86-96-4Relevant academic research and scientific papers
Synthesis of quinazoline-2,4(1H,3H)-dione from carbon dioxide and 2-aminobenzonitrile using mesoporous smectites incorporating alkali hydroxide
Fujita, Shin-Ichiro,Tanaka, Masahiro,Arai, Masahiko
, p. 1563 - 1569 (2014)
A series of magnesium containing mesoporous smectites has been prepared with and without incorporation of alkali hydroxide (NaOH, KOH or LiOH) and employed for the reaction of CO2 with aminobenzonitrile to produce quinazoline-2,4(1H,3H)-dione. The effects of the quantity and kind of the incorporated alkali atoms on the catalytic properties of the smectites were investigated. Characterization of the smectites has shown that the incorporation of alkali atoms reduces their surface area and total pore volume but enhances the amount and strength of their basic sites. The product yield increases with the amount of alkali atoms incorporated. The incorporation of Li was less effective than that of Na and K for the enhancement of the yield. It has been suggested that weak and/or moderate base sites are responsible for the reaction. The active sites should be alkali hydroxide particles existing between the smectite layers for the alkali incorporated smectites, while for the un-incorporated smectite, the active sites should be the Mg atoms and/or the neighboring O atoms. The Na incorporated smectite was deactivated by repeated catalyst recycling, while such deactivation was not observed with the un-incorporated smectite. The reason for the deactivation was discussed in connection with the structures of the active sites and the actions of the reaction intermediate. This journal is the Partner Organisations 2014.
Synthetic approaches, functionalization and therapeutic potential of quinazoline and quinazolinone skeletons: The advances continue
Khan, Imtiaz,Ibrar, Aliya,Ahmed, Waqas,Saeed, Aamer
, p. 124 - 169 (2015)
The presence of N-heterocycles as an essential structural motif in a variety of biologically active substances has stimulated the development of new strategies and technologies for their synthesis. Among the various N-heterocyclic scaffolds, quinazolines and quinazolinones form a privileged class of compounds with their diverse spectrum of therapeutic potential. The easy generation of complex molecular diversity through broadly applicable, cost-effective, practical and sustainable synthetic methods in a straightforward fashion along with the importance of these motifs in medicinal chemistry, received significant attention from researchers engaged in drug design and heterocyclic methodology development. In this perspective, the current review article is an effort to recapitulate recent developments in the eco-friendly and green procedures for the construction of highly challenging and potentially bioactive quinazoline and quinazolinone compounds in order to help medicinal chemists in designing and synthesizing novel and potent compounds for the treatment of different disorders. The key mechanistic insights for the synthesis of these heterocycles along with potential applications and manipulations of the products have also been conferred. This article also aims to highlight the promising future directions for the easy access to these frameworks in addition to the identification of more potent and specific products for numerous biological targets.
ZIF-8-Nanocrystalline Zirconosilicate Integrated Porous Material for the Activation and Utilization of CO2 in Insertion Reactions
Srivastava, Diksha,Rani, Poonam,Srivastava, Rajendra
, p. 1132 - 1139 (2020)
The conversion of CO2 to useful chemicals, especially to atom economical products, is the best approach to utilize an excess of CO2 present in the atmosphere. In this study, a metal-organic framework (ZIF-8) is integrated with nanocrystalline zirconosilicate zeolite to develop an integrated porous catalyst for CO2 insertion reactions. The catalyst exhibits excellent activity for the CO2 insertion reaction of epoxide to produce cyclic carbonate in neat condition without the addition of any co-catalyst. The catalyst is stable and recyclable during the cyclic carbonate synthesis. Further, the catalyst also exhibits very good activity in another CO2 insertion reaction to produce quinazoline-2,4(1H, 3H)-dione.
Delineating the Mechanism of Ionic Liquids in the Synthesis of Quinazoline-2,4(1H,3H)-dione from 2-Aminobenzonitrile and CO2
Hulla, Martin,Chamam, Sami M. A.,Laurenczy, Gabor,Das, Shoubhik,Dyson, Paul J.
, p. 10559 - 10563 (2017)
Ionic liquids (ILs) are versatile solvents and catalysts for the synthesis of quinazoline-2,4-dione from 2-aminobenzonitrile and CO2. However, the role of the IL in this reaction is poorly understood. Consequently, we investigated this reaction and showed that the IL cation does not play a significant role in the activation of the substrates, and instead plays a secondary role in controlling the physical properties of the IL. A linear relationship between the pKa of the IL anion (conjugate acid) and the reaction rate was identified with maximum catalyst efficiency observed at a pKa of >14.7 in DMSO. The base-catalyzed reaction is limited by the acidity of the quinazoline-2,4-dione product, which is deprotonated by more basic catalysts, leading to the formation of the quinazolide anion (conjugate acid pKa 14.7). Neutralization of the original catalyst and formation of the quinazolide anion catalyst leads to the observed reaction limit.
