Search Results (172)

An important field of research in medicinal and organic chemistry involves halogen-containing heterocyclic synthones, which form the backbone of more complex organic compounds. This study aimed to design and synthesize 28 novel derivatives of 7-aryl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one. The derivatives were created from 7-bromoquinoline intermediates to evaluate their potential as cholinesterase inhibitors for treating neurodegenerative diseases such as Alzheimer’s disease. The conditions for the Suzuki–Miyaura cross-coupling reaction were optimized to improve yield and purity. The derivatives were evaluated for their anticholinesterase activity using Ellman’s method, revealing that it most effectively inhibited cholinesterase within the micromolar range. 7-(3-Chloro-4-fluorophenyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one derivative exhibited the highest inhibitory potency, with an IC₅₀ value of 6.084 ± 0.26 μM. Additionally, molecular dynamics simulations provided insight into how this lead compound interacts with the enzyme, suggesting its potential as a drug candidate for Alzheimer’s disease. Full article

WRN helicases play a key role in DNA replication, repair, and other processes in a variety of tumors. It has become one of the hot targets of genotoxic drugs, but the effect and mechanism of targeting WRN against prostate cancer is still unclear. In our previous study, we found a quinazoline compound kzl052, which has a WRN-dependent inhibitory effect on prostate cancer cells, but its molecular mechanism needs to be further explored. In this study, kzl052 significantly inhibited the growth of PC3 (IC₅₀ = 0.39 ± 0.01 μM) and LNCaP (IC₅₀ = 0.11 ± 0.01 μM) cells in vitro and showed a good inhibition effect on PCa in vivo. It inhibits PC3 cell growth by binding to WRN proteins and affecting its non-enzymatic function. Then the mechanism of kzl052 against prostate cancer progression was revealed to be by regulating the stability of DNA replication forks and the RB pathway. This study will provide a theoretical basis and treatment strategy for targeting WRN helicase in the treatment of prostate cancer. Full article

A new class of spiro[1,2,4]triazolo[1,5-c]quinazoline derivatives is presented as promising modulators of diacylglycerol kinase α (DGK-α), a target implicated in cancer, neurological disorders, and immune dysfunction. Through structure-based computational design using the CB-Dock2 platform with human DGK-α (PDB ID: 6IIE), 40 novel compounds were systematically evaluated along with established inhibitors (ritanserin, R59022, R59949, BMS502, and (5Z,2E)-CU-3) across five distinct binding pockets. Several compounds demonstrated binding profiles at the level of or surpassing the reference compounds. The physicochemical analysis revealed balanced drug-like properties with favorable molecular weights (252–412 g/mol) and appropriate three-dimensionality. The toxicological assessment indicated reassuring safety profiles with predicted LD₅₀ values of 1000–2000 mg/kg and minimal hepatotoxicity, carcinogenicity, and mutagenicity potential. Notably, compound 33 (adamantyl-substituted) emerged as exceptionally promising, exhibiting strong binding affinity, moderate solubility, and selective CYP inhibition patterns that minimize drug–drug interaction risks. Detailed molecular interaction mapping identified critical binding determinants, including strategic hydrogen bonding with TRP151, GLU166, and ARG126. The multidimensional evaluation identified compounds 13, 18, 33, and 40 as particularly promising candidates that balance potent target engagement with favorable pharmaceutical profiles, establishing this scaffold as a valuable platform for developing next-generation therapeutics targeting DGK-α -mediated signaling pathways. Full article

Background: Staphylococcus aureus is a highly lethal Gram-positive bacterium that is responsible for over one million deaths annually. As a member of the ESKAPE pathogens, its methicillin-resistant strains (MRSA) are prevalent worldwide and exhibit significant antimicrobial resistance (AMR). Bacterial efflux pumps play a pivotal role in the development of AMR by facilitating the expulsion of a range of antimicrobial agents. Methods: The S. aureus strain SA-1199B, which overexpresses NorA and carries a GrlA mutation, was utilized to comprehensively profile the mechanism of the compounds PQQ16P and PQK4F. To assess the toxicity and genotoxicity of these compounds, RAW macrophages, HEK 293T, and HepG2 cell lines were utilized. Female BALB/c mice were utilized to assess the in vivo synergism of EPIs with CPX, Results: NorA efflux pump inhibitors (EPIs), PQQ16P and PQK4F, enhanced the efficacy of the antibacterial ciprofloxacin (CPX) against resistant S. aureus strains. The mechanism of EPIs involved the inhibition of NorA efflux pump, without compromising bacterial membrane permeability, ATP levels, or mammalian calcium channels. Moreover, the EPIs significantly augmented the bactericidal and post-antibiotic effects of CPX, elevating its mutation prevention concentration without manifesting substantial toxicity to human cells. Furthermore, the EPIs reduced S. aureus invasiveness in macrophages, indicating a role for NorA in bacterial virulence. Notably, the in vivo synergism of these EPIs with CPX was observed in a mouse infection model. Conclusions: This study provides substantial evidence for the potential of employing EPIs in a combination with CPX to counteract AMR, both in vitro and in vivo. Full article

