Synthesis, characterization, and biological activity of some 2,4-diketo esters containing dehydrozingerone fragment: DNA and protein binding study.

Due to the increased resistance to antibiotics, in recent years there has been a growing interest in the discovery of new antimicrobial agents from different sources. Bacteria that are resistant to most antibiotics are a global public health concern. In order to find a new antimicrobial drug, we synthesized a small series of 2,4-diketo esters and tested them on some gram-positive and gram-negative bacterial strains. Two compounds showed very good antibacterial activity against Staphylococcus aureus and Bacillus subtilis, respectively. Trichophyton mentagrophytes proved to be the most sensitive of the tested species regarding antifungal activity. Also, research was conducted on the biomolecule of bovine serum albumin. Examining these interactions, we concluded that all compounds have the appropriate binding affinity for bovine serum albumin, which is vital. Furthermore, to investigate the potential antitumor activity, interactions with DNA were carried out. Examining the interactions between our compounds and DNA using fluorescence, we concluded that all but one of the compounds interacts with the DNA molecule by intercalation. In addition, a molecular docking study was performed to investigate the binding mode of the tested compounds to DNA and bovine serum albumin. In conclusion, all the results indicate a great potential for the future application of these compounds in clinical practice in the future.

Investigation of the radical scavenging potential of vanillin-based pyrido-dipyrimidines: experimental and in silico approach.

Antioxidants have a significant contribution in the cell protection against free radicals which may induce oxidative stress, and permanently damage the cells causing different disorders such as tumors, degenerative diseases, and accelerated aging. Nowadays, a multi-functionalized heterocyclic framework plays an important role in drug development, and it is of great importance in organic synthesis and medicinal chemistry. Encouraged by the bioactivity of the pyrido-dipyrimidine scaffold and vanillin core, herein, we made an effort to thoroughly investigate the antioxidant potential of the vanillin-based pyrido-dipyrimidines A-E to reveal novel promising free radical inhibitors. The structural analysis and the antioxidant action of the investigated molecules were performed in silico by DFT calculations. Studied compounds were screened for their antioxidant capacity using in vitro ABTS and DPPH assays. All the investigated compounds showed remarkable antioxidant activity, especially derivative A exhibiting inhibition of free radicals at the IC50 value (ABTS and DPPH assay 0.1 mg ml-1 and 0.081 mg ml-1, respectively). Compound A has higher TEAC values implying its stronger antioxidant activity compared to a trolox standard. The applied calculation method and in vitro tests confirmed that compound A has a strong potential against free radicals and may be a novel candidate for application in antioxidant therapy.

Anticancer potential of some ß-diketonates: DNA interactions, protein binding properties, and molecular docking study.

With the goal to discover a new antitumor drug with the better or similar effects to existing, a small series of ß-diketonate was tested on a cisplatin-resistant MDA-MB-231 and HeLa tumor cell lines, and nontumor MRC-5 cell line. All compounds showed notable cytotoxicity against both tumor cell lines and good selectivity. Importantly, ß-diketonates displayed greater selectivity than cisplatin, which is the crucial factor for a new antitumor drug candidate. Further, investigations with biomacromolecules such as DNA and serum albumin were performed. Investigations showed that tested compounds bind to DNA through intercalation and have appropriate affinity for binding to bovine serum albumin. In addition, the molecular docking study was performed to investigate more specifically the sites and binding mode of tested ß-diketonate to DNA or bovine serum albumin. In conclusion, all results indicated the big potential of these compounds for application in clinical practice in future.

Synthesis, characterization, antitumor potential, and investigation of mechanism of action of copper(ii) complexes with acylpyruvates as ligands: interactions with biomolecules and kinetic study.

