Synthesis, Photophysical Properties, Theoretical Studies, and Living Cancer Cell Imaging Applications of New 7-(Diethylamino)quinolone Chalcones.

In this article, three unsymmetrical 7-(diethylamino)quinolone chalcones with D-π-A-D and D-π-A-π-D type push-pull molecular arrangements were synthesized via a Claisen-Schmidt reaction. Using 7-(diethylamino)quinolone and vanillin as electron donor (D) moieties, these were linked together through the α,ß-unsaturated carbonyl system acting as a linker and an electron acceptor (A). The photophysical properties were studied, revealing significant Stokes shifts and strong solvatofluorochromism caused by the ICT and TICT behavior produced by the push-pull effect. Moreover, quenching caused by the population of the TICT state in THF-H2O mixtures was observed, and the emission in the solid state evidenced a red shift compared to the emission in solution. These findings were corroborated by density functional theory (DFT) calculations employing the wb97xd/6-311G(d,p) method. The cytotoxic activity of the synthesized compounds was assessed on BHK-21, PC3, and LNCaP cell lines, revealing moderate activity across all compounds. Notably, compound 5b exhibited the highest activity against LNCaP cells, with an LC50 value of 10.89 µM. Furthermore, the compounds were evaluated for their potential as imaging agents in living prostate cells. The results demonstrated their favorable cell permeability and strong emission at 488 nm, positioning them as promising candidates for cancer cell imaging applications.

Using Quinolin-4-Ones as Convenient Common Precursors for a Metal-Free Total Synthesis of Both Dubamine and Graveoline Alkaloids and Diverse Structural Analogues.

The Rutaceae family is one of the most studied plant families due to the large number of alkaloids isolated from them with outstanding biological properties, among them the quinoline-based alkaloids Graveoline 1 and Dubamine 2. The most common methods for the synthesis of alkaloids 1 and 2 and their derivatives involves cycloaddition reactions or metal-catalyzed coupling processes but with some limitations in scope and functionalization of the quinoline moiety. As a continuation of our current studies on the synthesis and chemical transformation of 2-aminochalcones, we are reporting here an efficient metal-free approach for the total synthesis of alkaloids 1 and 2 along with their analogues with structural diversity, through a two-step sequence involving intramolecular cyclization, oxidation/aromatization, N-methylation and oxidative C-C bond processes, starting from dihydroquinolin-4-ones as common precursors for the construction of the structures of both classes of alkaloids.

Biological activity of lyophilized chitosan scaffolds with inclusion of chitosan and zinc oxide nanoparticles.

The constant demand for biocompatible and non-invasive materials for regenerative medicine in accidents and various diseases has driven the development of innovative biomaterials that promote biomedical applications. In this context, using sol-gel and ionotropic gelation methods, zinc oxide nanoparticles (NPs-ZnO) and chitosan nanoparticles (NPs-CS) were synthesized with sizes of 20.0 nm and 11.98 nm, respectively. These nanoparticles were incorporated into chitosan scaffolds through the freeze-drying method, generating a porous morphology with small (<100 µm), medium (100-200 µm), and large (200-450 µm) pore sizes. Moreover, the four formulations showed preliminary bioactivity after hydrolytic degradation, facilitating the formation of a hydroxyapatite (HA) layer on the scaffold surface, as evidenced by the presence of Ca (4%) and P (5.1%) during hydrolytic degradation. The scaffolds exhibited average antibacterial activity of F1 = 92.93%, F2 = 99.90%, F3 = 74.10%, and F4 = 88.72% against four bacterial strains: K. pneumoniae, E. cloacae, S. enterica, and S. aureus. In vivo, evaluation confirmed the biocompatibility of the functionalized scaffolds, where F2 showed accelerated resorption attributed to the NPs-ZnO. At the same time, F3 exhibited controlled degradation with NPs-CS acting as initiation points for degradation. On the other hand, F4 combined NPs-CS and NPs-ZnO, resulting in progressive degradation, reduced inflammation, and an organized extracellular matrix. All the results presented expand the boundaries in tissue engineering and regenerative medicine by highlighting the crucial role of nanoparticles in optimizing scaffold properties.

Graphene Oxide (GO) for the Treatment of Bone Cancer: A Systematic Review and Bibliometric Analysis.