We hereby report a simple and efficient method for the preparation of (E)-3-aryl-2-styryl-2,3-dihydroquinazolin-4-(1H)-ones, from isatoic anhydride, anilines, and cinnamaldehydes in the presence of 20 mol% citric acid in methanol at 60 °C for 2 h. The styryl-dihydroquinazolin-4-(1H)-one products were obtained in moderate and good yields (30–80%) through the three-component condensation reaction, under an environment-friendly protocol. The latter were easily transformed into styrylquinazolin-4-(3H)-one derivatives with 57–91% yields using a mild oxidation with an I₂/DMSO system for less than 60 min. Full article

Background/Objectives: Angiogenesis plays a crucial role in tumor development and is a driving force for the aggressiveness of several types of cancer. Our team developed a novel series of thiosemicarbazone-containing quinazoline derivatives, TSC1-TSC10, as potential VEGFR2 inhibitors with proven anti-angiogenic and antiproliferative potential. Methods: The TSC1-TSC10 series was synthesized and characterized by spectral data. Extensive methodology was applied both in vitro (Alamar Blue assay, Scratch assay, CAM assay, and VEGFR2 kinase assay) and in silico (docking studies, MDs, and MM-PBSA) for the confirmation of the biological potential. Results: TSC10 emerged as the most promising compound, with a favorable cytotoxic potential across the cell panel (Ea.Hy296, HaCaT, and A375) in agreement with the in vitro VEGFR2 kinase assay (IC₅₀ = 119 nM). A comparable motility reduction in the vascular endothelial cells to that of the reference drug sorafenib was provided by TSC10, with a similar anti-angiogenic potential in the more complex in ovo model of the CAM assay. The in silico experiments confirmed the successful accommodation of the active site of the kinase domain similar to sorafenib for the entire TSC1-TSC10 series, providing valuable key insight into the complex stability driving force for the evaluated compounds. Conclusions: The in vitro evaluations of the biological potential correlated with the in silico predictions by computer-aided complex simulations provided a solid confirmation of the initial hypothesis for the TSC1-TSC10 series. Full article

Quinazolinones, essential quinazoline derivatives, exhibit diverse biological activities with applications in pharmaceuticals and insecticides. Some derivatives have already been developed as commercial drugs. Given the rising cancer incidence, there is a critical need for new anticancer agents, and quinazolinones show promising potential in this domain. The present review focuses on novel advances in the synthesis of these important scaffolds and other medicinal aspects involving drug design, the structure–activity relationship, and action mechanisms of quinazoline and quinazolinone derivatives, to help in the development of new quinazoline and quinazolinone derivatives. Full article

Quinazoline, a privileged scaffold in medicinal chemistry, offers promising potential in the synthesis of anti-Alzheimer’s disease (AD) drugs. This heterocyclic compound, characterized by its fused benzene and pyrimidine rings, enables the design of multifunctional agents targeting AD pathology. The drug-like aspects and pharmaceutical features of quinazoline derivatives have the potential to give rise to various therapeutic drugs. AD is a progressive neurodegenerative condition marked by memory decline, cognitive deterioration, and language disorders. Given its complexity and multifaceted nature, there is a pressing need to discover multi-target drugs to effectively address this debilitating disorder. A comprehensive literature review has demonstrated that quinazoline derivatives exhibit a wide range of therapeutic potential for AD. These compounds function as inhibitors of cholinesterases, β-amyloid aggregation, oxidative stress, and tau protein, among other protective effects. Here, we highlight the most significant and recent research on quinazoline-based anti-AD agents, aiming to support the development and discovery of novel treatments for AD. Full article

