- New potential antitumor quinazolinones derived from dynamic 2-undecyl benzoxazinone: Synthesis and cytotoxic evaluation
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Since the quinazoline and its derivatives have been considered as a novel class of cancer chemotherapeutic agents that show promising activity against different tumors, a new series of 6-iodo-2-undecylquinazolin-4(3H)-ones were prepared via reaction of 6-iodo-2-undecyl-4H-benzoxazin-4-one with nitrogen nucleophiles, namely, primary amines, 4-amino antipyrine, hydrazine hydrate, diamines, ethanol amine, and/or hydrazide derivatives and screened for their antitumor activity in vitro against a panel of three human tumor cell lines namely; hepatocellular carcinoma (liver) HepG2, colon cancer HCT-116, and mammary gland breast MCF-7. Compounds 14, 16, and 18 showed remarkable broad spectrum antitumor activity. All compounds were fully characterized by means of IR, MS, and 1H-NMR spectra.
- Hekal, Mohamed H.,Abu El-Azm, Fatma S. M.
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- Discovery of novel quinazolinones and their acyclic analogues as multi-kinase inhibitors: design, synthesis, SAR analysis and biological evaluation
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This work deals with the design and synthesis of some novel 6-iodo-2-(pyridin-3/4-yl)-3-substituted quinazolin-4-one derivatives 8a-l, 10a-h, 13-18 in addition to certain acyclic analogues thereof viz.9a-n and 12a-h. The molecular design strategy was based on structural analogy between the new compounds and reported quinazolines and their acyclic analogues. This design scheme led to the synthesis of 8 new intermediates and 58 new final quinazolinones. The target compounds were evaluated for their antitumor activity against a panel of nine cancer cell lines viz. breast cancer (MCF-7, MDAMB-231, MDAMB-435 and HS-578T), colon cancer (HT-29 and HCC-2998) and leukemia (CCRF-CEM, K-562 and HL-60). The quinazolinones 10a-h displayed exceptional antitumor activity and compounds 12a-h showed superior potency against MCF-7. These compounds were further subjected to in vivo study. Kinase inhibitory assay was also carried out to investigate the mechanism of action of the target compounds and they displayed the highest activity against ABL, ALK and c-RAF kinases. The 3-substituted quinazolinones 10a-h showed the highest kinase activity inhibitory potency against ABL, ALK and c-RAF with the most active compound in this study being the fluoro-3-pyridyl derivative 10a. These results are in compliance with the observed antitumor activity. Finally, a molecular modeling study was performed to interpret the potential molecular interactions of these chemotypes with the most responsive biomolecular target ABL.
- El Sayed, Nehad A.,Eissa, Amal A.,El Masry, Ghada F.,Abdullah, Mohamed?M.,Arafa, Reem K.
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p. 111767 - 111786
(2016)
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- Synthesis of Benzyl C-Analogues of Dapagliflozin as Potential SGLT2 Inhibitors
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Sodium-glucose co-transporter (SGLT) inhibitors are a novel class of therapeutic agents for the treatment of type 2 diabetes based on blocking of renal reabsorption of glucose. Dapagliflozin, a C-aryl glucoside, has emerged as a successful drug in the market based on this concept. We have synthesized hitherto unreported C-benzyl glucoside analogues of Dapagliflozin carrying the same aglycon present in the drug. The synthetic strategy involves in situ generation of functionalized arylmagnesium bromide with Weinreb-amide (WA) functionality for the first time, and addition on to the 1-β-formyl-2,3,4,6-tetra-O-benzyl-D-glucopyranoside for the synthesis of a C-benzyl glucoside building block 16. The WA functionality therein enabled variation in the nature of the distal ring of biarylmethane aglycon for convenient access to other analogues. All the new compounds were screened for their sodium-glucose co-transporters (SGLT1 and SGLT2) inhibition activity using cell-based nonradioactive fluorescence glucose uptake assay. Among them, 14 with IC50: 0.64 nm emerged as the most potent SGLT2 inhibitor with the best selectivity for inhibition of SGLT2 (IC50:0.64 nm) over SGLT1 (IC50: 500 nm) as compare to Dapagliflozin. On the other hand, compound 15a exhibited moderate selectivity for inhibition of SGLT2 (IC50: 4.94 nm) over SGLT1 (IC50: 68.46 nm). These results presented herein amply demonstrate the promise of C-benzyl analogues of Dapagliflozin as novel SGLT2 inhibitors for future investigations.
