Aug 2026· European journal of medicinal chemistry· Vol 318, pp.
119211
· 0 citations· 40 references
Medicine
TL;DR
Results suggested that 6h could be regarded as a promising lead compound against tubulin and FLT3 for further investigation.
Abstract
A novel series of 1H-pyrazole-3-amine derivatives was designed, synthesized, and their antitumor activities were evaluated. Among them, 6h showed potent antiproliferative activity against solid tumor cell lines and leukemia cell lines, with IC50 values ranging from 3.3 to 25.0 nM. Mechanism studies revealed that 6h could effectively inhibit microtubule polymerization (IC50 = 3.6 μM) via targeting the colchicine binding site and disrupted cellular microtubule networks. Notably, the preliminary kinase selectivity results showed 6h displayed selectivity for FLT3 kinase (IC50 = 58.6 nM) over other kinases screened, including the homologous c-KIT. Western blot analysis demonstrated that 6h inhibited the phosphorylation of FLT3 and its downstream signaling mediator STAT5 in MOLM-13 cells. 6h could induce tumor cell cycle arrest and apoptosis. Furthermore, in a MOLM-13 xenograft model, 6h at the dosage of 30 mg/kg exhibited effective antitumor activity without notable body-weight loss and the major organ damage. Pharmacokinetic evaluation of 6h in rats revealed an oral bioavailability of 5.6 %. Molecular docking and dynamics simulations supported stable binding modes of 6h with both tubulin and FLT3. Collectively, these results suggested that 6h could be regarded as a promising lead compound against tubulin and FLT3 for further investigation.
Structural–activity relationship analysis revealed the importance of the TZD core, electron-rich aromatic moieties, and balanced lipophilicity for enhanced anticancer activity, identifying TZD hybrids as promising EGFR-targeted anticancer leads.
Rajyalaxmi Injamuri, D. Makula· International journal of res...· 0 citations
Microtubule-targeting agents remain among the most effective chemotherapeutics for the treatment of cancer. Inspired by the natural tubulin polymerization inhibitor combretastatin A-4 (CA-4), a series of novel thiazolidine-2,4-dione derivatives was designed, synthesized, and evaluated as potential tubulin-targeting anticancer agents. The cytotoxic activities of the compounds were assessed against the MDA-MB-231, while human umbilical vein endothelial cells (HUVEC) were employed to evaluate selectivity. Compounds 2 and 3 emerged as the most active members of the series (IC50 = 3.60 and 3.71 μM, respectively), accompanied by remarkably high selectivity indices of 49.7 and 51.3. To elucidate their mechanism of action, compounds 2 and 3 were further evaluated in an in vitro tubulin polymerization assay. Compound 3 displayed the strongest inhibitory activity (IC50 = 1.07 μM), surpassing the reference inhibitor CA-4 (IC50 = 2.73 μM). Flow cytometric analysis showed that compound 3 induced G2/M cell-cycle arrest, increasing the G2/M population from 21.8% to 30.8%, and markedly promoted apoptosis, with total apoptotic cells increasing from 0.13% to 43.9% in MDA-MB-231 cells. Molecular docking and MM-GBSA calculations revealed favorable binding within the colchicine-binding site of tubulin, with compounds 2 and 3 exhibiting substantially stronger predicted binding affinities (ΔG = -89.53 and -92.86 kcal/mol, respectively) than CA-4 (ΔG = -70.08 kcal/mol). Molecular dynamics simulations confirmed the stability of the ligand-protein complexes throughout the simulation period, supporting the proposed binding mode. Furthermore, in silico ADME analysis suggested favorable drug-likeness, high predicted oral absorption, and improved pharmacokinetic characteristics compared with paclitaxel. The present study identifies compounds 2 and 3 as promising lead candidate that combines potent and selective antiproliferative activity, strong tubulin polymerization inhibition, and favorable binding characteristics.
F. S. Tokalı, Şeyma Ateşoğlu, Pelin Tokalı et al.· European journal of medicina...· 0 citations
Pyrazoles and chalcones have been extensively studied over time due to their broad range of therapeutic potentials. In this study, a new series of pyrazole-carboxylate derivatives were synthesized, characterized, and evaluated for their antibacterial, anticancer and anti-inflammatory activities. Among the synthesized derivatives, compound 5a exhibited significant percentage inhibition in colony counting assay. Compound 5c demonstrated significant cytotoxic activity with an IC50 value of 9.91 µg mL−1, while also exhibiting lower cytotoxicity towards non-cancerous HEK-293T cells (IC50 = 36.31 µg mL−1), indicating favourable selectivity. Mechanistic studies, including DAPI staining and flow cytometric analysis, indicated that compounds 5c and 5f inhibited cancer cell growth predominantly by inducing apoptosis rather than cell cycle arrest. Anti-inflammatory activity was determined using protein denaturation assay where compound 5f demonstrated promising activity with an IC50 value of 59.37 ± 0.149 µg mL−1. Furthermore, molecular docking analysis further provided insights into the binding interactions of the derivatives and the targeted protein. In addition, drug-likeness evaluation using swissADME indicates that the compounds satisfied Lipinski's rule of five.