Cancer is a severe disease that, in 2022, caused more than 9.89 million deaths worldwide. One worrisome type of cancer is bone cancer, such as osteosarcoma and Ewing tumors, which occur more frequently in infants. This study shows an active interest in the use of graphene oxide and its derivatives in therapy against bone cancer. We present a systematic review analyzing the current state of the art related to the use of GO in treating osteosarcoma, through evaluating the existing literature. In this sense, studies focused on GO-based nanomaterials for potential applications against osteosarcoma were reviewed, which has revealed that there is an excellent trend toward the use of GO-based nanomaterials, based on their thermal and anti-cancer activities, for the treatment of osteosarcoma through various therapeutic approaches. However, more research is needed to develop highly efficient localized therapies. It is suggested, therefore, that photodynamic therapy, photothermal therapy, and the use of nanocarriers should be considered as non-invasive, more specific, and efficient alternatives in the treatment of osteosarcoma. These options present promising approaches to enhance the effectiveness of therapy while also seeking to reduce side effects and minimize the damage to surrounding healthy tissues. The bibliometric analysis of photothermal and photochemical treatments of graphene oxide and reduced graphene oxide from January 2004 to December 2022 extracted 948 documents with its search strategy, mainly related to research papers, review papers, and conference papers, demonstrating a high-impact field supported by the need for more selective and efficient bone cancer therapies. The central countries leading the research are the United States, Iran, Italy, Germany, China, South Korea, and Australia, with strong collaborations worldwide. At the same time, the most-cited papers were published in journals with impact factors of more than 6.0 (2021), with more than 290 citations. Additionally, the journals that published the most on the topic are high impact factor journals, according to the analysis performed, demonstrating the high impact of the research field.

Evaluation of the Antibacterial, Anti-Cervical Cancer Capacity, and Biocompatibility of Different Graphene Oxides.

Cancer stands as one of the deadliest diseases in human history, marked by an inferior prognosis. While traditional therapeutic methods like surgery, chemotherapy, and radiation have demonstrated success in inhibiting tumor cell growth, their side effects often limit overall benefits and patient acceptance. In this regard, three different graphene oxides (GO) with variations in their degrees of oxidation were studied chemically and tissue-wise. The accuracy of the synthesis of the different GO was verified by robust techniques using X-ray photoelectron spectroscopy (XPS), as well as conventional techniques such as infrared spectroscopy (FTIR), RAMAN spectroscopy, and X-ray diffraction (XRD). The presence of oxygenated groups was of great importance. It affected the physicochemical properties of each of the different graphene oxides demonstrated in the presence of new vibrational modes related to the formation of new bonds promoted by the graphitization of the materials. The toxicity analysis in the Hep-2 cell line of graphene oxide formulations at 250 µg/mL on the viability and proliferation of these tumor cells showed low activity. GO formulations did not show high antibacterial activity against Staphylococcus aureus and Escherichia coli strains. However, the different graphene oxides showed biocompatibility in the subdermal implantation model for 30, 60, and 90 days in the biomodels. This allowed healing by restoring hair and tissue architecture without triggering an aggressive immune response.

Recent Advances in the Synthesis of Propargyl Derivatives, and Their Application as Synthetic Intermediates and Building Blocks.

The propargyl group is a highly versatile moiety whose introduction into small-molecule building blocks opens up new synthetic pathways for further elaboration. The last decade has witnessed remarkable progress in both the synthesis of propargylation agents and their application in the synthesis and functionalization of more elaborate/complex building blocks and intermediates. The goal of this review is to highlight these exciting advances and to underscore their impact.

N-Arylation of 3-Formylquinolin-2(1H)-ones Using Copper(II)-Catalyzed Chan-Lam Coupling.

3-formyl-2-quinolones have attracted the scientific community's attention because they are used as versatile building blocks in the synthesis of more complex compounds showing different and attractive biological activities. Using copper-catalyzed Chan-Lam coupling, we synthesized 32 new N-aryl-3-formyl-2-quinolone derivatives at 80 °C, in air and using inexpensive phenylboronic acids as arylating agents. 3-formyl-2-quinolones and substituted 3-formyl-2-quinolones can act as substrates, and among the products, the p-methyl derivative 9a was used as a substrate to obtain different derivatives such as alcohol, amine, nitrile, and chalcone.

Synthesis, Anticancer and Antitubercular Properties of New Chalcones and Their Nitrogen-Containing Five-Membered Heterocyclic Hybrids Bearing Sulfonamide Moiety.

