Novel thienopyrimidine-aminothiazole hybrids: Design, synthesis, antimicrobial screening, anticancer activity, effects on cell cycle profile, caspase-3 mediated apoptosis and VEGFR-2 inhibition

El-Dash, Yara; El-Zayat, Emad; Abdou, Amr M.; Hassan, Rasha A.

doi:10.1016/j.bioorg.2021.105137

Cited by 47 publications

(25 citation statements)

References 49 publications

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“…Tumor development and reproduction were linked to increased vascularity (angiogenesis) in cancer cells, so the anti-angiogenesis mechanism was considered one of the potential strategies to fight cancer [1]. Vascular endothelial growth factor (VEGF) pathway was identified as a key regulator of angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, anti-proliferative evaluation, docking, and MD simulations studies of new thiazolidine-2,4-diones targeting VEGFR-2 and apoptosis pathway

et al. 2022

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We report herein, the design and synthesis of thiazolidine-2,4-diones derivatives as new inhibitors for VEGFR-2. The designed members were assessed for their in vitro anticancer activity against four cancer cell lines; A549, Caco-2, HepG-2 and MDA-MB-231. Compound 14a showed the most potent effects against Caco-2, and HepG-2 cell lines (IC50 = of 1.5 and 31.5 μM, respectively). Next, the in vitro VEGFR-2 inhibitory activity, safety profiles and selectivity indices were examined for all the synthesized members against the normal Vero cell line. Compound 14a (the safest member against Caco-2 cell line) was further investigated for its ability to inhibit Caco-2 cells migration and healing. Moreover, the apoptotic induction of compound 14a against Caco-2 cell line was investigated by assessing against four apoptotic genes (Bcl2, Bcl-xl, TGF, and Survivin). The results revealed that compound 14a can exert apoptosis through significant reduction of Bcl2, Survivin, and TGF gene expression levels. Finally, deep computational studies including molecular docking, ADMET, toxicity studies, and MD simulation were carried out. Also, the DFT calculations were performed and discussed, and the results confirmed the inhibitory reactivity of 14a against VEGFR-2. Compound 14a is expected to be used as a potential lead in the development of new VEGFR-2 inhibitors with increased potency.

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Section: Introductionmentioning

confidence: 99%

Design, synthesis, anti-proliferative evaluation, docking, and MD simulations studies of new thiazolidine-2,4-diones targeting VEGFR-2 and apoptosis pathway

et al. 2022

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“…Cancer therapy is a challenging area for medicinal chemistry scientists to discover safe and effective targeted chemotherapeutic agents that fight cancer’s growth through the inhibition of specific molecular targets [ 2 ]. It is well-known that tumor development as well as reproduction are highly linked to the increased vascularity (angiogenesis) in the malignant cells, so utilizing anti-angiogenesis mechanisms is a potential strategy to combat cancer [ 3 ]. EGFR plays a key role in angiogenesis and cancer cell growth [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

A New Anticancer Semisynthetic Theobromine Derivative Targeting EGFR Protein: CADDD Study

Eissa

Yousef

Elkady

et al. 2023

Life

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A new lead compound has been designed as an antiangiogenic EGFR inhibitor that has the pharmacophoric characteristics to bind with the catalytic pocket of EGFR protein. The designed lead compound is a (para-chloro)acetamide derivative of the alkaloid, theobromine, (T-1-PCPA). At first, we started with deep density functional theory (DFT) calculations for T-1-PCPA to confirm and optimize its 3D structure. Additionally, the DFT studies identified the electrostatic potential, global reactive indices and total density of states expecting a high level of reactivity for T-1-PCPA. Secondly, the affinity of T-1-PCPA to bind and inhibit the EGFR protein was studied and confirmed through detailed structure-based computational studies including the molecular docking against EGFRWT and EGFRT790M, Molecular dynamics (MD) over 100 ns, MM-GPSA and PLIP experiments. Before the preparation, the computational ADME and toxicity profiles of T-1-PCPA have been investigated and its safety and the general drug-likeness predicted. Accordingly, T-1-PCPA was semi-synthesized to scrutinize the proposed design and the obtained in silico results. Interestingly, T-1-PCPA inhibited in vitro EGFRWT with an IC50 value of 25.35 nM, comparing that of erlotinib (5.90 nM). Additionally, T-1-PCPA inhibited the growth of A549 and HCT-116 malignant cell lines with IC50 values of 31.74 and 20.40 µM, respectively, comparing erlotinib that expressed IC50 values of 6.73 and 16.35 µM, respectively.

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“…Against this background, the development of chemotherapeutic agents, which interact with specific molecular targets and subsequently damage cancer cells, is a challenging endeavor for medicinal chemists. The progression of tumors and their spreading are linked to the development of angiogenesis [ 2 , 3 ]. Therefore, anti-angiogenesis treatments are considered the most promising methods to defeat cancer [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Docking, DFT, MD Simulation Studies of a New Nicotinamide-Based Derivative: In Vitro Anticancer and VEGFR-2 Inhibitory Effects

et al. 2022

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A nicotinamide-based derivative was designed as an antiproliferative VEGFR-2 inhibitor with the key pharmacophoric features needed to interact with the VEGFR-2 catalytic pocket. The ability of the designed congener ((E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazono)ethyl)phenyl)nicotinamide), compound 10, to bind with the VEGFR-2 enzyme was demonstrated by molecular docking studies. Furthermore, six various MD simulations studies established the excellent binding of compound 10 with VEGFR-2 over 100 ns, exhibiting optimum dynamics. MM-GBSA confirmed the proper binding with a total exact binding energy of −38.36 Kcal/Mol. MM-GBSA studies also revealed the crucial amino acids in the binding through the free binding energy decomposition and declared the interactions variation of compound 10 inside VEGFR-2 via the Protein–Ligand Interaction Profiler (PLIP). Being new, its molecular structure was optimized by DFT. The DFT studies also confirmed the binding mode of compound 10 with the VEGFR-2. ADMET (in silico) profiling indicated the examined compound’s acceptable range of drug-likeness. The designed compound was synthesized through the condensation of N-(4-(hydrazinecarbonyl)phenyl)benzamide with N-(4-acetylphenyl)nicotinamide, where the carbonyl group has been replaced by an imine group. The in-vitro studies were consonant with the obtained in silico results as compound 10 prohibited VEGFR-2 with an IC50 value of 51 nM. Compound 10 also showed antiproliferative effects against MCF-7 and HCT 116 cancer cell lines with IC50 values of 8.25 and 6.48 μM, revealing magnificent selectivity indexes of 12.89 and 16.41, respectively.

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Novel thienopyrimidine-aminothiazole hybrids: Design, synthesis, antimicrobial screening, anticancer activity, effects on cell cycle profile, caspase-3 mediated apoptosis and VEGFR-2 inhibition

Cited by 47 publications

References 49 publications

Design, synthesis, anti-proliferative evaluation, docking, and MD simulations studies of new thiazolidine-2,4-diones targeting VEGFR-2 and apoptosis pathway

Design, synthesis, anti-proliferative evaluation, docking, and MD simulations studies of new thiazolidine-2,4-diones targeting VEGFR-2 and apoptosis pathway

A New Anticancer Semisynthetic Theobromine Derivative Targeting EGFR Protein: CADDD Study

Design, Synthesis, Docking, DFT, MD Simulation Studies of a New Nicotinamide-Based Derivative: In Vitro Anticancer and VEGFR-2 Inhibitory Effects

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