86-96-4Relevant articles and documents
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 and Anti-Proliferation Activity Evaluation of Novel 2-Chloroquinazoline as Potential EGFR-TK Inhibitors
Jin, Hao,Rao, Guo-Wu,Xu, Xuan-Bo,Zhang, Wen,Zheng, Quan
, (2021/10/23)
A novel series of 2-chloroquinazoline derivatives had been synthesized and their anti-proliferation activities against the four EGFR high-expressing cells A549, NCI-H1975, AGS and HepG2 cell lines were evaluated. The preliminary SAR study of the scaffold of new compounds showed that the compounds with a chlorine substituent on R3 had a better anti-proliferation activity than those substituted by hydrogen atom or vinyl group. Among them, 2-chloro-N-[2-chloro-4-(3-chloro-4-fluoroanilino)quinazolin-6-yl]acetamide (10b) had the best activity, and the corresponding IC50 were 3.68, 10.06, 1.73 and 2.04 μM, respectively. And compound 10b had better or equivalent activity against four cell lines than Gefitinib. The activity of the compound 10b on the EGFR enzyme was subsequently tested. The Wound Healing of A549, AGS and HepG2 cells by this compound showed that the compound can inhibit the migration of cancer cells. Finally, the action channel of the compound 10b was supported by western blotting experiments. It provides useful information for the design of EGFR-TK inhibitors.
1,2,4-Triazolo[4,3-c]quinazolines: a bioisosterism-guided approach towards the development of novel PCAF inhibitors with potential anticancer activity
El-Shershaby, Mohamed H.,Ghiaty, Adel,Bayoumi, Ashraf H.,Ahmed, Hany E. A.,El-Zoghbi, Mona S.,El-Adl, Khaled,Abulkhair, Hamada S.
, p. 11136 - 11152 (2021/07/06)
Targeting PCAF with small inhibitor molecules has emerged as a potential therapeutic strategy for the treatment of cancer. Recently, L-45 was identified as a potent triazolophthalazine inhibitor of the PCAF bromodomain. Here, we report the bioisosteric modification of the triazolophthalazine ring system of L-45 to its bioisosteric triazoloquinazoline while maintaining other essential structural fragments for effective binding with the binding site of PCAF. Consequently, a set of sixteen triazoloquinazoline derivatives were designed, synthesized, and investigated for their anticancer activity against four human cancer cell lines. Five derivatives demonstrated comparable cytotoxic activity with that of doxorubicin as a reference anticancer drug. Among them, compound23showed the most potent activity with IC50values of 6.12, 4.08, 7.17, and 6.42 μM against HePG2, MCF-7, PC3, and HCT-116, respectively. Also, compound21exhibited comparable cytotoxic effects with that of doxorubicin against the selected cancer cell lines with IC50values in the range of 7.41-9.58 μM. Molecular docking and pharmacokinetic studies were additionally performed to rationalize the binding affinities of the newly designed triazoloquinazolines toward the active site of histone acetyltransferase PCAF and to evaluate the druggability of new compounds. The results of these studies suggested that PCAF binding could be the mechanism of action of these derivatives.
From triazolophthalazines to triazoloquinazolines: A bioisosterism-guided approach toward the identification of novel PCAF inhibitors with potential anticancer activity
El-Shershaby, Mohamed H.,Ghiaty, Adel,Bayoumi, Ashraf H.,Al-Karmalawy, Ahmed A.,Husseiny, Ebtehal M.,El-Zoghbi, Mona S.,Abulkhair, Hamada S.
, (2021/06/21)
Inhibition of PCAF bromodomain has been validated as a promising strategy for the treatment of cancer. In this study, we report the bioisosteric modification of the first reported potent PCAF bromodomain inhibitor, L-45 to its triazoloquinazoline bioisosteres. Accordingly, three new series of triazoloquinazoline derivatives were designed, synthesized, and assessed for their anticancer activity against a panel of four human cancer cells. Three derivatives demonstrated comparable cytotoxic activity with the reference drug doxorubicin. Among them, compound 22 showed the most potent activity with IC50 values of 15.07, 9.86, 5.75, and 10.79 μM against Hep-G2, MCF-7, PC3, and HCT-116 respectively. Also, compound 24 exhibited remarkable cytotoxicity effects against the selected cancer cell lines with IC50 values of 20.49, 12.56, 17.18, and 11.50 μM. Compounds 22 and 25 were the most potent PCAF inhibitors (IC50, 2.88 and 3.19 μM, respectively) compared with bromosporine (IC50, 2.10 μM). Follow up apoptosis induction and cell cycle analysis studies revealed that the bioisostere 22 could induce apoptotic cell death and arrest the cell cycle of PC3 at the G2/M phase. The in silico molecular docking studies were additionally performed to rationalize the PCAF inhibitory effects of new triazoloquinazoline bioisosteres.
