Synthesis and In vitro and In silico Anti-inflammatory Activity of New Thiazolidinedione-quinoline Derivatives.

BACKGROUND: Inflammation is a series of complex defense-related reactions. The inflammation cascade produces various pro-inflammatory mediators. Unregulated production of these pro-inflammatory mediators can lead to a wide range of diseases, including rheumatoid arthritis, sepsis, and inflammatory bowel disease. In the literature, the anti-inflammatory action of quinoline and thiazolidinedione nuclei are well established, alone, and associated with other nuclei. The synthesis of hybrid molecules is a strategy for obtaining more efficient molecules due to the union of pharmacophoric nuclei known to be related to pharmacological activity. OBJECTIVES: Based on this, this work presents the synthesis of thiazolidinedione-quinoline molecular hybrids and their involvement in the modulation of cytokines involved in the inflammatory reaction cascade. METHODS: After synthesis and characterization, the compounds were submitted to cell viability test (MTT), ELISA IFN-γ and TNF-α, adipogenic differentiation, and molecular docking assay with PPARy and COX-2 targets. RESULTS: LPSF/ZKD2 and LPSF/ZKD7 showed a significant decrease in the concentration of IFN- γ and TNF-α, with a dose-dependent behavior. LPSF/ZKD4 at a concentration of 50 µM significantly reduced IL-6 expression. LPSF/ZKD4 demonstrates lipid accumulation with significant differences between the untreated and negative control groups, indicating a relevant agonist action on the PPARγ receptor. Molecular docking showed that all synthesized compounds have good affinity with PPARγ e COX-2, with binding energy close to -10,000 Kcal/mol. CONCLUSION: These results demonstrate that the synthesis of quinoline-thiazolidinedione hybrids may be a useful strategy for obtaining promising candidates for new anti-inflammatory agents.

Synthesis of 4-(Phenylchalcogenyl)tetrazolo[1,5-a]quinolines by Bicyclization of 2-Azidobenzaldehydes with Phenylchalcogenylacetonitrile.

A general methodology to access valuable 4-(phenylchalcogenyl)tetrazolo[1,5-a]quinolines was developed by the reaction of 2-azidobenzaldehyde with phenylchalcogenylacetonitriles (sulfur and selenium) in the presence of potassium carbonate (20 mol%) as a catalyst. The reactions were conducted using a mixture of dimethylsulfoxide and water (7:3) as solvent at 80 °C for 4 h. This new methodology presents a good functional group tolerance to electron-deficient and electron-rich substituents, affording a total of twelve different 4-(phenylchalcogenyl)tetrazolo[1,5-a]quinolines selectively in moderate to excellent yields. The structure of the synthesized 4-(phenylselanyl)tetrazolo[1,5-a]quinoline was confirmed by X-ray analysis.

Synthesis and spectroscopic and structural characterization of three new 2-methyl-4-styrylquinolines formed using Friedländer reactions between (2-aminophenyl)chalcones and acetone.

Three new 2-methyl-4-styrylquinoline derivatives have been synthesized in high yields using Friedländer reactions between chalcones [1-(2-aminophenyl)-3-arylprop-2-en-1-ones] and acetone, and characterized using IR, 1H and 13C NMR spectroscopy, and mass spectrometry, and by crystal structure analysis. In (E)-4-(4-fluorostyryl)-2-methylquinoline, C18H14FN, (I), the molecules are joined into cyclic centrosymmetric dimers by C-H...N hydrogen bonds and these dimers are linked into sheets by π-π stacking interactions. The molecules of (E)-2-methyl-4-[4-(trifluoromethyl)styryl]quinoline, C19H14F3N, (II), are linked into cyclic centrosymmetric dimers by C-H...π hydrogen bonds and these dimers are linked into chains by a single π-π stacking interaction. There are no significant hydrogen bonds in the structure of (E)-4-(2,6-dichlorostyryl)-2-methylquinoline, C18H13Cl2N, (III), but molecules related by translation along [010] form stacks with an intermolecular spacing of only 3.8628 (2) Å. Comparisons are made with the structures of some related compounds.

Stereoselective Reduction of Alkynes: Synthesis of 4-Organoselenyl Quinolines.

