Synthesis and Antitumor Activity of Novel Hybrids of Pyrimidine/Benzimidazole Scaffolds

Ismail, Magda M. F.; El‐Sehrawi, Hend M.; Elzahabi, Heba S. A.; Shawer, Taghreed Z.; Ammar, Yousry A.

doi:10.1080/10406638.2020.1833050

Cited by 8 publications

(7 citation statements)

References 20 publications

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“…The target hybrids 3–11 were synthesized in good yields via nucleophilic aromatic substitution of fluoride − of the starting material 2,4-dinitrofluorobenzene with various N , S , and O nucleophiles 1a–i , namely, (3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-1-phenyl-1 H -pyrazol-5-yl)methylacetate ( 1a ), 3-methylquinoxalin-2(1 H )-one ( 1b ), 3-benzylquinoxalin-2(1 H )-one ( 1c ), benzo[ d ]thiazole-2-thiol ( 1d ), 1-methyl-2-thiouracil ( 1e ), 8-hydroxyquinoline ( 1f ), 2,6-di- tert -butylphenol ( 1g ), piperazine ( 1h ), and imidazole ( 1i ), under reflux in acetone as an aprotic solvent in the presence of anhydrous K 2 CO 3 to enhance nucleophilic aromatic substitutions, as shown in Scheme . The structures of 2,4-dinitrophenyl derivatives 3–11 were established based on their spectral data.…”

Section: Resultsmentioning

confidence: 99%

Exploration of Nitroaromatic Antibiotics via Sanger’s Reagent: Synthesis, In Silico, and Antimicrobial Evaluation

et al. 2022

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Facile synthesis of molecular hybrids containing a 2,4-dinitrophenyl moiety was achieved via nucleophilic aromatic substitution of the fluoride anion of Sanger’s reagent (2,4-dinitrofluorobenzene) with various N, S, and O nucleophiles, considered as bioactive moieties. Antimicrobial evaluation of the new hybrids was carried out using amoxicillin and nystatin as antibacterial and antifungal reference standards, respectively. MIC test results identified the compounds 3, 4, and 7 as the most active hybrids against standard strains and multidrug-resistant strains (MDR) of Staphylococcus aureus, Escherichia coli, and Pseudomonas aurginosa. Most of the hybrids displayed two times the antibacterial activity of AMOX against MDR Pseudomonas aeruginosa, E. coli, and a standard strain of P. aeruginosa (ATCC 29853), while demonstrating a weak antifungal profile against Candida albicans. Selectivity profiles of the promising compounds 3, 4, 6, 7, 8, and 11 on WI-38 human cells were characterized, which indicated that compound 3 is the safest one (CC50 343.72 μM). The preferential anti-Gram-negative activity of our compounds led us to do docking studies on DNA gyrase B. Docking revealed that the potential antimicrobial compounds fit well into the active site of DNA gyrase B. Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) predictions revealed that most of the new compounds have high gastrointestinal absorption and a good oral bioavailability with no BBB permeability.

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Section: Resultsmentioning

confidence: 99%

Exploration of Nitroaromatic Antibiotics via Sanger’s Reagent: Synthesis, In Silico, and Antimicrobial Evaluation

et al. 2022

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“…23 The hybridization approach of bringing two scaffolds together in a single molecule showed some benefits. 21 The hybridization of benzimidazole and pyridazine (17, 18, and 19) introduced extra H bonding with Glu917, bonds that cannot be formed by the quinoline scaffold of lenvatinib (Fig. S4, ESI †).…”

Section: Molecular Modeling Studymentioning

confidence: 99%

“…17 Ligand hybridization and core morphing and redesigning have been successfully employed for the discovery of novel VEGFR2 inhibitors. 21,31,45 Herein, core scaffold expansion using heterocyclic systems such as imidazole, thiazole, pyridazine, and quinazoline was employed for generating potent and selective VEGFR2 inhibitors. Molecular modeling studies of compounds 17, 18, and 19 unveiled that these molecules are bound to the hinge region in an ATP-competitive mode, with the benzimidazotriazine core undergoing bidentate H-bonding with Cys919 and the Glu917 backbone, and these are the predominant forces providing the inhibitor activity (Fig.…”

Section: Physicochemical Properties and In Silico Adme Predictionsmentioning

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The design and synthesis of potent benzimidazole derivatives via scaffold hybridization and evaluating their antiproliferative and proapoptotic activity against breast and lung cancer cell lines

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“…[98] The SAR illustrated that the linker between benzimidazole and pyrimidine moieties influenced the activity remarkably and thioether linker was more favorable than the amino linker. [98][99][100][101] Among them, hybrids 44 (Figure 8; IC 50 : 6.5-10.4 µM, MTT assay) and 45 (IC 50 : 2.2-7.3 µM, MTT assay) were found to be most active in each series and hybrid 45 was comparable to nocodazole (IC 50 : 2.0-3.5 µM), whereas hybrid 46 (inhibitory rate: 32.7%-88.4% at 10.0 µM, SRB assay) possessed broad-spectrum activity against a panel of 25 cancer cell lines. Mechanistically, hybrid 45 impaired migration, inhibited the colony formation, arrested the G2/M phase, enhanced microtubule disruption, inhibited tubulin polymerization, and induced apoptosis with triggering of ROS generation and loss of mitochondrial membrane potential.…”

Section: Benzimidazole-cinnamic Acid Hybridsmentioning

confidence: 99%

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

Feng

Cheng

et al. 2022

Archiv der Pharmazie

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Cancer, characterized by a deregulation of the cell cycle which mainly results in a progressive loss of cellular differentiation and uncontrolled cellular growth, remains a prominent cause of death across the world. Almost all currently available anticancer agents used in clinical practice have developed multidrug resistance, creating an urgent need to develop novel chemotherapeutics. Benzimidazole derivatives could exert anticancer properties through diverse mechanisms, inclusive of the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, antiangiogenesis, and blockage of glucose transport. Moreover, several benzimidazole-based agents have already been approved for the treatment of cancers. Hence, benzimidazole derivatives are useful scaffolds for the development of novel anticancer agents. In particular, benzimidazole hybrids could exert dual or multiple antiproliferative activities and had the potential to overcome drug resistance, demonstrating the potential of benzimidazole hybrids as potential prototypes for clinical deployment in the control and eradication of cancers. The purpose of the present review article is to provide a comprehensive landscape of benzimidazole hybrids as potential anticancer agents, and the structure-activity relationship as well as mechanisms of action are also discussed to facilitate the further rational design of more effective candidates, covering articles published from 2019 to 2021.

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Synthesis and Antitumor Activity of Novel Hybrids of Pyrimidine/Benzimidazole Scaffolds

Cited by 8 publications

References 20 publications

Exploration of Nitroaromatic Antibiotics via Sanger’s Reagent: Synthesis, In Silico, and Antimicrobial Evaluation

Exploration of Nitroaromatic Antibiotics via Sanger’s Reagent: Synthesis, In Silico, and Antimicrobial Evaluation

The design and synthesis of potent benzimidazole derivatives via scaffold hybridization and evaluating their antiproliferative and proapoptotic activity against breast and lung cancer cell lines

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

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