A new series of sulfonamides, 8a-b, 10, 12, and 14a-b, were synthesized by N-sulfonation reaction with sulfonyl chlorides 6a-b. Five new series of chalcone-sulfonamide hybrids (16-20)a-f were prepared via Claisen-Schmidt condensation of the newly obtained sulfonamides with aromatic aldehydes 15a-f in basic medium. Chalcones substituted with chlorine at position 4 of each series were used as precursors for the generation of their five-membered heterocyclic pyrazoline (22-23)a-d, (24-25)a-b and carbothioamide 27a-f derivatives. The synthesized compounds were evaluated for their anticancer and antituberculosis activities. To determine their anticancer activity, compounds were screened against sixty human cancer cell lines at a single dose (10 µM). Compounds 17a-c were highly active against LOX IMVI (melanoma), with IC50 values of 0.34, 0.73 and 0.54 µM, respectively. Chalcone 18e showed remarkable results against the entire panel of leukemia cell lines with IC50 values between 0.99-2.52 µM. Moreover, compounds 20e and 20f displayed growth inhibition of Mycobacterium tuberculosis H37Rv at concentrations below 10 µM. Although they showed low selectivity in cytotoxicity tests against the Vero cell line, further optimization could advance the potential biological activity of the selected compounds.

QSAR Studies, Molecular Docking, Molecular Dynamics, Synthesis, and Biological Evaluation of Novel Quinolinone-Based Thiosemicarbazones against Mycobacterium tuberculosis.

In this study, a series of novel quinolinone-based thiosemicarbazones were designed in silico and their activities tested in vitro against Mycobacterium tuberculosis (M. tuberculosis). Quantitative structure-activity relationship (QSAR) studies were performed using quinolinone and thiosemicarbazide as pharmacophoric nuclei; the best model showed statistical parameters of R2 = 0.83; F = 47.96; s = 0.31, and was validated by several different methods. The van der Waals volume, electron density, and electronegativity model results suggested a pivotal role in antituberculosis (anti-TB) activity. Subsequently, from this model a new series of quinolinone-thiosemicarbazone 11a-e was designed and docked against two tuberculosis protein targets: enoyl-acyl carrier protein reductase (InhA) and decaprenylphosphoryl-ß-D-ribose-2'-oxidase (DprE1). Molecular dynamics simulation over 200 ns showed a binding energy of -71.3 to -12.7 Kcal/mol, suggesting likely inhibition. In vitro antimycobacterial activity of quinolinone-thiosemicarbazone for 11a-e was evaluated against M. bovis, M. tuberculosis H37Rv, and six different strains of drug-resistant M. tuberculosis. All compounds exhibited good to excellent activity against all the families of M. tuberculosis. Several of the here synthesized compounds were more effective than the standard drugs (isoniazid, oxafloxacin), 11d and 11e being the most active products. The results suggest that these compounds may contribute as lead compounds in the research of new potential antimycobacterial agents.

Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp.

P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure-activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4-7 and 12 is required for inhibition.

Design, synthesis, and molecular docking study of novel quinoline-based bis-chalcones as potential antitumor agents.

A novel series of quinoline-based symmetrical and unsymmetrical bis-chalcones was synthesized via a Claisen-Schmidt condensation reaction between 3-formyl-quinoline/quinolone derivatives with acetone or arylidene acetones, respectively, by using KOH/MeOH/H2 O as a reaction medium. Twelve of the obtained compounds were evaluated for their in vitro cytotoxic activity against 60 different human cancer cell lines according to the National Cancer Institute protocol. Among the screened compounds, the symmetrical N-butyl bis-quinolinyl-chalcone 14g and the unsymmetrical quinolinyl-bis-chalcone 17o bearing a 7-chloro-substitution on the N-benzylquinoline moiety and 4-hydroxy-3-methoxy substituent on the phenyl ring, respectively, exhibited the highest overall cytotoxicity against the evaluated cell lines with a GI50 range of 0.16-5.45 µM, with HCT-116 (GI50 = 0.16) and HT29 (GI50 = 0.42 µM) (colon cancer) representing best-case scenarios. Notably, several GI50 values for these compounds were lower than those of the reference drugs doxorubicin and 5-FU. Docking studies performed on selected derivatives yielded very good binding energies in the active site of proteins that participate in key carcinogenic pathways.

Synthesis of Biologically Active Molecules through Multicomponent Reactions.

Focusing on the literature progress since 2002, the present review explores the highly significant role that multicomponent reactions (MCRs) have played as a very important tool for expedite synthesis of a vast number of organic molecules, but also, highlights the fact that many of such molecules are biologically active or at least have been submitted to any biological screen. The selected papers covered in this review must meet two mandatory requirements: (1) the reported products should be obtained via a multicomponent reaction; (2) the reported products should be biologically actives or at least tested for any biological property. Given the diversity of synthetic approaches utilized in MCRs, the highly diverse nature of the biological activities evaluated for the synthesized compounds, and considering their huge structural variability, much of the reported data are organized into concise schemes and tables to facilitate comparison, and to underscore the key points of this review.

