DESIGN AND SYNTHESIS OF NOVEL 2, 3-DISUBSTITUTED QUINAZOLINES: EVALUATION OF IN VITRO ANTICANCER ACTIVITY AND IN SILICO STUDIES (original) (raw)
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An acetylhydrazide derivative containing a quinazoline nucleus has been utilized to design and synthesize a series of 2,4-disubstituted quinazolines via reaction with several carbon electrophiles including 4-methoxybenzaldehyde and carbon disulfide as well as acetyl and benzoyl chloride. Another series of 2,3-disubstituted-4(3H)-quinazolinones has been also obtained from reactions of a 3-aminoquinazolin-4(3H)-one derivative with other carbon electrophiles, such as chloroacetamide, acetic anhydride, phenyl isocyanate, and ethyl chloroacetate. The structures of the new compounds have been assigned from their spectral data (IR, 1 H NMR, 13 C NMR and MS) and elemental analyses. The newly synthesized compounds were evaluated for their in vitro cytotoxic activity against breast cancer, hepatocellular carcinoma, cervical cancer, and human promyelocytic leukemia cell lines. All the tested compounds showed anticancer activity.
European Journal of Medicinal Chemistry, 2010
Novel derivatives of quinazoline (1e27) have been synthesized and tested for their antitumor activity against three tumor cell lines among these cell lines the human breast carcinoma cell line (MCF-7) in which EGFR is highly expressed. All tested compounds showed potent and selective activity against breast cancer (MCF-7) with IC 50 range of 3.35e6.81 mg/ml. With regarding broad-spectrum activity compounds 5, 9, 15, 18 and 20 exploited potent antitumor against human liver cell line (HEPG2), human breast cell line (MCF-7) and human cervix cell line (HELA) with IC 50 range of 3.35e5.59 mg/ml. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors.
Objective: The present investigation is designed to synthesize some new isomeric series of quinazoline-4-one/4-thione derivatives, depending upon on the pharmacophoric model of in-vivo anticancer activity by modifying the structures retaining the fundamental structural features for the activity and screened for their antitumor properties. Methods: A new series of 7-chloro-3-[substituted (amino/phenyl amino)]-2-phenyl quinazolin-4 (3H)-one/thione derivatives and 1-(7-chloro-4-oxo/-2-phenylquinazoline-3 (4H-yl)) substituted urea derivatives were synthesized. The reaction scheme proceeds through 7-chloro-2-phenyl-4H-benzo [d] [1, 3] oxazin-4-one which is the intermediate one. The structures of the newly synthesized compounds were characterised from infrared (IR), H 1 nuclear magnetic resonance (NMR) and mass spectra (m/z) and elemental analysis. The in-vivo antitumor activity was evaluated by body weight analysis, mean survival time and percentage increase in life span methods in Swiss albino mice bearing Ehrilich ascites carcinoma (EAC). Result: The physico-chemical and spectroscopic data established the synthesis of quinazoline derivatives with a common pharmacophore. The synthesized compounds were evaluated for their antitumor properties. Among the newly quinazoline derivatives screened, six compounds (IIh, IIi, IIj, IIIh, IIIi, IIIj)) have shown significant antitumor activity. Conclusion: The quinazoline derivatives obtained from the present study indicates that the amino group at 3 rd position and urea/thiourea group in phenyl hydrazine ring at 3 rd position of quinzoline skeleton are essential for antitumor activity. Compounds IIh, IIi, IIj, IIIh, IIIi and IIIj were found to be biologically active which may be useful as potential resource for the discovery of anti-tumor compound having common quinazoline pharmacophore with lesser toxic effects. Keywords: 7-chloro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one, quinazoline derivatives, in-vivo anti-tumour activity.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2011
Twenty-two quinazoline derivatives have been synthesised and examined for their anti-tumour activity against three tumour cell lines, namely human breast cancer cell line (MCF-7), human cervical cancer cell line (HeLa) and human hepatoma cell line (HepG2). Twelve of the tested compounds have shown promising anti-tumour activity with an IC 50 range of 5.0-9.7 µg/mL. Regarding the spectrum of activity, five compounds exhibited interesting anti-proliferative properties against the three tested cell lines comparable to the reference drug (dasatinib).
Synthesis, molecular modeling and anti-cancer evaluation of a series of quinazoline derivatives
Carbohydrate Research, 2019
Quinazolines were surveyed as biologically relevant moieties against different cancer cell lines, so in the present study, we analyzed novel derivatives as target-oriented chemotherapeutic anti-cancer drugs. A series of 3-substituted 2-thioxo-2,3-dihydro-1H-quinazolin-4-ones 4a-e were synthesized via the reaction of 2-aminobenzoic acid (1) with isothiocyanate derivatives 2a-e. S-alkylation and S-glycosylation were carried via the reaction of 4a-e with alkyl halides and α-glycopyranosyl bromides 7a,b under anhydrous alkaline and glycoside conditions, respectively. The S-alkylated and S-glycosylated structures, and not that of the N-alkylated and N-glycosylated isomers, have been selected for the products. Conformational analysis has been studied by homo-and heteronuclear two-dimensional NMR methods (DQF-COSY, HMQC, and HMBC). The S site of alkylation and glycosylation were determined from the 1 H, 13 C heteronuclear multiple-quantum coherence (HMQC) experiments. All derivatives were subjected to molecular docking calculations, which selected some derivatives (5n, 8c, 8g, 9c, and 9a) as promising ones based on their excellent binding affinities towards the EGFR tyrosine kinase molecular target. The in vitro cytotoxic activity against MCF-7 and HepG2 cell lines showed effective anti-proliferative activity of the analyzed derivatives with lower IC 50 values especially 9a with IC 50 = 2.09 and 2.08 μM against MCF-7 and HepG2, respectively, and their treatments were safe against the normal cell line Gingival mesenchymal stem cells (GMSC). Moreover, RT-PCR reaction investigated the apoptotic pathway for the compound 9a, which activated the P53 genes and its related genes. So, further work is recommended for developing it as a chemotherapeutic drug.