- Aidhen, Indrapal Singh,Banerjee, Sanjay K.,Kumar, Roshan,Mukkamala, Ramesh
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- Improved method for microwave-assisted synthesis of benzodiazepine-2,5-diones from isatoic anhydrides mediated by glacial acetic acid
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An improved and simpler method for the synthesis of benzodiazepin-2,5-diones and 7-iodobenzodiazepin-2,5-diones catalyzed by glacial acetic acid using isatoic anhydride and 6-iodoisatoic anhydride, respectively, as starting materials is reported. The target products were achieved in good yields (up to 71percent) using microwave irradiation as the activating mode of reaction in the presence of acetic acid instead of the traditional polar aprotic solvents as dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or dimethylacetamide (DMAC). Moreover, relatively simple purification workup is required. The optimal temperature to obtain the benzodiazepin-2,5-dione derivatives was 130 °C, while the best irradiation time was 3 min. In addition, the methodology for the selective preparation of 6-iodoisatoic anhydride with an overall yield of 62percent is presented. Printed in Brazil-
- De La Cruz, Armando,Vega-Acevedo, Carlos Alejandro,Rivero, Ignacio A.,Chávez, Daniel
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p. 1607 - 1611
(2018/06/29)
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- Synthesis, biological evaluation of 2,3-disubstituted-imidazolyl/benzimidazolyl-quinazolin-4(3H)-one derivatives
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A series of disubstituted-quinazolin-4(3H)-ones derivatives have been synthesized and confirmed through IR, 1H- and 13C-NMR, MS spectroscopy and elemental analysis. Synthesized compounds were screened for in vitro and in vivo anti-inflammatory using human red blood cell membrane stabilization method and carrageenan-induced rat paw edema. The antimicrobial potency was measured by disk diffusion method. The compounds with imidazole (3g) and benzimidazole nucleus (4b and 4f) displayed a significant anti-inflammatory activity by in vitro method. Moreover, the compounds 3d and 4a exhibited a significant anti-inflammatory activity in vivo. The compounds 3d, 3f and 4g were found to be active antimicrobial agents, when compared with reference drug ciprofloxacin and amphotericin B. Thus, these compounds can serve as promising leads for further biological studies.
- Patil, Dilip A.,Surana, Sanjay J.
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p. 1125 - 1139
(2016/07/06)
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- Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties
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DNA-encoded chemical libraries are increasingly used to identify leads for drug discovery or chemical biology. Despite the resurging interest in covalent inhibitors, libraries are typically designed with synthon filtered out for reactive functionalities that can engage a target through covalent interactions. Herein, we report the synthesis of two libraries containing Michael acceptors to identify cysteine reactive ligands. We developed a simple procedure to discriminate between covalent and high affinity non-covalent inhibitors using DNA display of the library in a microarray format. The methodology was validated with known covalent and high affinity non-covalent kinase inhibitors. Screening of the library revealed novel covalent inhibitors for MEK2 and ERBB2.
- Zambaldo,Daguer,Saarbach,Barluenga,Winssinger
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supporting information
p. 1340 - 1351
(2016/07/21)
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- Synthesis of 2,1-benzisoxazole-3(1H)-ones by base-mediated photochemical N-O bond-forming cyclization of 2-azidobenzoic acids
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The base-mediated photochemical cyclization of 2-azidobenzoic acids with the formation of 2,1-benzisoxazole-3(1H)-ones is reported. The optimization and scope of this cyclization reaction is discussed. It is shown that an essential step of the ring closure of 2-azidobenzoic acids is the formation and photolysis of 2-azidobenzoate anions.
