Design, synthesis, docking and QSAR study of substituted benzimidazole linked oxadiazole as cytotoxic agents, EGFR and erbB2 receptor inhibitors (original) (raw)
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Egyptian Pharmaceutical Journal, 2015
4-Anilino-6-substituted-quinazolines were designed, synthesized and evaluated for EGFR-TK and tumor growth inhibitory activities. The target compounds were designed with enamine ester or urea moieties appended at the C-6 of quinazoline as additional hydrogen bond acceptor functions. Most of the synthesized compounds displayed potent EGFR-TK inhibitory activity at 10 mM and the 6-ureido-anilinoquinazoline derivative 7a showed IC 50 value of 0.061 mM. Moreover, six compounds were tested by National Cancer Institute (NCI), USA for their anti-proliferative activity at 10 mM in full NCI 60 cell panel. Compound 7a was further assayed for five dose molar ranges in full NCI 60 cell panel and exhibited remarkable growth inhibitory activity pattern against Non-Small Cell Lung Cancer EKVX (GI 50 ¼ 0.37 mM), NCI-H322M (GI 50 ¼ 0.36 mM), Renal Cancer A498 (GI 50 ¼ 0.46 mM), TK-10 (GI 50 ¼ 0.99 mM) and Breast Cancer MDA-MB-468 (GI 50 ¼ 1.096 mM) which are of high EGFR expression. Docking study was performed for the active compounds into ATP binding site of EGFR-TK which showed similar binding mode to gefitinib and additional binding with Cys-773 at the gatekeeper of EGFR-TK enzyme.
POLYCYCLIC AROMATIC COMPOUNDS, 2024
Herein, we prepared some new imidazole-1,2,4-oxadiazole hybrids (6a-6o) and investigated their antiproliferative potential on three human cancer cell lines (HepG2, A549 and MCF-7) using Erlotinib as standard drug. In common, most of the compounds showed better potential on MCF-7 in comparison to HepG2 and A549. Out of all, compound 6o had greater activity on MCF-7, while, it, had most promising activity on HEPG2 and A549. Compounds 6f, 6j and 6l also exhibited significant activity on MCF-7. As well, in vitro anti-EGFR evaluation of most active compounds 6f, 6j, 6l, and 6o revealed that compound 6o displayed most promising activity as compared to Erlotinib. Molecular docking studies revealed the possible binding interactions of derivatives 6f, 6j, 6l, and 6o with EGFR (PDB ID-4HJO). Finally, compounds 6f, 6j, 6l, and 6o are possessing 'druglikeness' with CLogP values ranging from 1.86 to 3.13.
Molecules
In the current study, new benzimidazole-based 1,3,4-oxadiazole derivatives have been synthesized and characterized by NMR, IR, MS, and elemental analysis. The final compounds were screened for cytotoxicity against MDA-MB-231, SKOV3, and A549 cell lines and EGFR for inhibitory activities. Compounds 10 and 13 were found to be the most active against all the tested cell lines, comparable to doxorubicin, and exhibited significant inhibition on EGFR kinase, with IC50 0.33 and 0.38 μM, respectively, comparable to erlotinib (IC50 0.39 μM). Furthermore, these two compounds effectively suppressed cell cycle progression and induced cell apoptosis in MDA-MB-231, SKOV3, and A549 cell lines. The docking studies revealed that these compounds showed interactions similar to erlotinib at the EGFR site. It can be concluded that the synthesized molecules effectively inhibit EGFR, can arrest the cell cycle, and may trigger apoptosis and therefore, could be used as lead molecules in the development of n...
Medicinal Chemistry Research, 2014
New series of benzothiazole and pyrimido[2, 1-b]benzothiazole derivatives were synthesized and characterized by analytical and spectrometrical methods (IR, HRMS, 1 H, and 13 C NMR). Eleven of the synthesized compounds were selected by the National Cancer Institute, USA to be screened for their antitumor activity at a single dose (10 lM) against a panel of 60 cancer cell lines. Also, the EGFR tyrosine kinase inhibitory activity of compounds 4, 5, 8, and 9 was studied. In the present work, structure-based pharmacophore mapping, molecular docking, protein-ligand interaction, fingerprints, and binding energy calculations were employed in a virtual screening strategy to identify the interaction between the compounds and the active site of EGFR tyrosine kinase.
EXCLI journal, 2014
In this study, we illustrate computer aided drug design of new benzothiazole and pyrimido[2,1-b]benzothiazole derivatives as epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors. Compounds 1-5 were screened at NCI, USA, for antitumor activity against non-small cell lung cancer (NCI-H522), colon cancer (HCT-116, HCT-15 and HT29) and breast cancer (MDA-MB-468 and MDA-MB-231/ATCC) cell lines in which EGFR is overexpressed in varying levels. Results indicated that these compounds are more potent antitumor agents compared to erlotinib against HT29 and MDA-MB-231/ATCC cell lines. Compound 3 showed GI50 value of 22.3 nM against NCI-H522 cell line, while erlotinib exhibited GI50 value of 1 µM against the same cell line. In addition, these compounds were studied for their EGFR tyrosine kinase inhibitory activity. Virtual screening utilizing molecular modeling and QSAR techniques enabled the understanding of the pharmacophoric requirements for antitumor activity. Docking the ...