Background/Objectives: Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), is characterized by colorectal immune infiltration and significant microbiota compositional changes. Gut microbiota homeostasis is necessary to maintain the healthy state of humans. MR2938, a quinazolin-4(3H)-one derivative derived from the marine natural product penipanoid C, alleviated DSS-induced colitis in a dose-dependent manner. Herein, we aimed to investigate the impact of MR2938 on the gut microbiota in dextran sodium sulfate (DSS)-induced colitis in mice and to elucidate the role of the gut microbiota in the therapeutic mechanism of MR2938 for alleviating colitis. Methods: Acute colitis was induced with DSS in mice. Mice were administered with 100 mg/kg or 50 mg/kg of MR2938. Cecal content was also preserved in liquid nitrogen and subsequently analyzed following 16S RNA sequencing. Antibiotic cocktail-induced microbiome depletion was performed to further investigate the relationship between MR2938 and gut microbiota. The inflammatory factor levels were performed by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). Alcian blue staining and immunofluorescence were used to estimate the intestinal barrier. Results: The 16S rRNA sequencing revealed microbiota modulation by MR2938. Compared with the model group, the 100 mg/kg MR2938 group was associated with higher abundances of Entercoccus and a lower abundance of Staphylococcus, while the 50 mg/kg MR2938 group was associated with higher abundances of Lactobacillus and a lower abundance of Staphylococcus. The antibiotic-mediated microbiota depletion experiments demonstrated that the gut microbiota primarily contributed to barrier function protection, with little impact on inflammatory factor levels during the MR2938 treatment. Conclusions: These findings suggest that intestinal flora play a crucial role in MR2938’s therapeutic mechanism for alleviating colitis. Full article

Three halo-substituted phenyl-quinazolinone derivatives were prepared and structurally characterized [1 = 3-(4-chlorophenyl)-6-iodo-2-methylquinazolin-4(3H)-one, 2 = 6-iodo-3-(4-methoxyphenyl)-2-methylquinazolin-4(3H)-one, and 3 = 7-chloro-2-methyl-3-[4-(trifluoromethoxy)phenyl]quinazolin-4(3H)-one)] in order to explore the relationship between structure and melting point in this group of compounds. Depending on the compound, molecules are interconnected by weak π∙∙∙π interactions, have I···Cl or Cl···Cl halogen bonding, or primarily form C–H∙∙∙N, C–H∙∙∙O, and π∙∙∙π interactions (no halogen bonding). The presence of the OCF₃ group leads to interactions between fluorine atoms that are shorter than the sum of the van der Waals radius for fluorine, suggesting that these interactions contribute to the overall lattice energy. The sequence of melting points cannot be fully explained by intermolecular interactions present in the solid state (enthalpy factor). To address this, a concept related to entropy called the functional group rotation influence, which relates to a decrease in fusion entropy caused by the rotational freedom of polyatomic groups, was introduced. Analysis of previously synthesized 3-phenylquinazolinones showed that the compounds with the highest melting point are the quinazoline-substituted and phenyl-nitro-substituted ones. Among halo-phenyl-substituted compounds, the melting point follows the sequence ortho < meta < para. Regarding the halogen atom type, the order of melting points is Cl ≈ Br > F > I for enantiopure and Br > I ≈ Cl > F for racemic compounds. Also, the melting point order correlates to halogen bond energy (I > Br > Cl > F) only when the geometry and energy of these interactions are favorable. Full article

This study explores a sustainable method for synthesizing quinazoline derivatives through visible light-driven photocatalysis using curcumin-sensitized titanium dioxide (TiO₂) nanoparticles. A one-pot, three-component reaction involving aldehydes, urea/thiourea, and dimedone was utilized to efficiently produce quinazoline compounds. The photocatalytic performance of curcumin-sensitized TiO₂ (Cur-TiO₂) was compared to pure TiO₂ (P-TiO₂), with Cur-TiO₂ showing significantly enhanced activity. Under optimized conditions—light intensity of 100 mW/cm², catalyst concentration of 1 mg/mL, and a reaction time of 40 min—a 97% product yield was achieved. The Cur-TiO₂ catalyst demonstrated excellent reusability, maintaining high efficiency over four consecutive cycles with minimal performance loss. This work underscores the potential of natural dye sensitization to extend light absorption of TiO₂ into the visible spectrum, providing an eco-friendly and cost-effective approach to sustainable organic synthesis. Full article

Nakaseomyces glabrata (Candida glabrata), the second most prevalent Candida pathogen globally, has emerged as a major clinical threat due to its ability to develop high-level azole resistance. In this study, two new 5,6-dihydrotetrazolo[1,5-c]quinazoline derivatives (c11 and c12) were synthesized and characterized using IR, LC-MS, ¹H, and ¹³C NMR spectra. Along with 13 previously reported analogues, these compounds underwent in vitro antifungal testing against clinical N. glabrata isolates using a serial dilution method (0.125–64 mg/L). Remarkably, compounds c5 and c1 exhibited potent antifungal activity, with minimum inhibitory concentrations of 0.37 μM and 0.47 μM, respectively—about a 20-fold improvement in μM concentration over standard drugs like amphotericin B, caspofungin, and micafungin. A detailed structure–activity relationship analysis revealed crucial molecular features enhancing antifungal potency. Extensive molecular docking studies across 18 protein targets explored potential binding pockets and affinities of the lead compounds. A robust 3D-QSAR model, incorporating molecular descriptors Mor26m and Mor29e, displayed good predictive ability for antifungal activity. In silico predictions indicated an absence of herbicidal effect, negligible environmental toxicity (to honeybees, avian species, and aquatic organisms), and mild human toxicity concerns for these compounds. This comprehensive approach aims to develop novel and effective antifungal compounds against the clinically relevant pathogen N. glabrata. Full article

