Design and synthesis of new triarylimidazole derivatives as dual inhibitors of BRAFV600E/p38α with potential antiproliferative activity

Youssif, Bahaa G.M.; Gouda, Ahmed M.; Moustafa, Amr H.; Abdelhamid, Antar A.; Gomaa, Hesham A.M.; Kamal, Islam; Marzouk, Adel A.

doi:10.1016/j.molstruc.2021.132218

Cited by 35 publications

(39 citation statements)

References 51 publications

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“…Youssif et al obtained novel triarylimidazole derivatives [ 30 ]. The selection of the triaryl imidazole core was made on previously reported data based on the rational drug design [ 31 , 32 ].…”

Section: The Most Potent Anti-melanoma Agent From Most Recent Studies...mentioning

confidence: 99%

“…The most promising compound (4) possessed the highest activity against melanoma cell line LOX IMV1 with a concentration of 50% of the maximal inhibition of cell proliferation (GI 50 = 0.17 µM), and inhibited BRAF V600E most effectively with the concentration of a substance that causes the death of 50% of the population (LC 50 = 0.33 ± 0.10 µM). The authors noted that the activity of arylcarboximidamide derivatives increased in the given series of substituents: 4-chlorophenyl < 2-naphthyl < 4-methoxyphenyl ≤ 1,3-benzodioxole for the most potent agent [ 30 ].…”

Section: The Most Potent Anti-melanoma Agent From Most Recent Studies...mentioning

confidence: 99%

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New Potential Agents for Malignant Melanoma Treatment—Most Recent Studies 2020–2022

Kozyra

Krasowska

Pitucha

2022

IJMS

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Malignant melanoma (MM) is the most lethal skin cancer. Despite a 4% reduction in mortality over the past few years, an increasing number of new diagnosed cases appear each year. Long-term therapy and the development of resistance to the drugs used drive the search for more and more new agents with anti-melanoma activity. This review focuses on the most recent synthesized anti-melanoma agents from 2020–2022. For selected agents, apart from the analysis of biological activity, the structure–activity relationship (SAR) is also discussed. To the best of our knowledge, the following literature review delivers the latest achievements in the field of new anti-melanoma agents.

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Section: The Most Potent Anti-melanoma Agent From Most Recent Studies...mentioning

confidence: 99%

Section: The Most Potent Anti-melanoma Agent From Most Recent Studies...mentioning

confidence: 99%

New Potential Agents for Malignant Melanoma Treatment—Most Recent Studies 2020–2022

Kozyra

Krasowska

Pitucha

2022

IJMS

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“…Cancer is considered a life‐threatening disease described by uncontrollable cell division and proliferation. [ 1 ] As being a huge worldwide health problem, its ranking came next to cardiovascular disorders. [ 2 ] Although anticancer drugs have been developed progressively in recent years, there is a continuing demand to establish more efficient scaffolds that can selectively target cancer cells without displaying drug resistance.…”

Section: Introductionmentioning

confidence: 99%

New 1,3,4‐oxadiazoles linked with the 1,2,3‐triazole moiety as antiproliferative agents targeting the EGFR tyrosine kinase

Mahmoud

Mohammed

Gomaa

et al. 2022

Archiv der Pharmazie

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A series of 1,3,4-oxadiazole-1,2,3-triazole hybrids bearing different pharmacophoric moieties has been designed and synthesized. Their antiproliferative activity was evaluated against four human cancer cell lines (Panc-1, MCF-7, HT-29, and A-549) using the MTT (3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyltetrazolium bromide) assay. The preliminary activity test displayed that the most active compounds, 6d, 6e, and 8a-e, suppressed cancer cell growth (GI 50 = 0.23-2.00 µM) comparably to erlotinib (GI 50 = 0.06 µM).Compounds 6d, 6e, and 8a-e inhibited the epidermal growth factor receptor tyrosine kinase (EGFR-TK) at IC 50 = 0.11-0.73 µM, compared to erlotinib (IC 50 = 0.08 ± 0.04 µM).The apoptotic mechanism revealed that the most active hybrid 8d induced expression levels of caspase-3, caspase-9, and cytochrome-c in the human cancer cell line Panc-1 by 7.80-, 19.30-, and 13-fold higher than doxorubicin. Also, 8d increased the Bax level by 40fold than doxorubicin, along with decreasing Bcl-2 levels by 6.3-fold. Cell cycle analysis after treatment of Panc-1 cells with hybrid 8d revealed a high proportion of cell accumulation (41.53%) in the pre-G1 phase, indicating cell cycle arrest at the G1 transition.Computational docking of the 8d and 8e hybrids with the EGFR binding site revealed their ability to bind with EGFR similar to erlotinib. Finally, in silico absorption, distribution, metabolism, and excretion/pharmacokinetic studies for the most active hybrids are discussed.

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“…Compound 4 showed significant antiproliferative action against a panel of cancer cell lines. It has an IC 50 of 0.33 µM and 0.19 µM against BRAF V600E and p38α, respectively 21 .…”

Section: Introductionmentioning

confidence: 99%

Novel piperine-carboximidamide hybrids: design, synthesis, and antiproliferative activity via a multi-targeted inhibitory pathway

Al-Wahaibi

Mahmoud

Mostafa

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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A new series of piperine-carboximidamide hybrids VIa-k was developed as a new cytotoxic agent targeting EGFR, BRAF, and CDK2. The antiproliferative effect against four cancer cells was investigated against erlotinib. Hybrids VIc , VIf , VIg , VIi , and VIk have the highest antiproliferative activity. Compounds VIc , VIf , VIg , VIi , and VIk inhibited EGFR with IC 50 values ranging from 96 to 127 nM. Compounds VIf and VIk had the most potent inhibitory activity as BRAF V600E (IC 50 = 49 and 40 nM, respectively) and were discovered to be potent inhibitors of cancer cell proliferation (GI 50 = 44 and 35 nM against four cancer cell lines, respectively). Compound VIk , the most effective derivative as an antiproliferative agent, demonstrated potent anti-CDK2 action with an IC 50 value of 12 nM, which is 1.5-fold more potent than the reference dinaciclib. Finally, VIc , VIf , and VIk have a high capacity to inhibit LOX-IMVI cell line survival.

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Design and synthesis of new triarylimidazole derivatives as dual inhibitors of BRAFV600E/p38α with potential antiproliferative activity

Cited by 35 publications

References 51 publications

New Potential Agents for Malignant Melanoma Treatment—Most Recent Studies 2020–2022

New Potential Agents for Malignant Melanoma Treatment—Most Recent Studies 2020–2022

New 1,3,4‐oxadiazoles linked with the 1,2,3‐triazole moiety as antiproliferative agents targeting the EGFR tyrosine kinase

Novel piperine-carboximidamide hybrids: design, synthesis, and antiproliferative activity via a multi-targeted inhibitory pathway

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