Rachel Alveera Menezes, Navas Shereef Ellyan, M. M. et al.· RSC Advances· 0 citations
The current study devised and synthesized a novel class of pyrazole derivatives based on indole as possible inhibitors of cyclin‐dependent kinase‐2 (CDK‐2). 1H NMR, 13C NMR, NOESY, HMQC, and elemental analysis were used to confirm the structural integrity of the synthesized compounds. Promising CDK‐2 inhibitory activity was observed in biological assays, and numerous compounds exhibited sub‐micromolar IC50 values. Compound 5 d outperformed the reference inhibitor Roscovitine (IC50 = 0.716 µM) as the most potent inhibitor (IC50 = 0.536 µM), followed by compound 9 g (IC50 = 0.675 µM). SAR analysis showed that the observed activity was significantly influenced by the electronic nature of the added substituents as well as the orientation of the indole bond, with brominated derivatives exhibiting greater potency. The antiproliferative activity of the most potent compounds against the cancer cell lines HepG2, HCT‐116, and MCF‐7 was further assessed. In addition to having an enhanced selectivity index for normal MCF‐10A cells (SI = 8.00 vs. 4.96 for Roscovitine), compound 5 d had the greatest activity against MCF‐7 cells (IC50 = 6.78 µM), surpassing Roscovitine (IC50 = 8.11 µM). According to mechanistic investigations, compound 5 d significantly reduced the S‐phase population, markedly promoted apoptosis, and caused G1 and G2/M cell‐cycle arrest. Additionally, the consistent binding of compound 5 d within the ATP‐binding pocket of CDK‐2 was confirmed by molecular docking and molecular dynamics simulations, and attractive drug‐like and pharmacokinetic features, similar to those of Roscovitine, were demonstrated by in silico ADMET predictions. All of these results point to compound 5 d as a promising lead scaffold for developing potent CDK‐2‐targeted anticancer agents.
Wagdy M. Eldehna, Zainab M Elsayed, Mohamed R. Elnagar et al.· Drug development research (P...· 0 citations
The development of dual-directed anticancer agents has emerged as an effective strategy to simultaneously modulate tumor proliferation and angiogenesis while overcoming resistance associated with single-target therapies. In the present study, a novel series of benzofuran-based aryl urea derivatives incorporating a 1,3,4-thiadiazole linker were designed as dual VEGFR-2/BRAFWT inhibitors using sorafenib as a pharmacophoric template. The in vitro cytotoxic activity of the synthesized compounds against cervix HeLa, prostate PC-3, colon HCT-116, and breast MCF-7 cancer cell lines was evaluated. Most derivatives showed variable activity, with 5-bromobenzofuran analogues displaying superior potency. Compound 7j emerged as the most active analogue, with IC50 values of 7.83-13.27 μM and reduced toxicity toward normal lung fibroblast WI-38 cells. Enzymatic assays revealed potent dual inhibition of VEGFR-2 and BRAFWT by 7j (IC50 = 0.044 and 0.071 μM, respectively), outperforming sorafenib and vemurafenib. Mechanistic studies showed that 7j induced G2/M cell cycle arrest and promoted apoptosis in HeLa cells. This effect was associated with upregulation of BAX, p53, and caspase-9, downregulation of Bcl-2, and activation of the intrinsic apoptotic pathway. Additionally, in silico studies including molecular docking and molecular dynamics simulations demonstrated stable ligand-target interactions and favorable binding modes of 7j across both VEGFR-2 and BRAF, supporting the proposed hybrid design strategy. Overall, compound 7j represents a promising dual VEGFR-2/BRAFWT inhibitor and highlights benzofuran-based scaffolds as valuable platforms for anticancer drug development.
Marwa I Serag, Mohamed R. Elnagar, Wafaa A. Ewes et al.· Bioorganic & Medicinal Chemi...· 0 citations
A novel set of imidazo[2,1-b]thiazolediones 4a,b and 5a-d, with anticipated EGFR and IDO1 inhibition activities, was designed and prepared. These novel derivatives were evaluated in the NCI 60 cell line panel in which the superior compounds 5b and 5d were chosen for further evaluation of their five dose cytotoxicity toward the most sensitive cancer cells namely non-small cell lung cancer EKVX and HOP-92, breast HS 578 T, and normal WI-38 cells. The presence of a substituted benzylidene moiety at position-2 of the imidazothiazole scaffold in compounds 5a-d positively influences anticancer activity, with the phenylallylidene moiety at position-6 exhibiting superior cytotoxic effects compared to the 2-thienylidene moiety. Among the examined hybrids, 5d showed significant antiproliferative effect against HS 578 T tumor cell. To explore the underlying cell-death mechanisms, secondary biological evaluations were conducted, including cell-free EGFR and IDO1 enzymatic inhibition, apoptosis assay, and cell cycle analysis. In cell-free biochemical assays, the most active derivatives demonstrated a promising potential dual inhibitory profile against EGFR and IDO1, with compound 5d exhibiting sub-micromolar activity against both target enzymes, providing a plausible biochemical rationale for its potent cell killing. Furthermore, compound 5d induced cell cycle arrest at the G2/M phase and triggered apoptosis in HS 578 T cells, as supported by the up-regulation of Caspase-3 and Bax accompanied by the down-regulation of Bcl-2. In-silico ADMET profiling and molecular docking simulations further supported the favorable drug-like properties and binding modes of the key compounds within the target active sites. Overall, these findings highlight compound 5d as a promising lead candidate for further optimization and cellular mechanistic validation in anti-cancer drug discovery.
M. Sarg, Fatma G. Abdulrahman, Yasmin S. Sheta et al.· Bioorganic & Medicinal Chemi...· 0 citations