Jul 2026· International Journal of Drug Delivery Technology· Vol 16· 0 citations· 40 references
TL;DR
Comparative evaluation with standard drugs demonstrated that while doxorubicin exhibited higher potency, benzimidazole derivatives offered better selectivity and broader applicability compared to imatinib, underscore the potential of benzimidazole derivatives as lead scaffolds for the development of novel antileukemic agents.
Abstract
Benzimidazole derivatives represent a versatile class of heterocyclic compounds with significant potential in
anticancer drug discovery. In the present study, a series of benzimidazole analogues was synthesized via the
modified Phillips condensation method and structurally characterized using FTIR, ¹H-NMR, ¹³C-NMR, mass
spectrometry, and elemental analysis. The synthesized derivatives were evaluated for cytotoxic activity against HL60 (acute promyelocytic leukemia) and K562 (chronic myelogenous leukemia) cell lines using the MTT assay, with
IC₅₀ values calculated through nonlinear regression analysis. Several compounds exhibited potent cytotoxic effects
in the low micromolar range, with halogen-substituted derivatives such as 2-chloro and 5-bromo analogues showing
IC₅₀ values below 6 μM. Selectivity indices confirmed preferential toxicity toward malignant cells compared to
normal peripheral blood mononuclear cells. Structure–activity relationship analysis revealed that electronwithdrawing substituents, extended π-conjugation, and para-position halogenation significantly enhanced biological
activity, while multiple hydroxyl substitutions reduced potency due to steric hindrance. Comparative evaluation with
standard drugs demonstrated that while doxorubicin exhibited higher potency, benzimidazole derivatives offered
better selectivity and broader applicability compared to imatinib. Statistical validation using ANOVA and logistic
dose–response models confirmed the robustness of experimental findings. These results underscore the potential of
benzimidazole derivatives as lead scaffolds for the development of novel antileukemic agents. Future directions
include in vivo validation, molecular docking, and ADMET predictions to refine pharmacological profiles and
facilitate clinical translation
Mechanistic studies indicated that compounds 5c and 5f inhibited cancer cell growth predominantly by inducing apoptosis rather than cell cycle arrest, indicating favourable selectivity.
Rachel Alveera Menezes, Navas Shereef Ellyan, M. M. et al.· RSC Advances· 0 citations
Herein, novel heterocyclic thiosemicarbazone compounds (Hb
1
, Hb
2
, Hb
3
) containing pyrimidine, imidazole, pyridine, and phenyl rings were synthesized via the condensation method as potential therapeutic agents for the treatment of non-small cell lung cancer. The structure of novel heterocyclic compounds was elucidated by using some spectroscopic techniques (organic elemental analysis, fourier transform infrared spectroscopy, proton/carbon nuclear magnetic resonance spectroscopy, scanning electron microscopy and energy dispersive X-ray image, and molar conductance measurement). The antiproliferative activity of novel heterocyclic thiosemicarbazone compounds using CVDK-8 cell viability assay. The viability assay was examined against A549 human non-small cell lung cancer cell line. All heterocyclic thiosemicarbazone compounds exhibited varying degrees of dose-dependent cytotoxic activity against A549 NSCLC cells. The results showed that the pyridine-based heterocyclic compound (Hb
3
) was the most potent antiproliferative agent, demonstrating a dose-dependent reduction in cell viability at concentrations of 50 µg/mL and higher.
Eda Güllü, E. Hasanoğlu Özkan, H. Kızıl et al.· Main group chemistry (Print)· 0 citations
The findings validate the medicinal-chemistry hypothesis that heterocyclic hybridization and rational substitution drive potency, binding affinity, and biological response across multiple pharmacological models.
Shaik Kaleem, K. Chaitanya prasad, K. Nagasree et al.· International journal of che...· 0 citations
The results revealed that the synthesised derivative 3h has potential binding affinity hence blocking the activity, and the synthesised piperazine derivatives are identified as promising lead compounds for further anticancer optimization.
