Search

[Display omitted] • Quinazolinone derivatives were designed keeping Ispinesib and Idelalisib as reference structures. • Compounds 3a, 3b, 3e, 3g and 3h revealed nanomolar potency against KSP and PI3Kδ. • Compounds were found to be active against MDA-MB-231 breast cancer cells. • Anticancer activity was found to be associated with their P53 -dependent apoptotic activity. Triple-negative breast cancer (TNBC) comprises 10 % to 20 % of breast cancer, however, it is more dangerous than other types of breast cancer, because it lacks druggable targets, such as the estrogen receptors (ER) and the progesterone receptor (PR), and has under expressed receptor tyrosine kinase, ErbB2. Present targeted therapies are not very effective and other choices include invasive procedures like surgery or less invasive ones like radiotherapy and chemotherapy. This study investigated the potential anticancer activity of some novel quinazolinone derivatives that were designed on the structural framework of two approved anticancer drugs, Ispinesib (KSP inhibitor) and Idelalisib (PI3Kδ inhibitor), to find out solutions for TNBC. All the designed derivatives (3a-l) were subjected to extra precision molecular docking and were synthesized and spectrally characterized. In vitro enzyme inhibition assay of compounds (3a, 3b, 3e, 3 g and 3 h) revealed their nanomolar inhibitory potential against the anticancer targets, KSP and PI3Kδ. Using MTT assay, the cytotoxic potential of compounds 3a, 3b and 3e were found highest against MDA-MB-231 cells with an IC 50 of 14.51 µM, 16.27 µM, and 9.97 µM, respectively. Remarkably, these compounds were recorded safe against the oral epithelial normal cells with an IC 50 values of 293.60 µM, 261.43 µM, and 222 µM, respectively. The anticancer potential of these compounds against MDA-MB-231 cells was revealed to be associated with their apoptotic activity. This was established by examination with the inverted microscope that revealed the appearance of various apoptotic features like cell shrinkage, apoptotic bodies, and membrane blebbing. Using flow cytometry, the Annexin V/PI-stained cancer cells showed an increase in early and late apoptotic cells. In addition, DNA fragmentation was revealed to occur after treatment with the tested compounds by gel electrophoresis. The relative gene expression of pro-apoptotic and anti-apoptotic genes revealed an overexpression of the P53 and BAX genes and a downregulation of the BCL-2 gene by real-time PCR. So, this work proved that compounds 3a, 3b, and 3e could be developed as anticancer candidates, via their P53-dependent apoptotic activity. [ABSTRACT FROM AUTHOR]

A series of new quinazolinone derivatives (5a-l) were designed as 3CL protease inhibitors for SARS-CoV-2 infection. The designed derivatives were efficiently synthesized by S -alkylation/arylation of an intermediate, 6-fluoro-3-(4-fluorophenyl)-2-mercaptoquinazolin-4(3 H)-one and their successful synthesis was established by analytical methods, viz. IR, 1H NMR, &13C NMR spectroscopy. The in silico inhibitory potential against 3CLpro of SARS-CoV-2 were studied by means of docking and dynamics simulations, and compared with the co-crystallized ligand (VR4) of SARS-CoV-2 3CLpro. The compounds interacted strongly within the active catalytic dyad (Cys-His) site, thereby anticipated to obstruct the function of 3CLpro of SARS-CoV-2. Compounds 5b , 5c , 5i , 5j and 5l showed efficient binding with protease 3CLpro with XP Gscore of −7.4, −8.3, −7.8, −7.5 and −8.2 respectively. Furthermore, molecular dynamic simulation study of these compounds (5b , 5c , 5i , 5j and 5 l) showed stable interaction over 50 ns production run. Swiss ADME and pkCSM web tools showed favorable physicochemical and pharmacokinetic properties and fulfilled the criteria for drug-likeness of these selected studied compounds. The toxicity determination of these selected compounds predicted that some compounds were hepatotoxic, but were not AMES toxic. Compounds 5b , 5c , 5i , 5j and 5 l revealed their inhibitory potential against the SARS-CoV-2 3CLpro, and their IC 50 values were attained at 1.58, 1.25, 1.97, 0.44 and 2.56 µM, respectively. In addition, these compounds were found to have devoid of any significant cytotoxicity even at a higher concentration of 20 µM against VeroE6 cells. These quinazolinone derivatives showed potent binding and inhibitory potential against SARS-CoV-2 3CLpro and may emerge as compounds that might act as prospective inhibitors. [ABSTRACT FROM AUTHOR]

