- Quinazolin-4(3H)-one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicity
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A series of quinazolin-4(3H)-one derivatives were synthesised and evaluated for their cytotoxicity against human Caucasian breast adenocarcinoma (MCF-7) and human ovarian carcinoma (A2780) cell lines. Cytotoxicity of the most tested compounds was 2- to 30-fold more than the positive control lapatinib (IC50 of 2j = 3.79 ± 0.96; 3j = 0.20 ± 0.02; and lapatinib = 5.9 ± 0.74) against MCF7 cell lines except two compounds (IC50 of 2 b = 15.72 ± 0.07 and 2e = 14.88 ± 0.99). On the other hand, cytotoxicity was 4 ? 87 folds (IC50 of 3a = 3.00 ± 1.20; 3 g = 0.14 ± 0.03) more the positive control lapatinib (IC50 = 12.11 ± 1.03) against A2780 cell lines except compound 2e (IC50 = 16.43 ± 1.80). Among the synthesised quinazolin-4(3H)-one derivatives, potent cytotoxic 2f-j and 3f-j were investigated for molecular mechanism of action. Inhibitory activities of the compounds were tested against multiple tyrosine protein kinases (CDK2, HER2, EGFR and VEGFR2) enzymes. As expected, all the quinazolin-4(3H)-one derivatives were showed comparable inhibitory activity against those kinases tested, especially, compound 2i and 3i showed potent inhibitory activity against CDK2, HER2, EGFR tyrosine kinases. Therefore, molecular docking analysis for quinazolin-4(3H)-one derivatives 2i and 3i were performed, and it was revealed that compounds 2i and 3i act as ATP non-competitive type-II inhibitor against CDK2 kinase enzymes and ATP competitive type-I inhibitor against EGFR kinase enzymes. However, in case of HER2, compounds 2i act as ATP non-competitive type-II inhibitor and 3i act as ATP competitive type-I inhibitor. Docking results of known inhibitors were compared with synthesised compounds and found synthesised 2i and 3i are superior than the known inhibitors in case of interactions. In addition, in silico drug likeness properties of quinazolin-4(3H)-one derivatives showed better predicted ADME values than lapatinib.
- Mirgany, Tebyan O.,Abdalla, Ashraf N.,Arifuzzaman, Md,Motiur Rahman,Al-Salem, Huda S.
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p. 2055 - 2067
(2021/09/28)
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- Design, synthesis and molecular modeling of new quinazolin-4(3H)-one based VEGFR-2 kinase inhibitors for potential anticancer evaluation
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Globally cancer is the second leading cause of death. So that this work is an attempt to develop new effective anti-cancer agents. In line with pharmacophoric features of VEGFR-2 kinase inhibitors, new nineteen quinazolin-4-one derivatives were designed,
- Abdallah, Abdallah E.,Eissa, Sally I.,Al Ward, Maged Mohammed Saleh,Mabrouk, Reda R.,Mehany, Ahmed B.M.,El-Zahabi, Mohamed Ayman
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- Design, Synthesis, Anticancer Activity, and Cell Cycle Analysis of Novel Quinazoline Derivatives Targeting VEGFR-2 Kinase
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Abstract: Novel quinazoline derivatives have been designed, synthesized and tested for cytotoxic activity against HCT116, and MCF-7 cell lines. The preliminary data indicate their promising antitumor potential. Enzyme inhibitory activity of the most active product against VEGFR-2 has been assessed. Apoptosis and cell cycle arrest during the G2/M phase has been triggered by the product, and according to the gene expression data, it increases BAX and caspase-3 expression while decreasing Bcl-2 expression.
- Ahmed, Marwa F.,Eed, Emad M.,Khalifa, Amany S.
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p. 2497 - 2505
(2022/01/22)
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- Divergent 2-Chloroquinazolin-4(3H)-one Rearrangement: Twisted-Cyclic Guanidine Formation or Ring-Fused N-Acylguanidines via a Domino Process
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A highly efficient 2-chloroquinazolin-4(3H)-one rearrangement was developed that predictably generates either twisted-cyclic or ring-fused guanidines in a single operation, depending on the presence of a primary versus secondary amine in the accompanying diamine reagent. Exclusive formation of twisted-cyclic guanidines results from pairing 2-chloroquinazolinones with secondary diamines. Use of primary amine-containing diamines permits a domino quinazolinone rearrangement/intramolecular cyclization, gated through (E)-twisted-cyclic guanidines, to afford ring-fused N-acylguanidines. This scalable, structurally tolerant transformation generated 55 guanidines and delivered twisted-cyclic guanidines with robust plasma stability and an abbreviated total synthesis of an antitumor ring-fused guanidine (4 steps, 55 % yield).