Vaibhav Daund, Pooja Agarwal, A. Jain et al.· Asian Journal of Chemistry· 0 citations
A series of novel pyridazine-thiazole compounds
6
,
7
,
9
, and
10
were synthesized by introducing various thiazole ring systems into the precursor 4-(pyridazin-3-yl)amino)benzohydrazide compound
4
. The DFT/B3LYP optimized structures of the synthesized hybrids exhibited a non-planar geometry. Frontier orbital structures of the studied derivatives were strongly influenced by structural modifications. For example, in the ester
3
and hydrazide
4
analogues, the HOMO was localized on the phenylamino-pyridazine, whereas the LUMO was mainly centered on the cyano-pyridazine moiety. While in the thiosemicarbazide hybrid
5
, the HOMO has shifted toward sulfur- and nitrogen-rich regions, indicating enhanced intramolecular charge-transfer character. The
in vitro
cytotoxic activity of the synthesized analogues against HepG2, HT-29, MCF-7, and WI-38 cell lines showed that analogue
10b
exhibited potent activity (IC₅₀ = 22.39 ±0.16 μM) against HepG2, while analogue
8
disclosed the good activity toward HT-29, (IC₅₀ = 16.54 ±0.38 μM) and analogue
10a
revealed proper efficacy (IC₅₀ = 16.44±0.31 μM) against MCF-7 higher than that of the reference doxorubicin. Besides, the carbonic anhydrase enzymes inhibitory potential against the tumor-related isoforms (CA IX and CA XII) presented hybrids
5
,
7a
,
10a
, and
10c
as good CA IX inhibitors, comparable to the reference inhibitor acetazolamide (AZA). Meanwhile, docking with human 5FL4 protein revealed that the pyridazine-hydrazinyl analogues displayed proper bindings due to their more separate electron density and effective interactions. The pharmacokinetics SwissADME
in silico
studies indicated that the low molecular weight conjugates respect Lipinski’s rule of five, with optimal value of lipophilicity (iLOGP < 3.27), and exhibit blood-brain barrier permeability. While bulky derivatives showed a reduced gastrointestinal absorption (GI) absorption with increased molecular weight, topological polar surface area.
Haifa Alharbi· Arabian Journal of Chemistry· 0 citations
Lercanidipine has previously been investigated in our laboratory as a reference compound in cancer-related combination studies, providing a comparative framework for the present evaluation of thiazole-substituted benzoylpiperazines. In the present study, we evaluated the cytotoxic, anti-inflammatory, and p38α MAPK-related activities of thiazole-substituted benzoylpiperazine derivatives. The cytotoxic profiles of the derivatives were evaluated in multiple human cancer cell lines using the MTT assay. Compound 29 showed the highest cytotoxic potency among the tested derivatives and was further evaluated in combination with cisplatin and lercanidipine. In SH-SY5Y cells, the combination treatments produced greater cytotoxic effects than the corresponding monotherapies; however, these findings were evaluated as combination effects rather than as evidence of pharmacological synergy. Mechanistic evaluation further revealed that Compound 29 inhibited p38α MAPK enzyme activity and increased caspase-3 and caspase-8 activities. Furthermore, the derivatives exhibited dose-dependent inhibition of TNF-α production, with statistically significant effects at increasing concentrations. Docking into the p38α ATP-binding pocket produced a Vina score of −8.749 kcal/mol and revealed interactions with Tyr35, Lys53, and Asp168. The co-crystallized inhibitor SB203580 showed a score of −9.347 kcal/mol and additionally formed the canonical hinge hydrogen bond with Met109. These complementary in vitro and in silico findings support p38MAPK as a plausible molecular target of Compound 29. These in vitro and in silico findings suggest that p38α MAPK may represent a potential molecular target of Compound 29. Overall, the findings demonstrate the cytotoxic and anti-inflammatory activities of thiazole-substituted benzoylpiperazines and identify Compound 29 as a potent member of this series for further investigation in vitro.
Sevde Nur Biltekin Kaleli· International Journal of Mol...· 0 citations
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