Aug 2026· ChemMedChem· Vol 21· 0 citations· 36 references
Medicine
TL;DR
Findings support the development of N2‐benzyl‐(S)‐1‐oxo‐1,2,3,4‐tetrahydropyrrolo[1,2‐a]pyrazine‐3‐carboxamide analogs, particularly compound B1, as selective therapeutic candidates for triple‐negative breast cancer.
Abstract
Triple‐negative breast cancer (TNBC) remains a major clinical challenge due to the absence of effective targeted therapies. In this study, thirty analogs of (S)‐1‐oxo‐1,2,3,4‐tetrahydropyrrolo[1,2‐a]pyrazine‐3‐carboxamide (A1–F5) were designed, synthesized, and evaluated for their cytotoxic activity against hormone receptor‐positive breast cancer (MCF‐7) and EGFR‐overexpressing TNBC (MDA‐MB‐468) cell lines. Notably, compounds B1 and B3 exhibited potent growth inhibition toward MDA‐MB‐468 cells, with GI50 values of 2.8 and 4.7 µM, respectively, surpassing the efficacy of the reference compound (Ref 2, GI50: 7.6 µM) and gefitinib (GI50: 16.5 µM). Flow cytometric analysis demonstrated significant apoptosis induction by compounds B1 and B3, with rates of 42.8% and 42.2%, respectively. Mechanistic investigations revealed that compounds B1 and B3 selectively inhibited Akt phosphorylation and enhanced JNK phosphorylation, suggesting a dual modulation of survival and apoptotic pathways. These findings support the development of N2‐benzyl‐(S)‐1‐oxo‐1,2,3,4‐tetrahydropyrrolo[1,2‐a]pyrazine‐3‐carboxamide analogs, particularly compound B1, as selective therapeutic candidates for triple‐negative breast cancer.
In the current work, a new series of novel Δ2‐pyrazoline‐1H‐1,2,3‐triazole derivatives (6a‐6j and 7a‐7f) were synthesized, followed by in situ biological evaluation to assess their antiproliferative and immunomodulatory potential against breast cancer cells (MDA‐MB‐231 and MCF‐7), HUVECs, and PBMCs. The compounds demonstrated antiproliferative effects with IC50 values ranging from 116.92 to 549.73 µM. Seven compounds (6c, 6f, 6h, 6i, 7b, 7e, and 7f) exhibited promising antiproliferative activities with IC50 values below 140 µM in both MDA‐MB‐231 and MCF‐7 cancer cell lines. Compound 7f demonstrated the highest antiproliferative effect with IC50 values of 116.92 µM in MDA‐MB‐231 and 124.72 µM in MCF‐7, with an acceptable cytotoxicity profile in normal HUVEC cells (IC50 = 208.41 µM); thus, immunomodulatory effects of 7f on checkpoint signaling were further evaluated. Compound 7f showed a dose‐dependent increase of TIGIT, PD‐1, and LAG‐3 expression in CD3+ T cells. These changes may enhance responsiveness to checkpoint‐targeted therapies while reflecting complex regulation of T‐cell function. In silico target fishing and molecular docking reflect calpain as a probable target for 7f, while DFT analysis indicates electrophilic and nucleophilic positions within 7f may help its interaction with the target. Molecular dynamics (MD) simulation supports strong binding of 7f with binding energy (−22.259 ± 4.71 kcal mol−1).
S. Khan, H. Moghtaderi, Ebrahimi Amirhossein et al.· Chemistry and Biodiversity· 0 citations
A series of fused [1,2,4]triazolo[4,3‐b]pyridazine derivatives was synthesized via hypervalent iodine‐mediated oxidative cyclization of hydrazone intermediates using iodobenzene diacetate under mild, metal‐free conditions. This method was applied to diverse 6‐(4‐nitrophenyl)‐substituted triazolopyridazines with various aryl and heteroaryl groups, producing the target compounds in good to excellent yields with broad substrate tolerance. All compounds were characterized by FT‐IR,
1
H NMR,
13
C NMR, and HRMS. Their antiproliferative activity was tested against the human triple‐negative breast cancer cell line MDA‐MB‐231 using the sulforhodamine B (SRB) assay. Compound 3c, containing a 3,4‐dimethoxyphenyl substituent, showed the highest activity, suggesting a beneficial effect of electron‐donating groups. Molecular docking against cancer‐related proteins showed favorable binding, especially with Topoisomerase IIα, though these computational results are preliminary and don't confirm the exact molecular target. This study presents an efficient synthesis strategy and identifies compound 3c as a promising lead for further biological and medicinal chemistry research.
S. Malik, N. Rani, M. Kinger et al.· ChemistrySelect· 0 citations
In this study, a series of indolyl hydrazone derivatives (
5–10
) were designed and synthesized from 2,4‐dimethoxybenzaldehyde (DMBA) (
1
) as potential chemotherapeutic agents. The structures of the synthesized compounds were confirmed by elemental analysis, FT‐IR, 1D, and 2D NMR spectroscopy, and high‐resolution mass spectrometry (HRMS). Their cytotoxic activities were evaluated against human breast (MCF‐7), liver (HepG2), and colorectal (DLD‐1) cancer cell lines. All compounds exhibited cytotoxic effects at micromolar concentrations, with IC
50
values ranging from 8.97–26.07 µM for MCF‐7, 22.50–70.99 µM for HepG2, and 5.93–66.31 µM for DLD‐1 cells. Compound
10
demonstrated the strongest activity against MCF‐7 and DLD‐1 cells, with IC
50
values of 8.97 ± 0.31 and 5.93 ± 0.11 µM, respectively. Compound
7
showed the highest antiproliferative activity against HepG2 cells (22.50 ± 1.23 µM), exceeding the activity of cisplatin (37.27 ± 2.42 µM). Molecular docking studies revealed favorable binding affinities of the most active compounds (
7
and
10
) toward selected targets. In addition, in silico ADME‐toxicity analyses predicted acceptable physicochemical and pharmacokinetic properties, supporting the potential of these derivatives as promising anticancer candidates.
