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This study focuses on the synthesis and structural characterization of new compounds that integrate thiazolidine-2,4-dione, acridine moiety, and an acetamide linker, aiming to leverage the synergistic effects of these pharmacophores for enhanced therapeutic potential. The newly designed molecules were efficiently synthesized through a multi-step process and subsequently transformed into their hydrochloride salts. Comprehensive spectroscopic techniques, including nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), infrared (IR) spectroscopy, and elemental analysis, were employed to determine the molecular structures of the synthesized compounds. Biological evaluations were conducted to assess the therapeutic potential of the new compounds. The influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC 50 values determined via MTT assays. An in-depth analysis of the structure-activity relationship (SAR) revealed intriguing insights into their cytotoxic profiles. Compounds with electron-withdrawing groups generally exhibited lower IC 50 values, indicating higher potency. The presence of the methoxy group at the linking phenyl ring modulated both the potency and selectivity of the compounds. The variation in the acridine core at the nitrogen atom of the thiazolidine-2,4-dione core significantly affects the activity against cancer cell lines, with the acridin-9-yl substituent enhancing the compounds' antiproliferative activity. Furthermore, compounds in their hydrochloride salt forms demonstrated better activity against cancer cell lines compared to their free base forms. Compounds 12c · 2HCl (IC 50 = 5.4 ± 2.4 μM), 13d (IC 50 = 4.9 ± 2.9 μM), and 12f · 2HCl (IC 50 = 4.98 ± 2.9 μM) demonstrated excellent activity against the HCT116 cancer cell line, and compound 7d · 2HCl (IC 50 = 4.55 ± 0.35 μM) demonstrated excellent activity against the HeLa cancer cell line. Notably, only a few tested compounds, including 7e · 2HCl (IC 50 = 11.00 ± 2.2 μM), 7f (IC 50 = 11.54 ± 2.06 μM), and 7f · 2HCl (IC 50 = 9.82 ± 1.92 μM), showed activity against pancreatic PATU cells. This type of cancer has a very high mortality due to asymptomatic early stages, the occurrence of metastases, and frequent resistance to chemotherapy. Four derivatives, namely, 7e · 2HCl , 12d · 2HCl , 13c · HCl , and 13d , were tested for their interaction properties with BSA using fluorescence spectroscopic studies. The values for the quenching constant ( K sv ) ranged from 9.59 × 10 4 to 10.74 × 10 4 M -1 , indicating a good affinity to the BSA protein.

Acridines possess two characteristics that have led many researchers to consider the agents interesting targets for future development as potential farmacophores: the planar acridine skeleton, which is able to intercalate into DNA, and the intense fluorescence of the agents. This review offers a study of the multifunctional character of acridines and the synthesis of novel acridine derivatives, with particular focus being placed on isothiocyanates and their congeners, e.g. thioureas, isothioureas, quaternary ammonium salts and platinum/gold conjugates. The review provides an overview of the structure, spectral properties, DNA binding and biological activity of acridinylthiourea congeners. These acridinylthiourea derivatives display significant cytotoxic activities against different types of cancer cell lines at micromolar concentrations. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Three new acridine-thiazolidinone derivatives (2a-2c) have been synthesized and their interactions with calf thymus DNA and a number of cell lines (leukemic cells HL-60 and L1210 and human epithelial ovarian cancer cell lines A2780) were studied. The compounds 2a-2c possessed high affinity to calf thymus DNA and their binding constants determined by spectrofluorimetry were in the range of 1.37 × 10(6)-5.89 × 10(6) M(-1). All of the tested derivatives displayed strong cytotoxic activity in vitro, the highest activity in cytotoxic tests was found for 2c with IC(50) = 1.3 ± 0.2 μM (HL-60), 3.1 ± 0.4 μM (L1210), and 7.7 ± 0.5 μM (A2780) after 72 h incubation. The cancer cells accumulated acridine derivatives very fast and the changes of the glutathione level were confirmed. The compounds inhibited proliferation of the cells and induced an arrest of the cell cycle and cell death. Their influence upon cells was associated with their reactivity towards thiols and DNA binding activity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