Synthesis, photophysical properties and theoretical studies of new bis-quinolin curcuminoid BF2-complexes and their decomplexed derivatives.

This paper presents the synthesis and characterization of two series of new bis-quinolin curcuminoid BF2-complexes 11 and their respective decomplexed bis-quinolin curcuminoid derivatives 12, in an attempt to understand their optical properties. The synthesized compounds showed interesting fluorescent characteristics in both solution and in solid-state. The characteristic of the electronic transitions involved in these systems were measured via Uv-vis spectroscopy and fluorescence spectroscopy. Results revealed that the absorption and emission bands are dependent of the structure of compounds 11 and 12 but also of the type of substituent, even showing a push-pull behavior in those derivatives substituted with methyl group. These findings were also confirmed through computational calculations at DFT level via simulations of the Uv-vis spectra and determining the topology of the border orbitals responsible for light absorption.

Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors.

Sphingosine-1-phosphate is now emerging as an important player in cancer, inflammation, autoimmune, neurological and cardiovascular disorders. Abundance evidence in animal and humans cancer models has shown that SphK1 is linked to cancer. Thus, there is a great interest in the development new SphK1 inhibitors as a potential new treatment for cancer. In a search for new SphK1 inhibitors we selected the well-known SKI-II inhibitor as the starting structure and we synthesized a new inhibitor structurally related to SKI-II with a significant but moderate inhibitory effect. In a second approach, based on our molecular modeling results, we designed new structures based on the structure of PF-543, the most potent known SphK1 inhibitor. Using this approach, we report the design, synthesis and biological evaluation of a new series of compounds with inhibitory activity against both SphK1 and SphK2. These new inhibitors were obtained incorporating new connecting chains between their polar heads and hydrophobic tails. On the other hand, the combined techniques of molecular dynamics simulations and QTAIM calculations provided complete and detailed information about the molecular interactions that stabilize the different complexes of these new inhibitors with the active sites of the SphK1. This information will be useful in the design of new SphK inhibitors.

Modeling the Antileukemia Activity of Ellipticine-Related Compounds: QSAR and Molecular Docking Study.

The antileukemia cancer activity of organic compounds analogous to ellipticine representes a critical endpoint in the understanding of this dramatic disease. A molecular modeling simulation on a dataset of 23 compounds, all of which comply with Lipinski's rules and have a structure analogous to ellipticine, was performed using the quantitative structure activity relationship (QSAR) technique, followed by a detailed docking study on three different proteins significantly involved in this disease (PDB IDs: SYK, PI3K and BTK). As a result, a model with only four descriptors (HOMO, softness, AC1RABAMBID, and TS1KFABMID) was found to be robust enough for prediction of the antileukemia activity of the compounds studied in this work, with an R2 of 0.899 and Q2 of 0.730. A favorable interaction between the compounds and their target proteins was found in all cases; in particular, compounds 9 and 22 showed high activity and binding free energy values of around -10 kcal/mol. Theses compounds were evaluated in detail based on their molecular structure, and some modifications are suggested herein to enhance their biological activity. In particular, compounds 22_1, 22_2, 9_1, and 9_2 are indicated as possible new, potent ellipticine derivatives to be synthesized and biologically tested.

Antimicrobial Activity of Quinoline-Based Hydroxyimidazolium Hybrids.

Eight quinoline-based hydroxyimidazolium hybrids 7a-h were prepared and evaluated in vitro against a panel of clinically important fungal and bacterial pathogens, including mycobacteria. Hybrid compounds 7c-d showed remarkable antifungal activity against Cryptococcus neoformans with a minimum inhibitory concentration (MIC) value of 15.6 µg/mL. Against other opportunistic fungi such as Candida spp. and Aspergillus spp., these hybrids showed MIC values of 62.5 µg/mL. Regarding their antibacterial activity, all the synthetic hybrids demonstrated little inhibition of Gram-negative bacteria (MIC ≥50 µg/mL), however, hybrid 7b displayed >50% inhibition against Klebsiella pneumoniae at 20 µg/mL and full inhibition at 50 µg/mL. Moreover, this hybrid was shown to be a potent anti-staphylococcal molecule, with a MIC value of 2 µg/mL (5 µM). In addition, hybrid 7h also demonstrated inhibition of Staphylococcus aureus at 20 µg/mL (47 µM). Hybrids 7a and 7b were the most potent against Mycobacterium tuberculosis H37Rv with MIC values of 20 and 10 µg/mL (46 and 24 µM), respectively. The 7b hybrid demonstrated high selectivity in killing S. aureus and M. tuberculosis H37Rv in comparison with mammalian cells (SI >20), and thus it can be considered a hit molecule for mechanism of action studies and the exploration of related chemical space.