- Dzhons, Daria Yu.,Budruev, Andrei V.
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supporting information
p. 874 - 881
(2016/07/06)
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- Synthesis of a polymerizable benzocyclobutene that undergoes ring-opening isomerization at reduced temperature
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1-Ethoxyvinylbenzocyclobutene is a substituted benzocyclobutene that undergoes radical polymerization to produce polymers that can be crosslinked at 100-150 °C. The 4- and 5-vinyl isomers are synthesized in a 1:4 ratio via a halogenated benzyne intermediate produced from anthranilic acid, followed by cycloaddition with ethyl vinyl ether and replacement of the halogen atom with a vinyl group. Georg Thieme Verlag Stuttgart · New York.
- Pugh, Coleen,Baker, James S.,Storms, William K.
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supporting information
p. 148 - 152
(2014/01/06)
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- Synthesis of novel quinazolinone derivatives with methyl (E)-2-(3-methoxy)acrylate moiety
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A new series of quinazolinone derivatives with methyl (E)-2-(3-methoxy) acrylate moiety have been designed and synthesized. All target compounds had been identified by 1H NMR spectrum, IR spectrum and HR-MS (high resolution mass spectrum). Three target compounds (10a, 10e, 10h) were chosen to preliminarily test the antibacterial activities, the results showed that all three target compounds exhibited antibacterial activities against three bacterial strains (Proteobacteria, Salmonella, Colibacillus).
- Dong, Kui-Kui,Zhou, Hua-Hong,Guo, A-Rong,Chen, Tian,Wang, Yu-Liang
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p. 1039 - 1042
(2013/05/08)
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- A practical iodination of aromatic compounds by using iodine and iodic acid
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This article describes simple and efficient method for the iodination of different aromatic amines, hydroxy aromatic aldehydes, hydroxy acetophenones and phenols using iodine and iodic acid in ethanol as a solvent. Notable advantages include mild reaction condition, no need of catalyst, short reaction time, simple practical procedure, giving excellent yield of the product. Copyright Taylor & Francis Group, LLC.
- Shinde, Avinash T.,Zangade, Sainath B.,Chavan, Shivaji B.,Vibhute, Archana Y.,Nalwar, Yogesh S.,Vibhute, Yeshwant B.
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experimental part
p. 3506 - 3513
(2011/02/22)
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- Convenient and efficient method for the iodination of aromatic amines by pyridinium iodochloride
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A simple and efficient method for the iodination of aromatic amines using pyridinium iodochloride (PyICl) in methanol as solvent is reported. Mild reaction conditions, short reaction time, and good to excellent yields of the product are the noteworthy advantages of the method. Pyridinium iodochloride is an efficient solid iodinating reagent and can be handled safely. Copyright Taylor & Francis Group, LLC.
- Khansole, Sandeep V.,Junne, Subhash B.,Sayyed, Mudassar A.,Vibhute, Yeshwant B.
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p. 1792 - 1798
(2008/09/20)
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- METHOD FOR PRODUCING 2-AMINO-5-IODOBENZOIC ACID
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A method for producing 2-amino-5-iodobenzoic acid which comprises bringing 2-aminobenzoic acid (A) and molecular iodine (B) into reaction with each other in the liquid phase in the presence of an oxidizing agent. Hydrogen peroxide is preferable as the oxidizing agent. This method does not require a step for purifying 2-amino-5-iodobenzoic acid or a step for recovering iodine, and 2-amino-5-iodobenzoic acid having excellent quality can be produced economically advantageously with a great yield. The product can be advantageously used as an intermediate for drugs, an agricultural chemical and a raw material for functional chemicals.
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Page/Page column 4-5
(2008/06/13)
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- NaIO4/KI/NaCl: a new reagent system for iodination of activated aromatics through in situ generation of iodine monochloride
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A new reagent system consisting of NaIO4/KI/NaCl in aq AcOH has been found to be effective in iodinating a variety of activated aromatic substrates via in situ-generated iodine monochloride, to furnish iodoaromatics in excellent yields. This iodination procedure has been applied successfully for a cost-effective synthesis of 3,3′-diaminobenzidine, a key intermediate for preparing proton conducting membranes for fuel cell applications, with high yield and a purity of 99.7%.
