Nine novel thieno[2,3-b]pyridine derivatives were rationally designed and synthesized based on a versatile key intermediate, representing a promising lead compound for the development of novel BLM-targeted anti-prostate cancer agents.
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
Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising therapeutic target due to its critical roles in regulating fundamental cellular processes such as proliferation, migration, and differentiation. Although several PRMT5 inhibitors have been reported, but none have gained clinical approval. Herein, we describe the discovery of a novel series of benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ones derivatives as MTA cooperative PRMT5 inhibitors. Compound 9u exhibited significant antiproliferative activity in MTAP-deleted HCT116 cancer cells, with an IC50 value of 13 nM, exhibiting 70-fold selectivity over MTAP wild type HCT116 cells. Furthermore, 9u displayed robust efficacy across diverse MTAP-deleted cancer cell lines, achieving IC50 values of <1.5-51 nM. Notably, it also showed favorable metabolic stability in both human and mouse liver microsomes. These findings establish a promising lead for the development of PRMT5-MTA inhibitors specifically targeting MTAP-deficient cancers.
Bing Liu, Shao-Yan Li, Hui Shi et al.· Bioorganic chemistry (Print)· 0 citations
Cancer remains a leading cause of mortality worldwide, necessitating the continuous development of more effective and selective therapeutic agents. Among heterocyclic scaffolds, 1,3,4-thiadiazole derivatives have attracted considerable attention due to their diverse pharmacological properties and favorable physicochemical characteristics. In this study, a novel thiadiazole-based compound namely 2-((5-acetamido-1,3,4-thiadiazol-2-yl)thio)-N-(naphthalen-2-yl)acetamide, was successfully synthesized in excellent yield (99%) and high thermal stability and was fully structurally characterized using FT-IR, NMR, and mass spectrometry. The anticancer potential of the synthesized compound was evaluated in vitro against three human cancer cell lines, namely breast adenocarcinoma (MCF-7), colorectal carcinoma (HCT-116), and hepatocellular carcinoma (HepG-2), using the MTT assay. The compound exhibited pronounced cytotoxic activity against MCF-7 and HCT-116 cell lines, with IC50 values of 1.07 ± 0.03 µM and 2.09 ± 0.55 µM, respectively, demonstrating superior potency compared to the reference drug doxorubicin. In contrast, no significant activity was observed against HepG-2 cells, indicating a degree of selectivity. These findings highlight the potential of the 1,3,4-thiadiazole scaffold as a promising platform for the development of novel anticancer agents with enhanced efficacy and selectivity. In silico investigations, including molecular docking, molecular dynamics simulations, and MM/GBSA analysis, revealed stable binding of the synthesized compound within the VEGFR2 active site, supported by favorable binding free energy and key ligand–residue interactions.
Mostafa Sayed, Ehdaa Mohammed, Doha H. Aboubaker et al.· RSC Advances· 0 citations
It is demonstrated that benzofuran-furan-pyrano[2,3-c]pyrazole hybrids possess promising multifaceted in vitro anticancer activity by inhibiting cancer cell proliferation, migration, invasion, and clonogenicity while inducing ROS-mediated mitochondrial apoptosis, highlighting these hybrid scaffolds as attractive candidates for further anticancer drug development.
E. Hutanu, Bassam A. Najri, A. Abdelsalam et al.· RSC Advances· 0 citations
A series of novel pyrimidine-based benzothiazole/phenyl hybrids was rationally designed and synthesized via molecular hybridization to develop promising anticancer agents. The compounds were evaluated against human lung carcinoma (A549) and breast adenocarcinoma (MCF-7) cell lines, while HEK-293 cells were used to assess selectivity toward normal cells. Among the derivatives, K12, K5, and K4 showed potent activity against A549 cells, with IC50 values of 6.18, 7.01, and 7.54 μM, respectively. K5 and K12 also showed significant activity against MCF-7 cells, with IC50 values of 8.33 and 9.30 μM, respectively. All compounds displayed minimal cytotoxicity toward HEK-293 cells, indicating favorable selectivity for cancer cells. UV-Vis DNA-binding studies suggested a probable intercalative binding mode, while DNA nicking assays demonstrated protection against oxidative DNA damage. K12 showed the strongest DNA-binding affinity and DNA-protective activity. Molecular docking against the VEGFR-2 kinase domain (PDB ID: 4ASD), followed by 501 ns MD simulations, revealed stable protein-ligand complexes, supported by RMSD, RMSF, DCCM, PCA, and free energy landscape analyses. MM/GBSA calculations indicated favorable binding free energies, dominated by van der Waals interactions. Overall, K12 emerged as the most promising lead compound, combining potent antiproliferative activity, high selectivity, efficient DNA-binding characteristics, and robust computational performance, highlighting its potential for further development as a novel anticancer agent.
Karan Kamle, Shreyansh R. Mevada, Reena Hirani et al.· Bioorganic chemistry (Print)· 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