A series of new quinazolin-2,4-dione derivatives incorporating amide/eight-membered nitrogen-heterocycles 2a–c, in addition, acylthiourea/amide/dithiolan-4-one and/or phenylthiazolidin-4-one 3a–d and 4a–d. The starting compound 1 was prepared by reaction of 4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-benzoyl chloride with ammonium thiocyanate and cyanoacetic acid hydrazide. The reaction of 1 with strong electrophiles, namely, o-aminophenol, o-amino thiophenol, and/or o-phenylene diamine, resulted in corresponding quinazolin-2,4-dione derivatives incorporating eight-membered nitrogen-heterocycles 2a–d. Compounds 3a–d and 4a–d were synthesized in good-to-excellent yield through a one-pot multi-component reaction (MCR) of 1 with carbon disulfide and/or phenyl isocyanate under mild alkaline conditions, followed by ethyl chloroacetate, ethyl iodide, methyl iodide, and/or concentrated HCl, respectively. The obtained products were physicochemically characterized by melting points, elemental analysis, and spectroscopic techniques, such as FT-IR, ¹H-NMR, ¹³C-NMR, and MS. The antibacterial efficacy of the obtained eleven molecules was examined in vitro against two Gram-positive bacterial strains (Staphylococcus aureus and Staphylococcus haemolyticus). Furthermore, Computer-Aided Drug Design (CADD) was performed on the synthesized derivatives, standard drug (Methotrexate), and reported antibacterial drug with the target enzymes of bacterial strains (S. aureus and S. haemolyticus) to explain their binding mode of actions. Notably, our findings highlight compounds 2b and 2c as showing both the best antibacterial activity and docking scores against the targets. Finally, according to ADMET predictions, compounds 2b and 2c possessed acceptable pharmacokinetics properties and drug-likeness properties. Full article

With the development of computer tools over the past 20 years, molecular modeling, and more precisely molecular docking (molecular docking), has very quickly entered the field of pharmaceutical research. Our work consists of studying the inhibition of the enzyme EGFR (1M17) involved in cancer with deferent inhibitors derived from quinazoline and quinoline by molecular docking. Ligands L_1 and L_2 are the best ligands for inhibiting the activity of 1M17 since they form a stable complex with this enzyme by better binding to the active site. The results obtained show that ligands L1 and L2 have weak interactions with the active site residue EGFR (1M17), which stabilize the complexes formed with these ligands, allow better binding at the level of the active site, and give an RMSD of L_1 [1.9563 Å] and of L_2 [1.2483 Å]. All the newly designed compounds passed the pharmacokinetic analysis (ADME–TOX) (adsorption, distribution, metabolism, excretion, and other physicochemical tests), passed the drug-likeness test, and also adhered to the Lipinski rule of five. Full article

Background/Objectives: In connection with previous work on V-shaped polycyclic thiazolo[5,4-f]quinazolin-9-one and [5,4-f]quinazoline derivatives that can modulate the activity of various kinases, the synthesis of straight thiazole-fused [4,5-g] or [5,4-g]quinazolin-8-ones and quinazoline derivatives hitherto undescribed was envisioned. Methods: An innovative protocol allowed to obtain the target structures. The synthesis of inverted thiazolo[4,5-h] and [5,4-h]quinazolin-8-one derivatives was also explored with the aim of comparing biological results. The compounds obtained were tested against a representative panel of eight mammalian protein kinases of human origin: CDK9/CyclinT, Haspin, Pim-1, GSK-3β, CK-1ε, JAK3, CLK1 and DYRK1A. Results and Conclusions: The results obtained show that the novel linear thiazoloquinazolines are not kinase inhibitors. The cytotoxicity of these newly synthesized compounds was assessed against seven representative tumor cell lines (human cancers: Huh7-D12, Caco-2, HCT-116, MCF-7, MDA-MB-231, MDA-MB-468 and PC-3). The majority of these novel molecules proved capable of inhibiting the growth of the tested cells. The 7-Benzyl-8-oxo-7,8-dihydrothiazolo[5,4-g]quinazolinones 5b and 6b are the most potent, with IC₅₀ values in the micromolar range. None of these compounds showed toxicity against normal cells. A larger program of investigations will be launched to investigate the real potential interest of such compounds in anticancer applications. Full article