A Schmidt rearrangement-mediated synthesis of novel tetrahydro-benzo[1,4]diazepin-5-ones as potential anticancer and antiprotozoal agents.

Novel tetrahydro-5H-benzo[e][1,4]diazepin-5-ones, several of them, containing the quinoline pharmacophore, were synthesized via a Schmidt rearrangement from their corresponding 1,2,3,4-tetrahydro-4-quinolones mediated by the NaN3/H2SO4 reaction conditions. Twelve of the obtained compounds were in vitro screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines, where compound 24a presented a remarkable activity against 58 of the 60 cancer cell lines, with the most important GI50 values ranging from 0.047 to 8.16 µM and LC50 values ranging from 9.4 to > 100 µM. Additionally, some of them were evaluated as antimalarial, antitrypanosomal and antileishmanial agents. The best antimalarial response was observed for compound 22g with an EC50 = 13.61 µg/mL for Plasmodium falciparum, while compound 24d exhibited high activity against Trypanosoma cruzi. and Leishmania (V) panamensis with EC50 = 2.78 µg/mL and 3.35 µg/mL respectively.

Microwave-Assisted Synthesis of Diversely Substituted Quinoline-Based Dihydropyridopyrimidine and Dihydropyrazolopyridine Hybrids.

An efficient, catalyst-free, and one-pot three-component procedure for the synthesis of novel and nitrogen rich dihydropyrido[2,3-d]pyrimidines and dihydro-1H-pyrazolo[3,4-b]pyridines bearing a quinoline pharmacophore fragment is provided. Reactions proceeded in DMF under microwave irradiation of three-component mixtures of formyl-quinoline derivatives, primary heterocyclic amines and cyclic 1,3-diketones. Interestingly, when conventional heating at reflux was used for the starting 5-amino-1-phenylpyrazole, the corresponding aromatized pyrazolopyridines were obtained as the main products. Single crystal X-ray analysis confirmed unequivocally the structure of both the dihydro- and aromatized products.

Synthesis of novel quinoline-2-one based chalcones of potential anti-tumor activity.

Novel quinoline-2-one based chalcones were synthesized from a Claisen-Schmidt condensation by using the couple KOH/1,4-dioxane as reaction medium. A relatively stable aldol was isolated and identified as the intermediate species in the formation of the target chalcones. Nine of the obtained compounds were in vitro screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines. Products 16c, 16d, 16h and 27 exhibited the highest activity, being compound 27 the most active, displaying remarkable activity against 50 human tumor cell lines, thirteen of them with GI(50) values ≤1.0 µM, being the HCT-116 (Colon, GI(50) = 0.131 µM) and LOX IMVI (Melanoma, GI(50) = 0.134 µM) the most sensitive strains. Compound 27 was referred to in vivo acute toxicity and hollow fiber assay by the Biological Evaluation Committee of the NCI. The acute toxicity study indicated that compound 27 was well tolerated intraperitoneally (150 mg/kg/dose) by athymic nude mice. This compound may possibly be used as lead compound for developing new anticancer agents.

Two closely related, and unexpected, quinolinone derivatives: a three-dimensional hydrogen-bonded framework structure and a hydrogen-bonded molecular ribbon of R(2)(2)(18) and R(4)(4)(24) rings.

1,5-Bis(4-chlorophenyl)-3-(2-oxo-1,2-dihydroquinolin-3-yl)pentane-1,5-dione, (Ia), and 1,5-bis(2-chlorophenyl)-3-(2-oxo-1,2-dihydroquinolin-3-yl)pentane-1,5-dione, (Ib), crystallize as an 84:16 mixture, 0.84C(26)H(19)Cl(2)NO(3)·0.16C(26)H(19)Cl(2)NO(3), in the space group I4(1)/a, where the molecules of the two isomers occupy very similar sites in the unit cell. A combination of one N-H...O hydrogen bond and one C-H...O hydrogen bond links the molecules, regardless of isomeric form, into a single three-dimensional framework structure. The molecules of (9RS,10RS)-8,9-bis(4-chlorobenzyl)-10-(2-oxo-1,2-dihydroquinolin-3-yl)-5,6,9,10-tetrahydrophenanthridine, C(36)H(22)Cl(2)N(2)O(4), (II), are linked by two hydrogen bonds, one each of the N-H...O and C-H...O types, into a molecular ribbon in which centrosymmetric rings of R(2)(2)(18) and R(4)(4)(24) types alternate. The hydrogen-bonded ribbons enclose channels, which contain highly disordered solvent molecules.