramolecular cyclization.

Discovery of a novel benzimidazole conjugated quinazolinone derivative as a promising SARS-CoV-2 3CL protease inhibitor.

This report presents the design and synthesis of quinazolinone-based derivatives as promising SARS-CoV-2 3CL protease inhibitors. Two novel series, namely, febrifugine analogues 4a-i and quinazolinone conjugated benzimidazoles 9a-c, were successfully synthesized starting from isatoic anhydride. The synthesized quinazolinone derivatives were evaluated for their cytotoxicity against cancer cell lines and SARS-CoV-2 3CL inhibitory activity. The results showed that the synthesized compounds did not have significant toxicity for the non-cancer HEK293 cell line and MCF-7, MDA-MB-231, HEPG2 and HEPG2.2.15 cancer cell lines. Notably, compound 9b exhibited anti-3CL enzymatic activity in a dose-dependent manner, with the calculated IC50 value of 10.73 ± 1.17 μM. Docking results highlighted the interaction between 9b and 3CL protease through hydrogen bonding with key amino acids, including His41, Met49, Cys145, Met165, Arg188, His164, and Glu166, at the active site of the protease. Pharmacokinetic studies and ADME analyses provide valuable insights into the potential of compound 9b as a drug candidate. These findings support the new scaffold as a candidate for 3CLpro inhibition and advanced anti-coronavirus drug research.

Mn-Catalyzed Electrooxidative Radical Cascade Cyclization for the Synthesis of 6-Phosphorylated Quinoxalino[2,1-b]quinazolin-12-ones.

Due to their important potential medicinal value, chemists are pursuing mild and efficient methods to synthesize structurally diverse quinazolinone derivatives. In this paper, a series of isocyano-tethered N-aryl quinazolinones were designed and synthesized to conduct electrocatalytic radical cascade cyclization reactions with phosphine oxides by utilizing inexpensive MnII salt as the catalyst. The desired 6-phosphorylated quinoxalino[2,1-b]quinazolin-12-ones were obtained in moderate to good yields.

Design, Synthesis, and Preclinical Evaluation of a High-Affinity 18F-Labeled Radioligand for Myocardial Growth Hormone Secretagogue Receptor Before and After Myocardial Infarction.

The peptide hormone ghrelin is produced in cardiomyocytes and acts through the myocardial growth hormone secretagogue receptor (GHSR) to promote cardiomyocyte survival. Administration of ghrelin may have therapeutic effects on post-myocardial infarction (MI) outcomes. Therefore, there is a need to develop molecular imaging probes that can track the dynamics of GHSR in health and disease to better predict the effectiveness of ghrelin-based therapeutics. We designed a high-affinity GHSR ligand labeled with 18F for imaging by PET and characterized its invivo properties in a canine model of MI. Methods: We rationally designed and radiolabeled with 18F a quinazolinone derivative ([18F]LCE470) with subnanomolar binding affinity to GHSR. We determined the sensitivity and invivo and ex vivo specificity of [18F]LCE470 in a canine model of surgically induced MI using PET/MRI, which allowed for anatomic localization of tracer uptake and simultaneous determination of global cardiac function. Uptake of [18F]LCE470 was determined by time-activity curve and SUV analysis in 3 regions of the left ventricle-area of infarct, territory served by the left circumflex coronary artery, and remote myocardium-over a period of 1.5 y. Changes in cardiac perfusion were tracked by [13N]NH3 PET. Results: The receptor binding affinity of LCE470 was measured at 0.33 nM, the highest known receptor binding affinity for a radiolabeled GHSR ligand. In vivo blocking studies in healthy hounds and ex vivo blocking studies in myocardial tissue showed the specificity of [18F]LCE470, and sensitivity was demonstrated by a positive correlation between tracer uptake and GHSR abundance. Post-MI changes in [18F]LCE470 uptake occurred independently of perfusion tracer distributions and changes in global cardiac function. We found that the regional distribution of [18F]LCE470 within the left ventricle diverged significantly within 1 d after MI and remained that way throughout the 1.5-y duration of the study. Conclusion: [18F]LCE470 is a high-affinity PET tracer that can detect changes in the regional distribution of myocardial GHSR after MI. In vivo PET molecular imaging of the global dynamics of GHSR may lead to improved GHSR-based therapeutics in the treatment of post-MI remodeling.