Considering the urgency of finding a cure for vicious diseases such as tumors, we have synthesized and characterized a small series of new copper(ii) complexes with biologically important ligands such as acylpyruvate. In addition to this, we used another four copper(ii) complexes, with ligands of the same type to examine the antitumor potential. The antitumor potential of the copper(ii) complexes was examined on three tumor cell lines and one normal human cell line using the MTT assay. All seven tested complexes showed very good cytotoxic effects. Two copper complexes that showed the best antitumor potential were selected for further testing that showed the best potential for potential application in the future. The mechanism of activity of these complexes was examined in detail using tests such as cell cycle, ROS level, oxidative DNA damage, and proteins related to hypoxia analysis. In addition, we examined the binding abilities of these complexes with biomolecules (Guo, Ino, 5'-GMP, BSA, and DNA). The results showed that the tested compounds bind strongly to DNA molecules through intercalation. Also, it has been shown that the tested compounds adequately bind to the BSA molecule, which indicates an even greater potential for some future application of these compounds in clinical practice.

Synthesis, Characterization, and Biological Evaluation of Tetrahydropyrimidines: Dual-Activity and Mechanism of Action.

In this paper, the synthesis, characterization, and biological evaluation of the novel tetrahydropyrimidines-THPMs are described. THPMs are well-known for wide pharmacological activities such as antimicrobial, anticancer, antiviral, etc. This research includes obtained results of in vitro antimicrobial, anticancer, and α-glucosidase inhibitory activities of the eleven novel THPMs. An antibiotic assessment was done against five bacteria (two Gram-positive and three Gram-negative) and five fungi by determining the minimal inhibitory concentration (MIC), using the broth tube dilution method. The most active antibacterial compounds were 4a, 4b, and 4d, while the best antifungal activity was shown by 4e, 4f, and 4k. The lowest MIC value (0.20 mg/mL) was measured for 4e, 4f, and 4k against the Trichophyton mentagrophytes. Moreover, examining the α-glucosidase inhibitory activity revealed the compound 4g as the one with the best activity. The cytotoxic activity was performed on the tumor cell lines (HeLa, K562, and MDA-MB-231) and normal cells (MRC-5). The best antitumor activity was shown by compounds 4b and 4k against HeLa cell lines. The influence on cell cycle and mechanism of action of the most active compounds were examined too. Compound 4b had good antibacterial and anticancer activities, while 4k showed promising antifungal and anticancer activities.

A new class of half-sandwich ruthenium complexes containing Biginelli hybrids: anticancer and anti-SARS-CoV-2 activities.

In order to discover new dual-active agents, a series of novel Biginelli hybrids (tetrahydropyrimidines) and their ruthenium(II) complexes were synthesized. Newly synthesized compounds were characterized by IR, NMR, and X-ray techniques and investigated for their cytotoxic effect on human cancer cell lines HeLa, LS174, A549, A375, K562 and normal fibroblasts (MRC-5). For further examination of the cytotoxic mechanisms of novel complexes, two of them were chosen for analyzing their effects on the distribution of HeLa cells in the cell cycle phases. The results of the flow cytometry analysis suggest that the proportion of cells in G2/M phase was decreased following the increase of subG1 phase in all treatments. These results confirmed that cells treated with 5b and 5c were induced to undergo apoptotic death. The ruthenium complexes 5a-5d show significant inhibitory potency against SARS-CoV-2 Mpro. Therefore, molecule 5b has significance, while 5e possesses the lowest values of ΔGbind and Ki, which are comparable to cinanserin, and hydroxychloroquine. In addition, achieved results will open a new avenue in drug design for more research on the possible therapeutic applications of dual-active Biginelli-based drugs (anticancer-antiviral). Dual-active drugs based on the hybridization concept "one drug curing two diseases" could be a successful tactic in healing patients who have cancer and the virus SARS-CoV-2 at the same time.

Antioxidant and Antimicrobial Potential, BSA and DNA Binding Properties of Some 3-Hydroxy-3-Pyrrolin-2-Ones Bearing Thenoyl Fragment.