Arabian Journal of Chemistry, 2013
A novel 3-(substituted benzylideneamino)-7-chloro-2-phenyl quinazoline-4(3H)-one (7-27) has been synthesized and characterised by IR, 1 H NMR, 13 C NMR spectroscopy, and elemental analysis. We changed the methodology for the synthesis of 3-amino 7-chloro-2-phenyl quinazolin-4(3H)-one 6 to fusion reaction at 250°C, instead of using solvent, to avoid the problem of ring opening, which is commonly observed while synthesizing quinazolines from benzoxazinone. NCI selected, 7-chloro-3-{[(4-chlorophenyl) methylidene] amino}-2-phenylquinazolin-4(3H)-one 12, with GI 50 value of À5.59 M, TGI value of À5.12 M, and LC 50 value of À4.40 M showed remarkable activity against CNS SNB-75 Cancer cell line. Rational approach and QSAR techniques enabled the understanding of the pharmacophoric requirement for 2,3,7-tri substituted quinazoline derivatives to inhibit EGFR-tyrosine kinase as antitumor agents and could be used as an excellent framework in this field that may lead to discovery of potent anti tumor agent.
Egyptian Journal of Chemistry, 2020
A series of 2,4-disubstituted quinazoline derivatives was designed and synthesized as multi-target therapeutic agents that may act as anti-cancer and antimicrobial agents. The target compounds were evaluated for primary anti-cancer activity followed by EGFR inhibition assay for most potent compounds. Compounds 6 and 8c exhibited good EGFR inhibition activity with IC50 values of 0.201 and 0.405 µM, respectively, in comparison to lapatinib as a reference with IC50 value of 0.115 µM. Docking study of the synthesized compounds into the binding site of EGFR tyrosine kinase was performed to compare the binding mode of these compounds to the known EGFR inhibitor, lapatinib. Moreover, antimicrobial activity, cytotoxity and hemolytic analysis were estimated according to CO-ADD (The Community for Antimicrobial Drug Discovery) procedures. Compounds 4 and 5c possessed potent antifungal activity with minimum inhibitory concentration (MIC) values of 8 and 4 µg/mL against C. albicans and C. neoformance, respectively, compared to fluconazole as a reference drug with MIC values of 0.125 and 8 µg/mL against same fungi.
Chemical and Pharmaceutical Bulletin, 2014
In this study, four series of 4-anilinoquinazoline derivatives were designed and synthesized as potential anti-proliferative agents. Mechanism of anticancer activity was explained through molecular docking of the target compounds into epidermal growth factor receptor tyrosine kinase (EGFR-TK) active site which displayed comparable binding mode of certain compounds to that of lapatinib. Moreover, the newly synthesized compounds were tested for their anti-proliferative activity on breast carcinoma cell line (MCF-7). 6-(4-Benzylpiperazin-1-ylsulfonyl)-4-(4-bromoanilino)quinazoline (14g) exhibited the most potent inhibitory activity (IC 50 5.52 µM).
Molecular insight into quinazoline derivatives with cytotoxic activity
Journal of Molecular Structure, 2019
Quinazoline nucleus is found in many bioactive molecules exhibiting anticancer activity. Herein we report crystallographic investigation, as well as in vitro determination of the biological activity of symmetrical molecules containing two quinazoline systems tethered by various polyamine linkers e.g. 4-bis(3-aminopropyl)piperazine (I), 4,9-dioxa-1,12dodecanediamine (II), 3,3′-diamino-N-methyldipropylamine (III). Three new crystal structures are determined that differ in the linker. Molecules of compounds I and II adopt stretched conformations and molecules of III adopt bent conformation in the crystal state. The arrangement of molecules in the crystal structures is determined by weak hydrogen bonds and stacking interactions. Geometry optimization for the molecules was carried out with ab initio calculations. Cytotoxic activity of quinazoline derivatives differs markedly depending upon the cancer cell line. Endometrial cancer cells are more sensitive to examined compounds than prostate or breast cancer cells. Investigated quinazoline derivatives are able to induce HEC1A cell death in concentration and time-dependent manner while they exhibit relatively low cytotoxicity to peripheral blood mononuclear cells (PBMCs). The most promising compound is quinazoline derivative with 4,9-dioxa-1,12-dodecanediamine as the linker (II) which induced HEC1A cells apotosis and necrosis in a significant manner.
Synthesis and evaluation of new 4(3H)-Quinazolinone derivatives as potential anticancer agents
Journal of Molecular Structure, 2019
A series of new 4(3H)-quinazolinones were synthesized and evaluated for their cytotoxic activity against a set of human cancer cell lines MDA-MB-231 and MCF-7 (breast), HCT-116 and HT-29 (colon) and A549 (lung). Among the tested compounds, 22a exhibited promising cytotoxic activity against MDA-MB-231 (IC 50 : 3.21 mM) and HT-29 (IC 50 : 7.23 mM) cell lines. The mechanism of action and the apoptosis inducing effect of the compound 22a were studied using the breast cancer cell line MDA-MB-231. Treatment of MDA-MB-231 cell line with compound 22a showed typical apoptotic morphology like cell shrinkage, chromatin condensation and horseshoe shaped nuclei formation. Flow cytometric analysis indicated that the compound induces G0/G1 phase of cell cycle arrest in a dose dependent manner. The binding modes of the potent compounds with EGFR target protein were investigated by docking studies.