- Emmanuvel, Lourdusamy,Shukla, Ravi Kant,Sudalai, Arumugam,Gurunath, Suryavanshi,Sivaram, Swaminathan
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p. 4793 - 4796
(2007/10/03)
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- Synthesis, insecticidal and antimicrobial activities of some heterocyclic derivatives of quinazolinone
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Some new 4-phenyl-2,3-dihydro-6-(substitutedaminoethyl)-10-iodo[1,2,4]- triazino[2,3-c]-quina-zolin-5-ones 6-14 have been synthesized from 4-(phenyl-2,3-dihydro-6-methyl-10-iodo [1,2,4]-triazino[2,3-c]quinazolin-5-one 5 by introducing different heterocyclic nuclei. Compounds 5 and 6-14 have been screened for insecticidal, anti-fungal and antibacterial activities. Compound 4-phenyl-2, 3-dihydro-6-(β-naphthylaminoethyl)-10-iodo[1, 2, 4]-triazino[2,3-c]-quinazolin-5-one 14 has been found to be the most potent compound of the present study which shows mortality of insects at 190.6 min while standard compounds exhibit at 280 min at a concentration of 5 g/L. Moreover, this compound also possesses anti-bacterial activity. The structures of these compounds have been elucidated by IR, 1H NMR, mass spectroscopy and elemental analysis.
- Singh, Tripti,Sharma, Shalabh,Srivastava, Virendra Kishore,Kumar, Ashok
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p. 2558 - 2565
(2007/10/03)
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- Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents
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In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivatives having quinazolones moiety were synthesised to achieve enhanced biological activity and wide spectrum of activity. Nalidixic Acid was first converted into its acid chloride using thionyl chloride as an acylating agent at laboratory temperature. Later it was converted to methyl ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a methyl ester of nalidixic acid. The ester on addition of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form Benzoxazine/Acetanthranil. 5-iodo-derivative of anthranilic acid was prepared and also utilised to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitro-Benzoxazine/Acetanthranil was obtained by nitration of acetanthranil using conc. H2SO4 and fuming HNO3. Equimolar proportions of the appropriate synthesised acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesise quinazolones. Elemental analysis and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compounds obtained have been established on the basis of Spectral (IR, 1H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar dilution and Punch well diffusion method) of synthesised quinazolone derivatives bearing nalidixic acid moiety on randomly collected microbial strains. The derivatives Ga (NAH), Gb (QN) and Gd (NiQNA) showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhoea in both children as well as adults. Among the respiratory pathogens included in study, derivative Gd (NiQNA) was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesised derivatives against Coagulase negative Staphylococcus. Derivative Ga (NAH) was found to show very high activity against the Candida colonies and derivative Gd (NiQNA) was also found to exhibit inhibitory activity against Candida albicans; a normal flora of the human body which plays an important role in causing opportunistic infections in immunocompromised hosts. Proteus vulgaris, a gram-negative bacteria included in our study was found to be inhibited by derivative Gb (QN).
- Grover, Gaurav,Kini, Suvarna G.
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p. 256 - 262
(2007/10/03)
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- Kinetics of iodination of aniline and anthranilic acid by iodine in aqueous medium
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The title reactions are fast and follow overall second order kinetics.The two reactions have been studied at pH 4.7 using a rotating platinum electrode.The rate constants and the energies of activation for the two reactions at 24.5 deg C are: 136 dm3 mol-1 s-1, 115 dm3 mol-1 s-1; and 82.1 kJ mol-1, 82.2 kJ mol-1, respectively.
- Dangat, V. T.,Bonde, S. L.,Gayakhe, A. S.,Ghorpade, B. S.
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p. 321 - 322
(2007/10/02)
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