Poly(ADP‐ribose) polymerase‐1 (PARP‐1) plays a central role in the repair of DNA single‐strand breaks and represents an established therapeutic target in cancer treatment. In this study, a series of novel oxadiazole–morpholine hybrid compounds was designed and synthesized using a structure‐based drug design approach to target the catalytic domain of PARP‐1. The synthesized compounds were evaluated for their cytotoxic activity against breast and ovarian cancer cells, PARP‐1 inhibitory potency, and apoptosis‐inducing effects. Among the tested compounds, 12a exhibited potent cytotoxic activity against MDA‐MB‐231 cells (IC50 = 1.23 μM), surpassing the reference drug olaparib (IC50 = 3.45 μM). Compound 12a also demonstrated strong PARP‐1 inhibitory activity (IC50 = 0.034 μM), comparable to olaparib (IC50 = 0.012 μM). Flow cytometric analyses revealed that compound 12a significantly induced apoptotic cell death and altered cell cycle progression. Molecular docking studies suggested plausible binding interactions within the PARP‐1 catalytic site, supporting the observed biological activity. These findings identify oxadiazole–morpholine hybrids as promising scaffolds for further optimization as PARP‐1 inhibitors.
Nader R Albujuq, Khaled M. Darwish, S. Fahmy et al.· Drug development research (P...· 0 citations
Hypoxia‐inducible factor‐1 α (HIF‐1α) is a key transcription factor for tumor cells to sense and adapt to the hypoxic microenvironment, regulate tumor progression such as tumor glycolysis, and is an important target for the development of anti‐tumor drugs. YC‐1 (1‐benzyl‐3‐(5’‐hydroxymethyl‐2’‐furyl)indazole), as a classic inhibitor of HIF‐1α, has received extensive attention in multiple anti‐tumor studies. Some derivatives that replace YC‐1 indazole with the benzimidazole skeleton have shown certain HIF‐1α inhibitory and anti‐tumor potential. In this study, a series of substituted benzimidazole derivatives were designed and synthesized, and their HIF‐1α inhibitory and anti‐tumor effects were screened and investigated. In vitro anti‐proliferation and dual‐luciferase reports showed that compound 9o had superior in vitro anti‐tumor (IC50 = 33.85 μM) and HIF‐1α transcriptional inhibitory activity (79.59% inhibition rate) compared with the positive control YC‐1. Meanwhile, compound 9o can also significantly inhibit the colony formation and survival rate of HCT‐116 cells. In addition, Western blotting, real‐time PCR and and lactic acid content experiments verified its inhibitory effect on HIF‐1α and downstream glycolysis. In addition, compound 9o was found to reduce platelet aggregation more than YC‐1, and the molecular docking results suggested that compound 9o weakened its interaction with soluble guanylate cyclase (sGC), which is beneficial for avoiding the bleeding risk during tumor treatment. In vivo studies have shown that compound 9o can inhibit tumor growth and reduce the levels of HIF‐1α and glycolysis rate‐limiting enzyme HK2 in HCT‐116 tumor‐bearing mice. The acute toxicity results also demonstrated the safety of compound 9o in vivo. Finally, we also explored its pharmacokinetic properties in rats, suggesting its potential for subsequent intravenous administration. These findings provide a basis for the further discovery of anti‐tumor candidate compounds based on HIF‐1α inhibitors.
Qixian Yang, Jing Zhang, Meijing Liu et al.· Drug development research (P...· 0 citations
A new series of benzothiazole–chalcone–indole
N
‐arylacetamide hybrids (
7a–e
) was designed, synthesized, and spectroscopically characterized as potential anticancer agents. Their antiproliferative activity was evaluated by MTT assay against HCT‐116, MCF‐7, HepG2, and Hep2 cancer cell lines, alongside normal WI‐38 fibroblasts. Compounds
7a
and
7d
exhibited the most potent and selective cytotoxicity, with low‐micromolar IC
50
values and selectivity indices exceeding that of doxorubicin. Lead compound
7a
significantly induced apoptosis and cell‐cycle arrest in MCF‐7 cells, as evidenced by increased apoptotic fraction, elevated sub‐G1 content, and accumulation of cells in the G2/M and S phases. It also showed strong antioxidant activity comparable to vitamin C. Mechanistic studies revealed upregulation of Bax, caspase‐3, ‐8, and ‐9, a slight reduction in Bcl‐2 and CDK expression, suggesting involvement of both intrinsic and extrinsic apoptotic pathways. Molecular docking predicted favorable binding of compound
7a
to BRAF, CDK6, EGFR, and c‐MET kinases, supporting its multitarget potential. Overall, compound
7a
represents a promising multitarget anticancer lead for further optimization.
Noha Yehia Badr, A. Almehdi, Mohamed A. Ragheb et al.· ChemistrySelect· 0 citations