New acridine derivatives bearing two symmetrical imidazolidinone rings, 3,6-bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides 6a-6e (alkyl=ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl), have been prepared and their interactions with calf thymus DNA and selected cell lines were studied. The DNA-binding of 6a-6e to ctDNA was examined by UV-vis, fluorescence, and CD spectroscopy. The binding constants determined by UV-vis spectroscopy were found in the range 1.9×10(5)-7.1×10(5) M(-1). An electrophoretic separation proved that ligands 6a-6e inhibited topoisomerase I in 40 μM concentration although only those with longer alkyl chains were able to penetrate the membranes and efficiently suppress the cell proliferation. The highest activity in cytotoxic tests was found for 3,6-bis((1-n-hexyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochloride (6e) with IC(50)=2.12 μM (HL 60) and 5.28 μM (L1210) after 72 h incubation. Molecular dynamics simulations and calculations of solvent-accessible surface areas (SASAs) were used to explore the intercalation mechanism. MD simulations favor stacking between adjacent C:G base pairs from the minor groove side. MD and SASAs calculations indicate that the decrease of K with alkyl extension is due to negative entropic change upon binding., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A series of acridin-3,6-diyl-dithiourea hydrochloride derivatives (alkyl-AcrDTU) was prepared and tested against sensitive and drug resistant leukemia cell lines for their cytotoxic/cytostatic activity. The products (ethyl-, n-propyl-, n-butyl-, n-pentyl-AcrDTU) showed high DNA binding affinity via intercalation (K=7.6-2.9 x 10(5) M(-1)). All derivatives inhibited proliferation of HL-60 cells and its resistant subline HL-60/ADR, unexpectedly the resistant subline was more sensitive than the parental one (IC(50)=3.5 microM, 48-treatment of HL-60/ADR with pentyl-AcrDTU). Cytotoxicity of tested compounds was associated with their DNA-binding properties and the level of intracellular thiols has been changed in the presence of AcrDTU.

Ten novel, potentially intercalating 4-acridonecarboxamide azomethines and ketimines have been prepared by the condensation reaction of 9-oxo-9,10-dihydroacridine-4-carboxylic acid hydrazide with various aldehydes and ketones. The structures of the compounds were characterized spectroscopically by NMR ((1)H, (13)C, (15)N nuclei and 2D experiments), UV-vis, IR and fluorescence methods and by quantum chemical calculations using DFT at the B3LYP/6-311+G(d,p) level of theory and semiempirical ZINDO and AM1 methods. NMR chemical shift variations for C-4' were assessed due to changes in the polarizability of the imine C(4')=N(3') bond rather than direct inductive effects arising from the C-4' substituents. In concert with this was the reversed order observed for the N-3' chemical shifts with DFT-calculated atomic charges confirming the bond polarization. Both intra- and intermolecular hydrogen bonds between the acridone NH hydrogen and the amidic carbonyl oxygen were found to exist by FT-IR spectroscopy. Quantum chemical calculations were used to evaluate the configurational, tautomeric, conformational and hydrogen bonding states of the molecules as well as predict the NMR and IR data. The hypsochromic shifts observed in the UV-vis spectra upon changing from m-cresol to DMA, DMF or methanol were evaluated in terms of solvent polarity (giving rise to solvated excited state destabilization) and solvent aromaticity (giving rise to solvated excited state stabilization). The fluorescence of the compounds were modest, except for the 2,6-dichloro derivative, with respect to 9-isothiocyanatoacridine.

The synthesis of novel 1',1''-(acridin-3,6-diyl)-3',3''-dialkyldiureas was reported. Their biological activity to inhibit cell proliferation was assessed by a MTT assay on two cell lines, HeLa and HCT-116, at micromolar concentration. 1',1''-(Acridin-3,6-diyl)-3',3''-dihexyldiurea hydrochloride was active on a HCT-116 cell line with an IC(50) value of 3.1 microM. The interaction of these compounds with calf thymus DNA was investigated by a variety of spectroscopic techniques including UV-vis, fluorescence and CD spectroscopy. From spectrofluorimetric titrations, binding constants for the DNA-drug complexes were determined (K=0.9-4.2x10(5) M(-1)). Antiproliferative activity of synthesized derivatives might be related to their intercalation into DNA.

Novel acridine derivatives, wherein the steric factor has been varied systematically through substitution at the 9 position of the acridine ring, were evaluated as convenient fluorescent probes for nucleic acid detection. The binding affinities of N-(9-acridinylthiocarbamoyl)amino acids (ATA) with plasmid DNA (pUC 19) were investigated using UV-vis spectrophotometry, fluorometric titration and quantum chemical calculations (AM1). From spectrofluorometric analysis, the binding constants for the DNA-ATA complexes were determined. To elucidate its DNA intercalation, the most preferable tautomeric structure of ATA was established by means of AM1 calculations.

Isothiocyanates (ITCs) are phytochemicals with promising cancer-preventive potential. To elucidate the mechanism of cytotoxicity of ITCs, their accumulation by cells and the role of intracellular glutathione, fluorescent 9-isothiocyanatoacridine (AcITC) was synthesized. The kinetic parameters for the reactions of AcITC with thiols were estimated and the influence of AcITC on human chronic myeloid leukemia cell line (K562) in regard to intracellular glutathione was studied. Cytotoxicity was evaluated by MTT assay, IC(50)=29.2 +/- 2.5 microM (48 h incubation). This acridine derivative was able to induce apoptosis of cells (morphological changes of cells and DNA fragmentation were observed) at least within certain dose that only decreased the level of intracellular glutathione, excessive doses (completely depleted intracellular pool of glutathione) induced necrosis rather than apoptosis. Our results indicated that apoptosis of leukemia cells induced by ITC is possible only if intracellular glutathione is not entirely depleted.