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Letters in Drug Design & Discovery - Online First
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Synthesis of New Xanthene and Acridine Derivatives from Cyclohexan-1,3-dione and the Study of their Antiproliferative Activities
Authors: Rehab A. Ibrahim and Rafat M. MoharebAvailable online: 29 October 2024More LessBackgroundIonic immobilized liquids and multi-component reactions are integral to green chemistry, facilitating the synthesis of biologically active compounds, such as xanthene and acridine derivatives. These approaches have garnered significant attention in recent years.
ObjectiveThe aim of this study was to synthesize novel xanthene and acridine derivatives with diverse substituents and heterocyclic rings. Furthermore, the research sought to evaluate their anticancer activity against various cancer cell lines and analyze their structure-activity relationships (SAR) to determine how structural modifications impact their biological effectiveness.
MethodThe core compounds in this study were synthesized from cyclohexane-1,3-dione and triethoxymethane under two distinct reaction conditions. The first involved the use of a solvent with either Et3N or NH4OAc as a catalyst, while the second employed a solvent-free approach using an ionic liquid catalyst (ILs).
ResultsThe anti-proliferative activity of all synthesized compounds was evaluated against six selected cancer cell lines, revealing that many compounds exhibited significant inhibitory effects. Furthermore, their inhibitory potential against tyrosine kinases and Pim-1 kinases was assessed, along with an investigation of their mechanism of action on tyrosine kinases.
ConclusionThe anti-proliferative activity of the newly synthesized compounds was evaluated against six cancer cell lines. Many of the compounds exhibited strong inhibitory effects not only against the tested cancer cell lines but also against tyrosine kinases and Pim-1 kinases.
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Exploring the Antitumor Potential of New Indazole-indolizines Designed by Molecular Hybridization
Authors: Liliana Ciurlă-Lucescu, Elena Bîcu, Dalila Belei and Alina GhinetAvailable online: 21 October 2024More LessBackgroundCancer represents the major health problem faced by the population of the world, remaining one of the main causes of death. Hence, the development of new targeted antitumor drugs with high efficacy and lower toxicity is still needed.
ObjectiveAs a continuation of our work to discover new molecules with cytotoxic properties, two heterocyclic scaffolds, namely indolizine, and indazole, were combined in the same molecule, aiming to improve the bioactivity. This article focused on the synthesis, characterization, and biological evaluation of a series of new indazole-indolizine hybrid compounds.
MethodsThe biological potential of the synthesized compound was investigated in vitro against the human farnesyltransferase enzyme and NCI 60 tumor cell lines panel. While the farnesyltransferase inhibitory activity was modest, a very good antiproliferative action was observed for compound 4a, which, at a concentration of 10 µM, inhibited the growth of 20 types of cancer cells by more than 50% and showed cytotoxic action against the ovarian cancer cell line OVCAR-4.
ResultsA series of novel indazole-indolizine hybrids were synthesized via a [3+2] cycloaddition reaction, fully characterized and biologically evaluated for antitumor potential.
ConclusionCompound 4a could be a promising starting point in the development of new antitumoral agents. Further biological investigations will be performed to identify the biological target of the compounds. Moreover, different synthetic strategies to introduce new substituents on the indolizine core will be addressed.
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A Novel Drug Delivery Platform Against Bacterial Resistance: Synthesis and Characterization of Ciprofloxacin-loaded MCM-41 Mesoporous Silica Nanoparticle
Available online: 16 October 2024More LessBackgroundsAdvances in nanotechnology have revealed innovative applications in pharmaceutical sciences to solve unmet medical needs. Over the past decades, antibiotic resistance has emerged as a global concern. This catastrophic phenomenon, with a rapid increase in frequency, indicates the urgent need for the introduction of new approaches. In this respect, as a class of inorganic nanomaterials, mesoporous silica nanoparticles (MSNs) are of interest. Amongst, MCM-41 (MCM-Mobil Composition of Matter) possesses many advantages suitable for biomedical applications such as high pore volume, large surface area capacity, and controlled release properties as well as high bioavailability.
ObjectivesIn the current study, we aimed to develop a new drug delivery platform of ciprofloxacin (CIP) to combat antibiotic resistance practically using MSNs.
MethodsThe MCM-41 nanoparticles were synthesized using surfactant as the templating agent. Afterward, drug molecules were loaded in the prepared mesoporous structure, and several experiments were conducted to assess physicochemical properties. As well, the encapsulation efficiency, release profile, and antibacterial properties were also evaluated.