A series of novel substituted quinazolinone derivatives was synthesized and characterized by 1 H NMR and LC–MS spectral techniques. The overall results of the antibacterial tests showed that these compounds had better bacteriostatic activity against Gram-positive bacteria than their parent compounds. Furthermore, compounds 5f , 6b and 6f showed potent activity against Enterococcus faecalis (ATCC 51299), with MIC values <0.2 μg/mL. Compounds 4e , 5g , 5e and 6c showed excellent activity, with MIC values <0.4 μg/mL. Gram-negative bacteria Escherichia coli (ATCC 35218) and Klebsiella (ATCC 700603) are more resistant to lower concentrations of the synthesized compounds. The anti-inflammatory activities of the synthesized compounds were evaluated using the Carrageenan-induced rat Paw oedema method and ibuprofen as a standard drug. Compounds 4a and 4b exhibited good activity. Additionally, docking stimulations were performed to position compounds 4e, 4g , 5e , 5f , 6a and 6f into the EGFR kinase domain and human oestrogen receptor active site to determine probable binding information. This study indicated that compounds 6a and 6f have significant binding activities of 58.36 and 57.67 kJ mol −1 , respectively. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Taibah University Medical Sciences is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A series of new quinazolinone derivatives have been synthesized. Elemental analysis, IR, 1 H NMR and mass spectral data elucidated the structures of all newly synthesized compounds. In vitro antimicrobial activities of the synthesized compounds were investigated against Gram-positive Bacillus subtilis (ATCC No. 6633), Staphylococcus aureus (ATCC No. 25923), Gram-negative Salmonella typhimurium (ATCC No. 23564), Pseudomonas aeruginosa (ATCC No. 27853) and fungi Candida albicans and Aspergillus niger . Among all the tested compounds, some of the tested compounds showed equipotent activity with standard. [ABSTRACT FROM AUTHOR]

A series of some new quinazolinone based MCT reactive dyes ( 7a–j ) were successfully and easily synthesized by the coupling route of diazotized 3-{4-[4-amino-2, 6-difluorobenzyl]-3,5-difluorophenyl}-6-nitro-2-phenylquinazolin-4(3 H )-one ( 4 ) with a diverse range of o -chloro- p -nitro anilino cyanurated coupling components ( 6a–j ). The structures of all dyes were confirmed by UV–Vis, IR, 1 H and 13 C NMR spectroscopies. All the newly synthesized dyes were tested for their in vitro antimicrobial screening (antibacterial and antifungal) against several bacteria and fungi. Some of the compounds showed significant antibacterial as well as antifungal activities. Furthermore colorimetric study (L ∗ , a ∗ , b ∗ , C ∗ , H ∗ , K/S), Fastness properties and thermogravimetric analysis (TGA) data were also discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] Plant bacteria and viruses have a huge negative impact on food crops in the world. Therefore, it is important to create new and efficient green pesticides. In this paper, a series of myricetin derivatives containing quinazolinone sulfide were introduced. Good antibacterial and antiviral activities of the drug molecules 2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4 H -chromen-3-yl)oxy)propyl)thio)-6-fluoro-3-phenylquinazolin-4(3 H)-one (T5) and 2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4 H -chromen-3-yl)oxy)butyl)thio)-6-methyl-3-phenylquinazolin-4(3 H)-one (T15) respectively were found by biological activity screening. The value of dissociation constant (K d) of compound T15 to TMV CP was 0.024 ± 0.006 μM, determined by Microscale thermophoresis (MST), which was far less than the value of 8.491 ± 2.027 μM of commercial drug ningnanmycin (NNM). The interaction between compound T15 and TMV CP was further verified by molecular docking. Compound T15 formed strong hydrogen bonds with residues SER:49 and SER:15 (1.92 Å, 2.20 Å, respectively), which were superior to the traditional hydrogen bonds formed by NNM with residue SER:215 (3.64 Å). In addition, the effects of compound T15 on the contents of chlorophyll and peroxidase (POD) in tobacco were studied, and the results indicated that compound T15 could enhance the disease resistance of tobacco plants to a certain extent. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The aim of the present work was to synthesize some novel fluorinated quinazolinones and to evaluate them for anticonvulsant activity and neurotoxicity. Methods: Eight compounds were synthesized. Their anticonvulsant activity was evaluated from maximal electroshock-induced seizures in eight groups of six Swiss mice given the test compounds (100mg/kg intraperitoneally), one control group given 10% DMSO (10ml/kg) and one given the reference compound phenytoin (100mg/kg). Neurotoxicity was evaluated by the rotarod test in eight groups of four Swiss mice given the test compounds (100mg/kg), one given saline (10ml/kg) and one given phenytoin (100mg/kg). The structure–activity relations of the compounds and ClogP correlations were determined to explain the results. Results: Four compounds showed significant anticonvulsant activity with low neurotoxicity when compared with the reference drug. Conclusion: The newly designed compounds could be useful templates for the design and optimization of more active analogues as anticonvulsant agents with low neurotoxicity. [Copyright &y& Elsevier]