BACKGROUND: It is known that pyrrolidinone derivates belong to a class of biologically active compounds with a broad spectrum of biological actions. Nowadays, many scientists are making an effort in the discovery of more effective ways to eliminate reactive oxygen species (ROS) that cause oxidative stress or to eliminate the harmful microorganisms from the organism in humans. Therefore, pyrrolidinones seem to be great candidates for the research of this field. METHODS: The antimicrobial activity of tested compounds was estimated by the determination of the minimal inhibitory concentration by the broth micro-dilution method against four species of bacteria and five species of fungi. The antioxidant activity was evaluated by free radical scavenging and reducing power. RESULTS: Among the tested compounds, P22 showed marked antibacterial activity on Staphylococcus aureus with a MIC value of 0.312 mg/mL. Maximum antifungal activity with MIC value 0.625 mg/mL was shown by P23 and P25 compounds against Trichophyton mentagrophytes. Tested samples showed a relatively strong scavenging activity on DPPH radical (IC50 ranged from 166.75- 727.17 µg/mL). The strongest DPPH radical scavenging activity was shown by P3 compound with an IC50 value of 166.75 µg/mL. Moreover, the tested compounds had effective reducing power. Compounds P3, P10, and P13 showed the highest reducing power than those from the other samples. Results of the interactions between DNA and P3 indicated that P3 had the affinity to displace EB from the EB-DNA complex through intercalation [Ksv = (1.4 ± 0.1) × 105 M-1], while Ka values obtained via titration of BSA with P23 or P25 [Ka = (6.2 ± 0.2) and (5.0 ± 0.2) × 105 M-1] indicate that the notable quantity of the drug can be transmitted to the cells. CONCLUSION: Achieved results indicate that our compounds are potential candidates for use as medicaments.

Synthesis, Characterization, Antitumor Potential, BSA and DNA Binding Properties, and Molecular Docking Study of Some Novel 3-Hydroxy-3- Pyrrolin-2-Ones.

BACKGROUND: In order to make progress in discovering the new agents for cancer treatment with improved properties and considering the fact that 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, we tested series of eleven novels 1,5-diaryl-4-(2- thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones for their antitumor potential. METHODS: All novel compounds were characterized by spectral (IR, NMR, MS) and elemental analysis. All novel 3-hydroxy-3-pyrrolin-2-ones were screened for their cytotoxic activity on two cancer cell lines, SW480 and MDA-MB 231, and non-transformed fibroblasts (MRC-5). RESULTS: Compounds B8, B9, and B10 showed high cytotoxicity on SW480 cells together with good selectivity towards MRC-5 cells. It is important to empathize that the degree of selectivity of B8 and B10 was high (SI = 5.54 and 12.09, respectively). Besides, we explored the mechanisms of cytotoxicity of novel derivatives, B8, B9, and B10. The assay showed that tested derivatives induce an apoptotic type of cell death in SW480 cells, with a minor percent of necrotic cells. Additionally, to better understand the suitability of the compounds for potential use as anticancer medicaments, we studied their interactions with biomacromolecules (DNA or BSA). The results indicated that the tested compounds have a great affinity to displace EB from the EB-DNA complex through intercalation. Also, DNA and BSA molecular docking study was performed to predict the binding mode and the interaction region of the compounds. CONCLUSION: Achieved results indicate that our compounds have the potential to become candidates for use as medicaments.

Antitumor activity, DNA and BSA interactions of novel copper(II) complexes with 3,4-dihydro-2(1H)-quinoxalinones.

In order to discover new therapeutically active agents a series of novel copper(II) complexes with 3,4-dihydro-2(1H)-quinoxalinones were synthesized. All complexes were characterized by IR and EPR spectroscopic techniques and examined for their cytotoxic effect on human cancer cell lines HeLa, LS174, A549 and normal fibroblasts (MRC-5). For further examination of the cytotoxic mechanisms of novel complexes, three of them were chosen for analysing their effects on the distribution of HeLa cells in the cell cycle phases. The results of the flow cytometry analysis suggest that tested complexes lead to time-dependent accumulation of the cells in S and G2/M phases. The strongest accumulation effect showed complex 2d after 48 h of incubation. Competitive experiments with ethidium bromide (EB) indicated that tested compound 2d have affinity to displace EB from the EB-DNA complex through intercalation. Also, the binding parameters values for 2d-BSA complex showed that a reversible 2d-BSA complex is formed and ligand 2d can be stored and carried by BSA.