Green Synthesis of Quinazolinones via Selective Electro‐oxidation Using Iron Electrode and NaCl Electrolyte as an Eco‐friendly Electrolyte

AbstractPrimary alcohols 2(a–h) and o‐aminobenzamides 1(a–h) can be selectively oxidized electrochemically to yield dihydroquinazolinone 4(a–h) and quinazolinones 5(a–h) in an efficient and chemoselective manner. This methodology employs sodium chloride (NaCl) 3(a) as a co‐catalyst and electricity as the oxidizing agent, utilizing cost‐effective and commercially available materials such as Graphite anode, Iron (Fe) cathode, and isopropyl alcohol (iPrOH) as a solvent and weak base. The synthesis yields various quinazolinone derivatives with diverse structural characteristics in good quantities, showcasing the method‘s broad applicability. This approach facilitates the production of a range of dihydroquinazolinones and quinazolinones (24 examples), highlighting its versatility and compatibility with different functional groups. Characterization of the synthesized derivatives included CHN analysis, 1HNMR spectroscopy, and determination of melting points.

Design and synthesis of novel main protease inhibitors of COVID-19: quinoxalino[2,1-b]quinazolin-12-ones.

The COVID-19 pandemic represents a substantial global challenge, being a significant cause of mortality in numerous countries. Thus, it is imperative to conduct research to develop effective therapies to combat COVID-19. The primary aim of this study is to employ a two-step tandem reaction involving 2,3-dichloroquinoxaline and 2-amino-N-substituted benzamides in alkaline media/DMF at an elevated temperature to design and synthesize a series of polycyclic derivatives endowed with quinoxalino[2,1-b]quinazolin-12-one framework. Following synthesis, the newly synthesized heterocycles were evaluated for their potential as inhibitors of the main protease of SARS-CoV-2 by means of molecular docking and dynamic simulation techniques. The in silico investigation demonstrated that all tested compounds effectively establish stable binding interactions, primarily through multiple hydrogen bonding and hydrophobic interactions, at the active site of the enzyme. These findings offer crucial structural insights that can be employed in future endeavors toward designing potent inhibitors targeting the main protease (Mpro). Among the investigated compounds, the p-tolylamino-substituted quinoxalino[2,1-b]quinazolinone derivative exhibited the most promise as an inhibitor of the main protease in COVID-19. Consequently, it warrants further investigation both in vitro and in vivo to identify it as a prospective candidate for anti-SARS-CoV-2 drug development.

Fused Thiazolo[2,3‐b]Quinazolinone–Chromone Hybrids: Synthesis, Characterization, In Vitro Antibacterial Activity and In Silico Screening

ABSTRACTAntimicrobial resistance is one of the biggest threats to public health across the globe. Bacteria, fungi, viruses, and protozoans have been exhibiting resistance against antimicrobial drugs making them ineffective. Hence, the development of new antibiotics with a different mode of action is highly desirable. In this study, 10 new chromone‐incorporated fused thiazolo[2,3‐b]quinazolinone derivatives, 8a‐j, have been prepared via Biginelli reaction involving aromatic aldehydes, 1‐tetralone, and thiourea followed by a reaction with 2‐chloro‐N‐phenylacetamide, and Knoevenagel condensation with 3‐formylchromone. All the structures of the compounds were characterized by NMR, FTIR, and mass spectrometry. The in vitro antibacterial activities of all the synthesized compounds against the four different microbial strains were evaluated. Among them, few compounds demonstrated prominent activity against Staphylococcus aureus, Streptococcus pyogenes, and Pseudomonas aeruginosa. No appreciable activity of any compound against Klebsiella pneumoniae was observed. Molecular docking studies were employed to reveal the interactions responsible for the potent compounds' activities against S. aureus, S. pyogenes, and P. aeruginosa. Both in vitro and in silico studies have been carried out by using standard agar well diffusion protocol and Auto Dock Vina in PyRx. The results indicated that compound 8c was the potential compound as it showed good affinity toward the receptors of all three organisms. Molecular dynamics simulation of the 8c‐1JIJ complex for 100 ns further confirmed the potentiality of 8c. The pharmacokinetic properties of the compounds indicate that the studied molecules have exhibited a favorable profile.