Design, synthesis, in silico ADMET, docking, and antiproliferative evaluations of [1,2,4]triazolo[4,3-c]quinazolines as classical DNA intercalators
Alesawy, Mohamed S.,Eissa, Ibrahim H.,El-Adl, Khaled,Ibrahim, Mohamed-Kamal
, (2022/01/13)
Eleven novel [1,2,4]triazolo[4,3-c]quinazolines were designed, synthesized, and evaluated against HepG2 and HCT-116 cells. The molecular design was performed to investigate the binding mode of the proposed compounds with the DNA active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling. HCT-116 was found to be the most sensitive cell line to the influence of the new derivatives. In particular, compounds 6f and 6e were found to be the most potent derivatives over all the tested compounds against the two HepG2 and HCT116 cancer cell lines, with IC50 = 23.44 ± 2.9, 12.63 ± 1.2, and 25.80 ± 2.1, and 14.32 ± 1.5 μM, respectively. Although compounds 6f and 6e displayed less activity than doxorubicin (IC50 = 7.94 ± 0.6 and 8.07 ± 0.8 μM, respectively), both could be useful as a template for future design, optimization, and investigation to produce more potent anticancer analogs. The most active derivatives 6a, 6c, 6e, and 6f were evaluated for their DNA-binding activities. Compound 6f displayed the highest binding affinity. This compound potently intercalates DNA at a decreased IC50 value (54.08 μM). Compounds 6a, 6c, and 6e exhibited good DNA-binding affinities, with IC50 values of 79.35, 84.08, and 59.35 μM, respectively. Furthermore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles were calculated for the four most active compounds in comparison to doxorubicin as a reference drug. Our derivatives 6a, 6c, 6e, and 6f displayed very good in-silico-predicted ADMET profiles. Doxorubicin violates three of Lipinski's rules, our derivatives 6a, 6c, 6e, and 6f do not violate any rule.
Synthesis, biological evaluation, and molecular docking of new series of antitumor and apoptosis inducers designed as VEGFR-2 inhibitors
Abdallah, Abdallah E.,Abo-Saif, Mariam A.,Al Ward, Maged Mohammed Saleh,Alesawy, Mohamed S.,Eissa, Sally I.,El-Feky, Ola A.,El-Zahabi, Mohamed Ayman,Elkaeed, Eslam B.,Mabrouk, Reda R.,Mehany, Ahmed B. M.
, p. 573 - 591 (2022/01/20)
Based on quinazoline, quinoxaline, and nitrobenzene scaffolds and on pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesised. VEGFR-2 IC50 values ranged from 60.00 to 123.85 nM for the new derivatives compared to 54.00 nM for sorafenib. Compounds 15a, 15b, and 15d showed IC50 from 17.39 to 47.10 μM against human cancer cell lines; hepatocellular carcinoma (HepG2), prostate cancer (PC3), and breast cancer (MCF-7). Meanwhile, the first in terms of VEGFR-2 inhibition was compound 15d which came second with regard to antitumor assay with IC50 = 24.10, 40.90, and 33.40 μM against aforementioned cell lines, respectively. Furthermore, Compound 15d increased apoptosis rate of HepG2 from 1.20 to 12.46% as it significantly increased levels of Caspase-3, BAX, and P53 from 49.6274, 40.62, and 42.84 to 561.427, 395.04, and 415.027 pg/mL, respectively. Moreover, 15d showed IC50 of 253 and 381 nM against HER2 and FGFR, respectively.
[TBDH][HFIP] ionic liquid catalyzed synthesis of quinazoline-2,4(1H,3H)-diones in the presence of ambient temperature and pressure
Phatake, Vishal V.,Gokhale, Tejas A.,Bhanage, Bhalchandra M.
, (2021/07/28)
The utilization of carbon dioxide under mild reaction conditions is an important aspect of the sustainable chemistry point of view. Herein, we prepared three bifunctional protic ionic liquids having 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) as a cation and an alcohol anions were prepared by simple neutralization of the super base TBD with proton donor alcohols such as hexafluoroisopropanol (HFIP), TFE (2,2,2-Trifluoroethanol) and TFA (2,2,2-Trifluoroacetic acid). These PILs were used as catalysts for chemical fixation of carbon dioxide into quinazoline-2,4(1H,3H)-diones. [TBDH+][HFIP-] protic ionic liquid (PIL) shows very good result compare to other PILs. As a bifunctional ionic liquid, it simultaneously activates 2-aminobenzonitrile as well as CO2 and shows excellent performance for the conversion of 2-aminobenzonitrile to quinazoline-2,4(1H,3H)-diones in presence of CO2 balloon pressure at 35 °C temperature. Moreover, the [TBDH+][HFIP-] PIL can be recycled up to six recycle run.
