Alzheimer’s disease (AD) is a neurodegenerative disease associated with decreased activity of the cholinergic system in the brain. Identifying a drug that has no side effects and can prevent or delay the progression of this neurodegenerative disease is crucial. In this study, 11 novel pyrano[3,4-b]indole derivatives (ECA-ECM) were designed and synthesized as AChE and BChE inhibitors, and their structures were elucidated by spectroscopic analyses. Enzyme activity studies were conducted in vitro. Inhibitory potentials for both cholinesterase enzymes were determined by in silico analyses, and protein–ligand interactions were elucidated. The ECB compound (AChE IC50 = 35.31 ± 0.81 nM and BChE IC50 = 28.91 ± 0.19 nM) is a potential candidate as a dual AChE/BChE inhibitor. These findings indicate that the synthesized pyrano[3,4-b]indole derivatives have inhibitory potential for AD. The cytotoxic activities of the synthesized compounds were evaluated in vitro. The ECK compound showed a strong cytotoxic effect in five different human cancer cell lines in the ranging concentrations from 10.37 ± 1.43 to 29.34 ± 1.71 μM. The ECD compound exhibited strong cytotoxic activity at a concentration of 9.27 ± 0.97 μM in the colon cancer cell line. The cytotoxic activities of ECK and ECM were found to be below 25 μM in four human cancer cell lines. In silico analyses, including molecular docking, molecular dynamics simulations, and binding free energy calculations, confirmed that the synthesized compounds are potential candidates targeting AChE and BChE. Consequently, the synthesized compounds showed promising results for the treatment of AD and cancer.
Cancer continues to be a leading cause of global mortality, highlighting the ongoing need for novel anticancer compounds that offer high efficacy with improved side effect profiles. In the present study, a series of 3H-1,2-dithiole-3-thione derivatives (DTT-S1-18) were synthesized as promising anticancer agents, and the structures of products were confirmed by spectral techniques. H2S-releasing experiments showed that most of the compounds released higher amounts of H2S slowly over time compared to standard ADT-OH. All compounds were tested for antiproliferative activity on HT-29, PC-3, MCF-7, and HUVEC cell lines. Compounds DTT-S6 (3-nitrophenyl derivative) and DTT-S8 (methionine derivative) have the lowest IC50 values of 41.6 and 38.9 µM on the MCF-7 cell line, respectively. Based on the wound healing and colony formation assays performed in MCF-7 cells, the wound areas were not significantly changed after treatment with compounds DTT-S6 and DTT-S8, whereas compound DTT-S8 at double IC50 dose inhibited colony formation by 81.82%. In addition, molecular docking, MD simulations, MM/GBSA binding free energy calculations, and binary QSAR analyses were performed to explore the potential target interactions and predicted activity profiles of the synthesized compounds toward inflammation-related proteins, including COX-1, COX-2, 5-LOX, and iNOS, thereby supporting the development of mechanistic hypotheses for future validation. Furthermore, structure-activity relationship (SAR) analyses were conducted to correlate the structural characteristics of the synthesized compounds with their H2S releasing potential and biological profiles. Overall, this work integrates experimental anticancer evaluation with computational pathway and structure-based cancer/inflammation analyses to characterize novel DTT-based H2S donors. The findings identify particularly compound DTT-S8, as a promising in vitro anticancer candidate, while the computational results suggest a putative involvement of inflammation-related targets, particularly the COX-2/5-LOX axis, which requires direct biochemical and cellular validation.
Semra Altunsoy, Y. Yilmaz, T. Güngör et al.· Molecular diversity· 0 citations
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