- Yan, Gang,Zekarias, Bereket L.,Li, Xiaoyu,Jaffett, Victor A.,Guzei, Ilia A.,Golden, Jennifer E.
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supporting information
p. 2486 - 2492
(2020/02/13)
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- Discovery of Potent and Novel Quinazolinone Sulfide Inhibitors with Anti-ToCV Activity
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A series of novel quinazolinone sulfide derivatives containing a dithioacetal moiety were designed and synthesized using Tomato chlorosis virus coat protein (ToCVCP) as a potential drug target, and the inhibitory effect of ToCV was systematically evaluate
- Hu, Deyu,Huang, Maoxi,Luo, Liangzhi,Ran, Leilei,Yang, Huanyu
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p. 5302 - 5308
(2020/06/04)
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- Synthesis of benzensulfonamides linked to quinazoline scaffolds as novel carbonic anhydrase inhibitors
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Carbonic anhydrase (CA) inhibitory activities of newly synthesized quinazoline-linked benzensulfonamides 10–29, 31, 32, 35, 36, and 45–51 against human CA (hCA) isoforms I, II, IX, and XII were measured and compared to that of acetazolamide (AAZ) as a standard inhibitor. Potent selective inhibitory activity against hCA I was exerted by compounds 14, 15, 17, 19, 20, 21, 24, 25, 28, 29, 31, 35, 45, 47, 49, and 51 with inhibition constant (KIs) values of 39.4–354.7 nM that were nearly equivalent or even greater than that of AAZ (KI, 250.0 nM). Compounds 15, 20, 24, 28, 29, 45 and 47 proved to have inhibitory activities against hCA II with (KIs, 0.73–16.5 nM) that were similar or improved to that of AAZ (KI, 12.0 nM). Compounds 13–29, 31–32, and 45–51 displayed potent hCA IX inhibitory activities (KIs, 1.6–32.2 nM) that were more effective than or nearly equal to AAZ (KI, 25.0 nM). Compounds 14, 15, 20, 21, 26, 45, and 47 exerted potent hCA XII inhibitory activities (KIs, 5.2–9.2 nM), indicating similar CAI activities as compared to that of AAZ (KI, 5.7 nM).
- El-Azab, Adel S.,Abdel-Aziz, Alaa A.-M.,Bua, Sivia,Nocentini, Alessio,El-Gendy, Manal A.,Mohamed, Menshawy A.,Shawer, Taghreed Z.,AlSaif, Nawaf A.,Supuran, Claudiu T.
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- Synthesis, biological evaluation and molecular modeling study of some new methoxylated 2-benzylthio-quinazoline-4(3H)-ones as nonclassical antifolates
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A new series of 2,3,6-substituted-quinazolin-4-ones was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 28 and 61 proved to be active DHFR inhibitors with IC500.02 and
- El-Messery, Shahenda M.,Hassan, Ghada S.,Nagi, Mahmoud N.,Habib, El-Sayed E.,Al-Rashood, Sarah T.,El-Subbagh, Hussein I.
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p. 4815 - 4823
(2016/09/13)
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- Synthesis, anticonvulsant activity and molecular modeling study of some new hydrazinecarbothioamide, benzenesulfonohydrazide, and phenacylacetohydrazide analogues of 4(3H)-quinazolinone
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A new series of quinazoline analogues was designed and synthesized to get the target compounds 18-21, 30-41, 46-53, and 57-76. The Obtained compounds were evaluated for their anticonvulsant activity using PTZ and picrotoxin convulsive models. Compounds 47, 63, 68 and 73 proved to be the most active compounds in this study with a remarkable 100% protection against PTZ induced convulsions. Compounds 47, 63, 68 and 73 proved to be 10, 4, 4, and 5 fold more active, respectively than the used positive control sodium valproate. Structure activity correlation concluded valuable pharmacophoric information which confirmed by molecular modeling studies. Molecular docking study of 68 suggested its agonistic behavior toward GABAA receptor. The studied quinazoline analogues could be considered as useful templates for future development and further derivatization.
