Combined pharmacophore-guided 3D-QSAR, molecular docking, and virtual screening on bis-benzimidazoles and ter-benzimidazoles as DNA–topoisomerase I poisons

Issar, Upasana; Arora, R; Kumari, Tripti; Kakkar, Rita

doi:10.1007/s11224-018-1257-3

Cited by 8 publications

(5 citation statements)

References 56 publications

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“…These enzymes play a role in starting, controlling, and changing topological DNA issues during cell proliferation, differentiation, and survival. As a result, mammalian DNA topoisomerases have been explored as potential molecular targets for anticancer drugs, and topoisomerase inhibition has been shown to decrease malignant cell development in a variety of carcinogenic cell types (Bansal et al, 2018; Issar et al, 2019). Topo I only break one DNA strand, whereas Topo II breaks both DNA strands.…”

Section: Anticancer Targets For Benzimidazole Derivativesmentioning

confidence: 99%

Recent advances of benzimidazole as anticancer agents

et al. 2023

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Cancer is the second leading cause of death globally, with 9.6 million deaths yearly. As a life-threatening disease, it necessitates the emergence of new therapies. Resistance to current chemotherapies drives scientists to develop new medications that will eventually be accessible. Because heterocycles are so common in biological substances, compounds play a big part in the variety of medications that have been developed. The "Master Key" is the benzimidazole nucleus, which consists of a six-membered benzene ring fused with a five-membered imidazole/ imidazoline ring, which is an azapyrrole. One of the five-membered aromatic nitrogen heterocycles identified in American therapies that have been approved by the Food and Drug Administration (FDA). Our results show that benzimidazole's broad therapeutic spectrum is due to its structural isosteres with purine, which improves hydrogen bonding, electrostatic interactions with topoisomerase complexes, intercalation with DNA, and other functions. It also enhances protein and nucleic acid inhibition, tubulin microtubule degeneration, apoptosis, DNA fragmentation, and other functions. Additionally, readers for designing the more recent benzimidazole analogues as prospective cancer treatments.

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Section: Anticancer Targets For Benzimidazole Derivativesmentioning

confidence: 99%

Recent advances of benzimidazole as anticancer agents

et al. 2023

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“…Aer the analysis of the SARs, it was hypothesized that it was necessary to introduce the carbonyl group into the benzimidazole structure at C-5 position and this adjustment markedly improved the anticancer activity of compounds 38 and 40. 18,[33][34][35] The studies to clarify the modes of action of the synthesized 2-phenylbenzimidazoles binding on the topo I and DNA complex are currently in progress.…”

Section: In Vitro Anticancer Activities and Structure-activity Relati...mentioning

confidence: 99%

Synthesis and insight into the structure–activity relationships of 2-phenylbenzimidazoles as prospective anticancer agents

Huynh¹,

Nguyen²,

Nguyen

et al. 2020

RSC Adv.

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“…Topo I inhibitors are divided into Topo I poisons and catalytic inhibitors based on their mode of action. , The Topo I poison stabilizes the DNA–Topo I complex to form a transient and cleavable DNA–Topo I covalent complex and prevent the cleaved DNA strand from relegation, thus leading to the accumulation of undesired truncated DNA. In contrast with the Topo I poison, the Topo I catalytic inhibitor inhibits Topo I-mediated DNA cleavage in more diverse manners.…”

Section: Introductionmentioning

confidence: 99%

New Benzimidazole-Triazole Derivatives as Topoisomerase I Inhibitors: Design, Synthesis, Anticancer Screening, and Molecular Modeling Studies

Çevik,

Kaya,

Celik

et al. 2024

ACS Omega

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In this study, we designed, synthesized, and evaluated a series of 1,2,4-triazole benzimidazoles for their cytotoxic effects against the A549, C6, and NIH3T3 cell lines. Additionally, these compounds were assessed for their inhibitory activity against DNA topoisomerase I, aiming to develop novel anticancer agents. The synthesized final compounds 4a−h were characterized using 1 H NMR, 13 C NMR, and HRMS. Among them, compounds 4b and 4h emerged as the most potent agents against the A549 cell line, exhibiting an IC 50 value of 7.34 ± 0.21 μM and 4.56 ± 0.18 μM, respectively. These results were compared to standard drugs, doxorubicin (IC 50 = 12.420 ± 0.5 μM) and Hoechst 33342 (IC 50 = 0.422 ± 0.02 μM). Notably, all tested compounds displayed higher cytotoxicity toward A549 cells than C6 cells. Compounds 4b and 4h demonstrated significant inhibitory activity against topoisomerase I, highlighting their potential as lead compounds in anticancer therapy. Subsequent in silico molecular docking studies were conducted to elucidate the potential binding interactions of compounds 4b and 4h with the target enzyme topoisomerase I. Molecular dynamics studies also assessed and validated the binding affinity and stability. These studies confirmed the promising binding affinity of these compounds, reinforcing their status as lead candidates. According to DFT, compound 4b having the lower energy gap value (ΔE = 3.598 eV) is more chemically reactive than the others, which is consistent with significant inhibitory activity against topoisomerase I. Furthermore, in silico ADME profiles for compounds 4b and 4h were evaluated using SwissADME, providing insights into their pharmacokinetic properties.

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Combined pharmacophore-guided 3D-QSAR, molecular docking, and virtual screening on bis-benzimidazoles and ter-benzimidazoles as DNA–topoisomerase I poisons

Cited by 8 publications

References 56 publications

Recent advances of benzimidazole as anticancer agents

Recent advances of benzimidazole as anticancer agents

Synthesis and insight into the structure–activity relationships of 2-phenylbenzimidazoles as prospective anticancer agents

New Benzimidazole-Triazole Derivatives as Topoisomerase I Inhibitors: Design, Synthesis, Anticancer Screening, and Molecular Modeling Studies

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