Synthesis of acyclic nucleoside phosphonates targeting flavin-dependent thymidylate synthase in Mycobacterium tuberculosis
Agrofoglio, Luigi A.,Becker, Hubert F.,Biteau, Nicolas G.,Lambry, Jean-Christophe,Myllykallio, Hannu,Roy, Vincent
, (2021/08/16)
Flavin-Dependent Thymidylate Synthase (FDTS) encoded by ThyX gene was discovered as a new class of thymidylate synthase involved in the de novo synthesis of dTMP named only in 30 % of human pathogenic bacteria. This target was pursed for the development of new antibacterial agents against multiresistant pathogens. We have developed a new class of ANPs based on the mimic of two natural's cofactors (dUMP and FAD) as inhibitors against Mycobacterium tuberculosis ThyX. Several synthetic efforts were performed to optimize regioselective N1-alkylation, cross-coupling metathesis and Sonogashira cross-coupling. Compound 19c showed a poor 31.8% inhibitory effect on ThyX at 200 μM.
Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors
Barbosa Da Silva, Elany,Rocha, Débora A.,Fortes, Isadora S.,Yang, Wenqian,Monti, Ludovica,Siqueira-Neto, Jair L.,Caffrey, Conor R.,McKerrow, James,Andrade, Saulo F.,Ferreira, Rafaela S.
, p. 13054 - 13071 (2021/09/13)
The cysteine proteases, cruzain and TbrCATL (rhodesain), are therapeutic targets for Chagas disease and Human African Trypanosomiasis, respectively. Among the known inhibitors for these proteases, we have described N4-benzyl-N2-phenylquinazoline-2,4-diamine (compound 7 in the original publication, 1a in this study), as a competitive cruzain inhibitor (Ki = 1.4 μM). Here, we describe the synthesis and biological evaluation of 22 analogs of 1a, containing modifications in the quinazoline core, and in the substituents in positions 2 and 4 of this ring. The analogs demonstrate low micromolar inhibition of the target proteases and cidal activity against Trypanosoma cruzi with up to two log selectivity indices in counterscreens with myoblasts. Fourteen compounds were active against Trypanosoma brucei at low to mid micromolar concentrations. During the optimization of 1a, structure-based design and prediction of physicochemical properties were employed to maintain potency against the enzymes while removing colloidal aggregator characteristics observed for some molecules in this series.
Synthesis and enzymological characterization of some 2-(Substituted-phenylamino)quinazolin-4(3h)-one derivatives as potent α-glucosidase inhibitors in vitro
Ayan, Emre Kadir,Soyer, Zeynep,Uysal, ?irin
, p. 723 - 732 (2021/10/02)
Background: α-Glucosidase is an important hydrolytic enzyme playing a vital role in digestion of carbohydrates. It catalyzes the final step of carbohydrates digestion in biological systems and converts unabsorbed oligosaccharides and disaccharides into monosaccharides, thus resulting in hyperglycemia for diabetic patients. In this respect, it has been considered as a therapeutic target for the treatment of type 2 diabetes since the enzyme inhibition delays carbohydrate digestion and monosaccharide absorption and subsequently reduces postprandial plasma glucose levels. Objective: In this study, fourteen 2-(substitutedphenylamino)quinazolin-4(3H)-one derivatives were synthesized and evaluated for their α-glucosidase inhibitory activities. Methods: The structures of the synthesized compounds were confirmed by spectral and elemental analyses. The biological activity and enzyme inhibition kinetic studies were performed by spectro-photometrical method using microplate reader. Physicochemical and drug-likeness properties of selected compounds were predicted by in silico method. Results: The biological activity results revealed that all of the synthesized compounds showed more potent α-glucosidase inhibitory activity in the range of IC50 = 58 ± 2-375 ± 15 μM when compared to the standard drug acarbose (IC50 = 892 ± 7 μM). Among the tested compounds, compound 12 bearing chlorine substituent at ortho position on N-phenyl ring displayed the highest inhibition with an IC50 value of 58 ± 2 μM against α-glucosidase. Furthermore, the enzyme inhibition kinetic study of the most active compound 12 indicated that the compound inhibited the α-glucosidase enzyme as uncompetitive with a Ki value of 63.46 μM. On the other hand, physicochemical and drug-likeness properties of selected compounds were predicted by in silico method. According to the results, it can be speculated that synthesized 2-phenylaminoquinazolin-4(3H)-one derivatives possessed favorable drug-likeness and pharmacokinetic profiles. Conclusion: In the light of results, 2-(substitutedphenylamino)quinazolin-4(3H)-one derivatives may serve as lead compounds to develop novel α-glucosidase inhibitors.