- Al-Salem, Huda S.A.,Hegazy, Gehan H.,El-Taher, Kamal E.H.,El-Messery, Shahenda M.,Al-Obaid, Abdulrahman M.,El-Subbagh, Hussein I.
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supporting information
p. 1490 - 1499
(2015/03/30)
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- Synthesis, biological evaluation and molecular modeling study of 2-(1,3,4-thiadiazolyl-thio and 4-methyl-thiazolyl-thio)-quinazolin-4-ones as a new class of DHFR inhibitors
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A new series of 2-(1,3,4-thiadiazolyl- or 4-methyl-thiazolyl)thio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 29, 34, and 39 proved to be the most active DHFR inhibitors with IC50values range of 0.1-0.6 μM. Compounds 28, 31 and 33 showed remarkable broad-spectrum antimicrobial activity comparable to the known antibiotic Gentamicin. Compounds 26, 33, 39, 43, 44, 50, 55 and 63 showed broad spectrum antitumor activity with GI values range of 10.1-100%. Molecular modeling study concluded that recognition with key amino acid Glu30, Phe31 and Phe34 is essential for binding. ADMET properties prediction of the active compounds suggested that compounds 29 and 34 could be orally absorbed with diminished toxicity.
- Al-Rashood, Sarah T.,Hassan, Ghada S.,El-Messery, Shahenda M.,Nagi, Mahmoud N.,Habib, El-Sayed E.,Al-Omary, Fatmah A.M.,El-Subbagh, Hussein I.
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p. 4557 - 4567
(2015/02/19)
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- Nonclassical antifolates, part 3: Synthesis, biological evaluation and molecular modeling study of some new 2-heteroarylthio-quinazolin-4-ones
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A new series of 2-heteroarylthio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 21, 25, and 39 proved to be active DHFR inhibitors with IC50 range of 0.3-0.8 μM. Compounds 25, 28, 33, 35 and 36 showed broad spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compound 29 showed broad spectrum antitumor activity toward several tumor cell lines with GI values range of 25.8-41.2%. Molecular modeling studies concluded that recognition with key amino acid Arg38 and Lys31 are essential for binding and biological activities. Flexible alignment; electrostatic and hydrophobic mappings revealed that the obtained model could be useful for the development of new DHFR inhibitors.
- Al-Omary, Fatmah A.M.,Hassan, Ghada S.,El-Messery, Shahenda M.,Nagi, Mahmoud N.,Habib, El-Sayed E.,El-Subbagh, Hussein I.
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- Design, synthesis and biological activity evaluation of 2-mercapto-4(3H)-quinazolinone derivatives as novel inhibitors of protein tyrosine phosphatase 1B
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A series of novel 2-mercapto-4(3H)-quinazolinone derivatives have been synthesized and their inhibitory effects on PTP1B and TCPTP are evaluated for the first time. Most of these derivatives showed good inhibitory activity on PTP1B and reasonable selectivity for PTP1B over TCPTP, among them 32 was the most potent PTP1B inhibitor (IC50 = 1.50 μ ;g/mL), and 27 possessed the best selectivity of 3.0-fold.
- Li, Hui,Wang, Jin-Ping,Yang, Fan,Liu, Ting,Qiu, Wen-Wei,Li, Jing-Ya,Li, Jia,Tang, Jie
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experimental part
p. 1897 - 1911
(2012/09/07)
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- One-pot synthesis of 2,3-dihydro-2-thioxoquinazolin-4(1H)-ones from nitro-compounds with the aid of tin(II) chloride
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(Chemical Equation Presented) A facile synthetic method using SnCl 2·2H2O system to promote the novel reductive cyclization of 2-nitrobenzamides and isothiocyanates is described. Sequentially, a series of 2,3-dihydro-2-thioxoquinazolin-4(1H)-ones were synthesized in good yields.
- Wang, Man-Man,Dou, Guo-Lan,Shi, Da-Qing
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experimental part
p. 939 - 943
(2010/09/03)
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