Toward discovery of mutant EGFR inhibitors; Design, synthesis and in vitro biological evaluation of potent 4-arylamino-6-ureido and thioureido-quinazoline derivatives

Mowafy, Samar; Galanis, Athanassios S.; Doctor, Zainab M.; Paranal, Raymond M.; Lasheen, Deena S.; Farag, Nahla A.; Jänne, Pasi A.; Abouzid, Khaled A. M.

doi:10.1016/j.bmc.2016.05.063

Cited by 42 publications

(23 citation statements)

References 22 publications

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“…One further quinazoline analogue from the kinetoplastid subsection 37 (MMV688273) shares several structural similarities with compounds 29 – 36 . However, while this compound has been reported as an intermediate in the synthesis of many anticancer compounds, no bioactivity data have been published.…”

Section: Kinetoplastids (Trypanosomiasis and Leishmaniasis)mentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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Section: Kinetoplastids (Trypanosomiasis and Leishmaniasis)mentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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“…Moreover, it was found that the majority of the approved and developed first‐generation EGFR inhibitors bear the 4‐anilino side chains linked to quinazoline/quinoline cores. These side chains occupy an important lipophilic selectivity pocket in the EGFR‐binding domain . In light of these facts the pharmacophore modeling, three‐dimensional quantitative structure–activity relationship (3D‐QSAR), and molecular docking of the two series of tricyclic tetrahydrobenzothieno[2,3‐ d ][1,2,3]triazine and dihydrocyclopentathieno‐[2,3‐ d ][1,2,3]triazine analogs have been used to provide insights into the key structural features required for designing EGFR inhibitors targeting lung carcinoma cell line H1299 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacophore modeling, 3D‐QSAR, synthesis, and anti‐lung cancer evaluation of novel thieno[2,3‐d][1,2,3]triazines targeting EGFR

Elrayess

Aziz

Elgawish

et al. 2020

Archiv der Pharmazie

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Two series of thieno[2,3-d][1,2,3]triazine derivatives were designed, synthesized, and biologically evaluated as potential epidermal growth factor receptor (EGFR) inhibitors targeting the non-small-cell lung cancer cell line H1299. Most of the synthesized compounds displayed IC 50 values ranging from 25 to 58 nM against H1299, which are superior to that of gefitinib (40 µM). 3-(5,6,7,8-Tetrahydro-7Hcyclohexa[4:5]thieno[2,3-d]-1,2,3-triazin-4-ylamino)benzene-1,3-diamine (6b) achieved the highest cytotoxic activity against H1299 with an IC 50 value of 25 nM; it had the ability to decrease the EGFR concentration in H1299 cells from 7.22 to 2.67 pg/ml. In vitro, the IC 50 value of compound 6b was 0.33 nM against EGFR, which is superior to that of gefitinib at 1.9 nM and erlotinib at 4 nM. The three-dimensional quantitative structure-activity relationships and molecular modeling studies revealed comparable binding modes of compound 6b, gefitinib, and erlotinib in the EGFR active site. The in silico ADME (absorption, distribution, metabolism, and excretion) prediction parameters of this compound revealed promising pharmacokinetic and physicochemical properties. Moreover, DFT (density functional theory) calculations showed the high reactivity of compound 6b toward the EGFR compared with other compounds. The designed compound 6b might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR. K E Y W O R D S 3D-QSAR, EGFR, H1299, molecular modeling, thieno[2,3-d][1,2,3]triazine

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“…The role of this protein is stabilization and regulation of oncogenic client proteins, therefore designing its inhibitors is a novel cancer therapy method. What is more, in different types of cancer, overexpression and mutation of the epidermal growth factor receptor (EGFR) have been observed; thus, finding inhibitors of EGFR kinases among (thio)ureido-quinazoline derivatives is also a promising approach to tumor treatment [ 22 , 23 ]. It was proven that the anticancer potency of symmetrical 1,3-phenyl bis-thiourea compounds were combined with their tubulin-binding properties [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Disubstituted 4-Chloro-3-nitrophenylthiourea Derivatives: Antimicrobial and Cytotoxic Studies

et al. 2018

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4-Chloro-3-nitrophenylthioureas 1–30 were synthesized and tested for their antimicrobial and cytotoxic activities. Compounds exhibited high to moderate antistaphylococcal activity against both standard and clinical strains (MIC values 2–64 μg/mL). Among them derivatives with electron-donating alkyl substituents at the phenyl ring were the most promising. Moreover, compounds 1–6 and 8–19 were cytotoxic against MT-4 cells and various other cell lines derived from human hematological tumors (CC50 ≤ 10 μM). The influence of derivatives 11, 13 and 25 on viability, mortality and the growth rate of immortalized human keratinocytes (HaCaT) was observed.

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Toward discovery of mutant EGFR inhibitors; Design, synthesis and in vitro biological evaluation of potent 4-arylamino-6-ureido and thioureido-quinazoline derivatives

Cited by 42 publications

References 22 publications

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Pharmacophore modeling, 3D‐QSAR, synthesis, and anti‐lung cancer evaluation of novel thieno[2,3‐d][1,2,3]triazines targeting EGFR

Disubstituted 4-Chloro-3-nitrophenylthiourea Derivatives: Antimicrobial and Cytotoxic Studies

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