Elemental Sulfur‐Promoted Annulative Coupling of 2‐Aminobenzamides and 2‐Aminobenzylamines with Sulfoxonium Ylides: Access to Quinazolinones and Quinazolines

A novel and straightforward approach for synthesizing quinazolinones and quinazoline derivatives employing sulfur‐mediated annulative coupling of 2‐aminobenzamides and 2‐aminobenzylamines in conjunction with sulfoxonium ylides has been described. This method demonstrates a broad substrate range and exhibits excellent tolerance towards various functional groups. Finally, this protocol has been successfully applied to synthesize pyrazino‐fused quinazolinone derivative with adjustable fluorescence properties and tryptanthrin, a compound known for its potent antitubercular activity.

Glucose-Water Synergy: An Organocatalytic System Driven synthesis of Benzimidazolo[2,3-b]quinazolinone and Benzothiazolo[2,3-b]quinazolinone Derivatives

Introduction: A simple and efficient one-pot synthesis of quinazolinone derivatives has been developed via a multicomponent reaction (MCR) involving the condensation of dimedone, benzaldehyde, and 2-aminobenzimidazole/2-aminobenzothiazole. Method: In this work, glucose water is used as a green, reusable, environmentally benign organocatalytic solvent system to synthesize desired products. Result: The main benefits of this one-pot method include its excellent yields, less time, cost-effectiveness, atom economy, environment benign, and easy workup. Conclusion: In conclusion, we successfully developed a green protocol for the environmentally benign synthesis of benzimidazo/benzothiazolo quinazolinones using glucose water as an organocatalytic medium.

Synthesis and antimicrobial activity of 6-iodo-2-(trifluoromethyl)-4(3H)-quinazolinone derivatives

Synthesis and antimicrobial activity of 6-iodo-2-(trifluoromethyl)-4(3H)-quinazolinone derivatives

Unveiling the Therapeutic Potential of Quinazolinone Derivatives in Cancer Treatment: A Comprehensive Exploration

AbstractQuinazolinone derivatives have garnered attention for their diverse biological activities, including anticancer properties. This review combines findings from 2018 to 2024, focusing on the impact of quinazolinones on cancer cells, tubulin formation, and EGFR/PI3 K pathways. By unraveling the intricacies of structure‐activity relationships, this review endeavors to provide guidance for researchers in identifying promising avenues for the development of cancer treatments. Although in vitro studies underscore significant potential, it is imperative that future research prioritizes pre‐clinical investigations to seamlessly traverse the transitional phase towards clinical applications, thereby propelling the advancement of quinazolinone‐based cancer therapy.

Green Synthetic and Pharmacological Developments in the Hybrid Quinazolinone Moiety: An Updated Review.

Bicyclic quinazolinone constitutes an important class of organic framework enveloping numerous biological properties which enthused organic and medicinal chemists to explore green synthetic strategies for the construction of quinazolinone hybrids with significantly improved pharmacodynamics and pharmacokinetic profiles. In this perspective, the present review summarizes the most recent green synthetic strategies, biological properties, structure-activity relationship, and molecular docking studies of the 4-quinazolinone-based scaffold. This review provides deeper insight into the hit-to-lead synthesis of quinazolinone derivatives in the development of clinically important therapeutic candidates.

New Quinazolinone‐Tethered 1,2,3‐Triazoles aSs Potent Antimicrobial Agents: Design, Synthesis, Biological Evaluation and in silico Docking Study