ResultsThe CIP-loaded MCM-41 (CIP@MCM-41) nanoparticles represented good physicochemical properties. The results of the DLS method showed a particle size of 93.73 nm with a low polydispersity index (PDI) of 0.21, while SEM imaging demonstrated spherical particles with relative shape uniformity and size distribution. The encapsulation efficacy of MCM-41 MSNs for CIP was measured to be 28.7% ± 0.37 followed by negligible changes over 60 days. The release profile of CIP from prepared nanoparticles was also demonstrated to follow the zero-order kinetic model. Moreover, CIP@MCM-41 nanoparticles exhibited high antibacterial properties against test microorganisms (Escherichia coli, Klebsiella pneumoniae, Staphylococcus epidermidis, and Micrococcus luteus).
ConclusionThe current formulation could be a promising candidate for the delivery of therapeutic agents to combat antibiotic resistance and promote public health.
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Design, Synthesis, Biological Evaluation, Molecular Docking, and Molecular Dynamics Simulation Studies of Fmoc-L-Lysine Carboxamides as Promising Cytotoxic Agents
Authors: Mahalakshmi C. S. Parepalli and Rajitha GallaAvailable online: 03 October 2024More LessBackgroundDespite advancements in treatment modalities, the search for new cytotoxic agents remains vital in the fight against cancer. This ongoing effort aims to introduce novel molecules that serve as potent cytotoxic agents while minimizing adverse effects.
ObjectiveThe objective of the study is to design, synthesize, and evaluate Fmoc-L-Lysine Carboxamides for cytotoxic activities.
MethodsThe title compounds 4a-l were synthesized by esterification followed by reduction of Fmoc-Lys (Boc)-OH to alcohol, then coupled with various aryl/alkyl/alicyclic carboxylic acids. These compounds were then analysed using 13C NMR, 1H NMR, FT-IR, and Mass spectroscopic techniques and evaluated for cytotoxic activity by MTT assay, apoptosis induction, cell cycle analysis, EGFR-TK inhibition activity, molecular docking, and molecular dynamics simulation studies.
ResultsThe results obtained by MTT assay indicated that compounds 4f and 4i demonstrated significant cytotoxicity against A549 and SKOV3 cell lines, with IC50 values of 2.75 and 1.91μM compared to doxorubicin. Further, the analysis of the Cell cycle and apoptosis proposed that 4f arrested the cell cycle in the G0/G1 phase, whereas 4i arrested the cell cycle in the G2/M phase and triggered apoptosis in cancer cells. Notably, compound 4i demonstrated the highest inhibition of EGFR with IC50, 0.189μM, and acted as its potential inhibitor. Molecular docking and dynamics simulation studies further confirmed the stability of 4i in the active site of EGFR.
ConclusionOverall, these results suggested that the synthesized derivatives offer a promising approach for the advancement of new and effective cancer therapies.
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A Theoretical Study on Derivatives of 1,2,4-trioxane as Potential Anti-malarials and an Analysis of the Mechanism of Drug Release in the Presence of Fe(III) Ions
Available online: 01 October 2024More LessIntroductionA mechanism has been proposed for the targeted transfer of an antimalarial drug, which involves 1, 2, and 4 trioxane (TRX) reagents. The trioxane ring is sensitive to ferrous iron, Fe)II(, and when exposed to it, it breaks down into smaller pieces, releasing the antimalarial drug mML (a mock form of DPA1 inhibitor ML4118S).
MethodThe oxane ring is attached to a nanoparticle called adamantane, which helps facilitate the reaction. The mechanism has been investigated using two reactants: TRX-R-mML and TRX-H-mML complexes (R is a side chain). The researcher used the transition state theory, the Hartree-Fock level (HF), and the ground state series 6-31G** to investigate the mechanism. The physicochemical and geometric properties of the components involved in the reaction were measured to explain the mechanism better.
ResultsThe results indicate that the R as a side chain significantly affects the mentioned mechanism and properties. Additionally, the results of the calculations show the stability of the complexes required as reactants in the reaction.
ConclusionThe TRX-mML-R complex has more strength, and polarity than TRX-mML-H, and the energy level of the transition state of TRX-mML-R is lower than that of TRX-mML-H, indicating faster passage of raw materials.
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