Pharmaceuticals
A library of novel naproxen based 1,3,4-oxadiazole derivatives (8–16 and 19–26) has been synthesized and screened for cytotoxicity as EGFR inhibitors. Among the synthesized hybrids, compound2-(4-((5-((S)-1-(2-methoxynaphthalen-6-yl)ethyl)-1,3,4-oxadiazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)phenol(15)was the most potent compound against MCF-7 and HepG2cancer cells with IC50 of 2.13 and 1.63 µg/mL, respectively, and was equipotent to doxorubicin (IC50 1.62 µg/mL) towards HepG2. Furthermore, compound 15 inhibited EGFR kinase with IC50 0.41 μM compared to standard drug Erlotinib (IC50 0.30 μM). The active compound induces a high percentage of necrosis towards MCF-7, HePG2 and HCT 116 cells. The docking studies, DFT and MEP also supported the biological data. These results demonstrated that these synthesized naproxen hybrids have EGFR inhibition effects and can be used as leads for cancer therapy.
BMC Chemistry, 2021
Background 1,2,4-oxadiazole derivatives exhibited significant anti-cancer activity when they were evaluated, against human cancer cell lines. They also showed anti-inflammatory, analgesic, diabetic, immunosuppressive, α,β3-receptor antagonist, antimicrobial, anti-helminthic, histamine-H3 and antiparasitic properties. A pyrimidine analog, 5 fluoro-uracil is a chemotherapeutic drug used for treating multiple solid malignant tumors. But its application is limited, as it has side effects like low bioavailability and high toxicity. Molecular docking is an exemplary tool, helps in identifying target and designing a drug containing high bio-availability and minimum toxicity. Results A set of 1,2,4-oxadiazole linked 5-fluoruracil derivatives (7a–j) were synthesized and their structures were confirmed by 1HNMR, 13CNMR and Mass spectral analysis. Further, these compounds were investigated for their anticancer activity towards a panel of four human cancer cell lines such as (MCF-7, MDA MB-231)...
Journal of Molecular Graphics and Modelling, 2010
Protein tyrosine kinases occupy a central position in the control of cellular proliferation and its inactivation might lead to the discovery of a new generation anticancer compounds. Substituted benzothiazoles have been found to mimic the ATP-competitive binding of genistein and quercetin to tyrosine kinase. A series of novel 2-phenyl-1,3-benzothiazoles were synthesized and characterised by IR, 1 H NMR and mass spectroscopy. All the compounds were tested for their anticancer activity against MCF-7 breast cancer cell line with the MTT assay. Most of the compounds showed moderate to good anti-breast cancer activity. Anticancer activity varied with substitution on the benzothiazole nucleus with halogens and at 4 position, substitution of the 2-phenyl moiety with methyl and methoxy groups was also explored. Among the compounds tested with MTT assay, mono fluoro substitution on benzothiazole nucleus and 4-methyl variations at 2-phenyl position demonstrated highest percent growth inhibition of MCF-7 cells. Docking studies of the synthesised compounds was done on EGFR using GRIP batch docking method to study their observed activity.
Bioorganic chemistry, 2018
A new series of benzimidazole linked pyrazole derivatives were synthesized by cyclocondensation reaction through one-pot multicomponent reaction in absolute ethanol. All the synthesized compounds were tested for their in vitro anticancer activities on five human cancer cell lines including MCF-7, HaCaT, MDA-MB231, A549 and HepG2. EGFR receptor inhibitory activities were carried out for all the compounds. Majority of the compounds showed potent antiproliferative activity against the tested cancer cell lines. Compound 5a showed the most effective activity against the lungs cancer cell lines (IC = 2.2 µM) and EGFR binding (IC = 0.97 µM) affinity as compared to other members of the series. Compound 5a inhibited growth of A549 cancer cells by inducing a strong G/M phase arrest. In addition, same compound inhibited growth of A549 cancer cells by inducing apoptosis. In molecular docking studies compound 5a was bound to the active pocket of the EGFR (PDB 1M17) with five key hydrogen bonds a...
Egyptian Journal of Chemistry
Molecular docking simulation of seven (7) compounds of 2,5-Disubstituted-1,3,4-Oxadiazole was carried out so as to evaluate their theoretical binding affinities, targeting breast and lung cancers. The chemical structure of the molecules was accurately drawn using ChemDraw Professional 16.0 software. The designed compounds were checked for their selectivity towards ER and EGFR by using GOLD suite software. All the theoretically designed compounds exhibited excellent binding energies with the receptor active pocket and had promising activity with these proteins. Compound Y1 and Y2 shown the highest PLP Fitness values, with breast cancer protein ER, their values were (98.17, 98.15) respectively, and with lung cancer protein EGFR, their values were (98.88, 99.59) respectively. In-silico ADME and drug-likeness studies were performed by using the Swiss ADME server. The results showed that most of the compounds expected to be passively and highly absorbed from the GIT. Besides, all of the synthesized compounds satisfied the Rule of five (RO5).