AbstractNovel 1,2,3‐triazole acetamide linked quinazolinone derivatives were synthesized via click reaction, by reacting of 3‐methyl‐2‐(prop‐2‐yn‐1‐ylthio)quinazolin‐4(3H)‐one with various aryl azides as prominent fungal pathogen Candida albicans interactions. The prepared triazole compounds were characterized using mass spectrometry, 1H NMR, 13C NMR, and IR spectroscopic techniques. Compounds were screened for their in vitro antibacterial and antifungal activity against a variety of microorganisms namely, Bacillus subtilis, Enterococcus faecalis, Klebsiella pneumonia, Escherichia coli, Aspergillus fumigatus, Candida albicans, and Aspergillus clavatus. Quinazolinone linked p‐hydroxyphenyl, o, p‐dihydroxyphenyl and o‐dimethylamino phenyl triazoles showed a remarkable antibacterial activity against E. faecalis with MIC values of 3.20±0.01, 4.01±0.04, and 4.10±0.01 μg mL−1, and screened compounds p‐nitrophenyl substituted triazole, and p‐methylphenyl substituted triazole displayed a significant antifungal activity against C. albicans with MICs of 3.16±0.01, 4.06±0.03 μg mL−1, compared to itraconazole (MIC=3.32±0.02 μg mL−1). For further exploration of the anti‐fungal mechanism of action, molecular docking was carried out for these compounds in C. albicans active site as one of the important antifungal inhibitors (PDB: 1A19). Furthermore, the ADMET profile was evaluated for all the final triazole compounds in contrast to reference drugs moxifloxacin and itraconazole. In conclusion, we discovered a novel quinazolinone linked 1,2,3‐triazoles with promising antimicrobial activity and a favorable pharmacokinetic profile.

Preparation and Characterization of Copper Ferrite Functionalized Graphitic Carbon Nitride Nanocomposite as an Effective and Reusable Catalyst for Synthesis of Spirooxindol Quinazolinone Derivatives

Preparation and Characterization of Copper Ferrite Functionalized Graphitic Carbon Nitride Nanocomposite as an Effective and Reusable Catalyst for Synthesis of Spirooxindol Quinazolinone Derivatives

Rhodium(III)-Catalyzed Annulation Synthesis of Difluorinated Quinazolinone Derivatives Using an Amide Carbonyl as the Directing Group.

The use of amide carbonyl groups of substrates as weakly coordinating directing groups has received a significant amount of attention. Recently, difluoromethylene alkynes have been successfully used in fluorination reactions, resulting in the preparation of various fluorine-containing compounds. This work describes a [4+2] annulation method for creating a range of fluorinated quinolino[2,1-b]quinazolinone derivatives. The derivatives are formed through Rh(III)-catalyzed cascade cyclization of 3-phenylquinazolinones and gem-difluoromethylene alkynes.

Synthesis of quinazolinone derivatives with a seven‐membered ring using borrowing hydrogen methodology

In this study, we synthesized 23 quinazolinone derivatives with the seven-membered C-ring through intramolecular borrowing hydrogen reaction of 3-(3-hydroxypropyl)-2-(1H-indol-2-yl)-quinazolin-4(3H)-one, in yields ranging from 31 % to 68 %. The reaction took place in the presence of cesium carbonate and DMF, using triphenylphosphine ruthenium chloride (PPh3)3RuCl2 as a catalyst and Xantphos as a ligand. Water was the only byproduct. Furthermore, pharmacological activity tests were conducted on these compounds, revealing that some of the products exhibited anti-inflammatory and anticancer properties.

Acid-catalyzed radical tandem alkylation/cyclization of unactivated alkenes with ketones: Access to ketoalkyl-substituted quinazolinone derivatives

A method for synthesizing polycyclic quinazolinone derivatives with ketoalkyl substitutions has been developed through strong acid-catalyzed radical tandem alkylation/cyclization of unactivated alkenes with readily available ketones under microwave irradiation. The transformation offers several advantages, including wide functional group compatibility, operational simplicity, and moderate to good yields. This methodology offers an appealing approach to obtaining keto-containing polycyclic quinazolinones with pharmaceutical value.

A literature review on pharmacological aspects, docking studies, and synthetic approaches of quinazoline and quinazolinone derivatives.

Quinazoline and quinazolinone derivatives piqued medicinal chemistry interest in developing novel drug candidates owing to their pharmacological potential. They are important chemicals for the synthesis of a variety of physiologically significant and pharmacologically useful molecules. Quinazoline and quinazolinone derivatives have anticancer, anti-inflammatory, antidiabetic, anticonvulsant, antiviral, and antimicrobial potential. The increased understanding of quinazoline and quinazolinone derivatives in biological activities provides opportunities for new medicinal products. The present review focuses on novel advances in the synthesis of these important scaffolds and other medicinal aspects involving drug design, structure-activity relationship, and action mechanisms of quinazoline and quinazolinone derivatives to help in the development of new quinazoline and quinazolinone derivatives.