Abstract: Some novel 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones bearing sulfonamide derivatives (4–11) were synthesized in good yields and evaluated for their possible antibacterial, anti-inflammatory activities and acute toxicity. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Their antibacterial activities were evaluated by the agar well diffusion method while their anti-inflammatory activities were evaluated by the carrageenan-induced hind paw edema test. All the tested compounds showed considerable antibacterial activities and high to moderate anti-inflammatory activities that last for 12h compared to ibuprofen. All the tested compounds showed no toxic symptoms or mortality rates 24h post-administration at tested anti-inflammatory doses. In addition, LD50 for all tested compounds was higher than that for ibuprofen implying their good safety margin. The obtained results showed that the most active compounds could be useful as a template for future design, modification and investigation to produce more active analogs. [Copyright &y& Elsevier]

Abstract: A series of 2-oxo-azetidinyl-quinazolin-4(3H)-ones 5a–k have been synthesized from Schiff bases 4a–k. Schiff bases were synthesized by the condensation reaction of compound 3 with substituted aromatic aldehydes. The benzoxazinone 2 was prepared by the cyclization reaction of acid chloride 1 with 5-bromo anthranilic acid. Further reaction of benzoxazinone 2 with hydrazine hydrate yielded compound 3. The structures of the synthesized compounds were elucidated on the basis of elemental analyses as well as IR and NMR spectral data. Schiff bases 4a–k and 2-azetidinones 5a–k were screened for antibacterial and antifungal activities in vitro. Compounds having chloro and methoxy groups exhibited good antimicrobial activity. [Copyright &y& Elsevier]

The in vitro biological assessment of novel hybrid phospha-oxazepino derivatives bearing ibuprofenyl quinazolinone moiety as preventing stroke symptoms and inhibitors of nitric oxide synthase (iNOS and nNOS) isoforms was described. In general, products tested exhibited iNOS inhibition than nNOS. The phosphaoxazepinoquinazolinyl derivatives (4, 7, 10–12) are among the most effective inhibitors of all compounds tested, being also endowed with iNOS over nNOS selectivity. The structures of these new heterocycles were elucidated using spectral data and elemental analysis. [ABSTRACT FROM AUTHOR]

Synthesis of new Schiff base derivatives bearing a 6-nitro-2-ibuprofenyl-4(3 H)-quinazolin-4-one skeleton, as well as their in vitro biological evaluation as inhibitors of nitric oxide synthase (iNOS and nNOS) isoforms, is defined. Structures of these novel heterocycles were confirmed based on their spectral, (IR, 1H NMR, 13C NMR and MS) and elemental analyses. In general, the assayed compounds behave as better iNOS than nNOS inhibitors. Quinazolinyl Schiff bases 9 a-e are the most active inhibitors of all tested compounds and the most iNOS/nNOS selective of all studied compounds, with expected potential as anti-stroke agents. [ABSTRACT FROM AUTHOR]

Two series of Benzothiazole, Quinazolinone derivatives bearing guanidinopropanoic acid (38 compounds including 27 intermediates) and one series of Schiff base derivatives (14 compounds) were synthesized, characterized then evaluated for their cytotoxicity against human cervix cell line (HeLa) by MTT assay; antimicrobial activity against 11 pathogenic bacteria, 10 pathogenic fungus using standard of ciprofloxacin and Clotrimazole respectively. Compounds 13 – 18 showed significant activity against HeLa with IC 50 range of 2–550 μM. Compound 3-(3-(6-hydroxybenzo[ d ]thiazol-2-yl)guanidino)propanoic acid ( 18 ) showed potent activity against human HeLa cell line with the half maximal inhibitory concentration (IC 50 ) values of 1.8 μM which was close to the value of the positive control, doxorubicin. Antimicrobial result indicated that, compounds showed differential activity against the tested fungus and bacteria. Compounds 11 , 14 , 38 and 49 exhibited potent antibacterial and antifungal activity. [ABSTRACT FROM AUTHOR]

A simple and efficient methodology was developed for the synthesis of new 4-(3,5-dimethyl-1-phenyl-1 H -pyrazol-4-ylazo)- N -(2-substituted-4-oxo-4 H -quinazolin-3-yl)benzenesulfonamide derivatives 10a – 10j in good amount of yields. They have been prepared using 2-acetamidobenzoic acid derivatives 2a – 2j via intermediates benzenesulfonamide substituted quinazolinone derivatives 8a – 8j , and its corresponding hydrazono derivatives 9a – 9j . Entitled compounds ( 10a – 10j ) were also obtained using microwave heating in good amount of yields. The structures of all the new compounds have been evaluated on the basis of elemental analysis, FT-IR, 1 H and 13 C NMR spectral studies. Entitle compounds have been screened for their in vitro antimicrobial activities and all these compounds displayed excellent to moderate activities, which were found to be significantly potent against bacteria compared to fungal. [ABSTRACT FROM AUTHOR]