This study describes the reaction of 2-amino arylalkynyl ketones with organoselenolates to form (Z)-vinyl selenides, which lead to 4-organoselenyl quinolines via an intramolecular condensation. Using the optimized reaction conditions, the generality of this cyclization was studied with various arylalkynyl ketones and diorganyl diselenides. The study of the reaction mechanisms led to the isolation and identification of a vinyl selenide, which was the key intermediate for this cyclization. To expand the structural diversity and to demonstrate the applicability of the 4-organoselenyl quinolines prepared, we studied their application as substrates in the cleavage of the carbon-selenium bond using n-butyllithium followed by the capture of the lithium intermediate by electrophiles and Suzuki and Sonogashira cross-coupling reactions.

Friedlӓnder's synthesis of quinolines as a pivotal step in the development of bioactive heterocyclic derivatives in the current era of medicinal chemistry.

In the current scenario of medicinal chemistry, quinoline plays a pivotal role in the design of new heterocyclic compounds with several pharmacological properties, so the search for new synthetic methodologies and their application in drug discovery has been widely studied. So far, many procedures have been performed for the preparation of quinoline scaffolds, among which Friedländer quinoline synthesis plays an important role in obtaining these heterocycles. The Friedländer reaction involves condensation between 2-aminobenzaldehydes and keto-compounds. The quinoline nucleus, once obtained through the Friedländer synthesis, has been extensively modified so that these derivatives can exhibit a large number of biological activities such as anticancer, antimalarial, antimicrobial, antifungal, antituberculosis, and antileishmanial properties. In this work, the focus is on the applicability of the Friedländer reaction in the synthesis of various types of bioactive heterocyclic quinoline compounds, which to date has not been reported in the context of medicinal chemistry. The main part of this review selectively focuses on research from 2010 to date and will present highlights of the Friedländer quinoline synthesis procedures and findings to address biological and pharmacological activities.

A simple quinoline salt derivative is active in vitro against Plasmodiumfalciparum asexual blood stages and inhibits the development of cerebral malaria in murine model.

Chloroquine (CQ) was the most effective and widely used drug for the prophylaxis and treatment of severe and non-severe malaria. Although its prophylactic use has led to resistance to P. falciparum in all endemic countries, CQ still remains the drug of choice for the treatment of vivax malaria. Otherwise, the speed in which parasite resistance to available antimalarials rises and spreads in endemic regions points to the urgent need for the development of new antimalarials. Quinoline derivatives have been used as a tool in the search for new drugs and were investigated in the present study in an attempt to produce a HIT compound to avoid the cerebral malarial (CM). Seven compounds were synthesized, including three quinoline derivate salts. The cytotoxicity and antiplasmodial activity were assayed in vitro, highlighting compound 3 as a HIT, which also showed interaction with ferriprotoporphyrin IX similarly to CQ. Physicochemical and pharmacokinetic properties of absorption were found to be favorable when analyzed in silico. The in vivo assays, using the experimental cerebral malaria (ECM) model, showed important values of parasite growth inhibition on the 7th day-post infection (Q15 15 mg/kg: 76.9%, Q30 30 mg/kg: 90,1% and Q50 50 mg/kg: 92,9%). Compound 3 also showed significant protection against the development of CM, besides hepatic and renal parameters better than CQ. In conclusion, this quinoline derivative demonstrated promising activity for the treatment of malaria and was able to avoid the development of severe malaria in mice.

1,2,3-Triazole- and Quinoline-based Hybrids with Potent Antiplasmodial Activity.

BACKGROUND: Malaria is a disease causing millions of victims every year and requires new drugs, often due to parasitic strain mutations. Thus, the search for new molecules that possess antimalarial activity is constant and extremely important. However, the potential that an antimalarial drug possesses cannot be ignored, and molecular hybridization is a good strategy to design new chemical entities. OBJECTIVE: This review article aims to emphasize recent advances in the biological activities of new 1,2,3-triazole- and quinoline-based hybrids and their place in the development of new biologically active substances. More specifically, it intends to present the synthetic methods that have been utilized for the syntheses of hybrid 1,2,3-triazoles with quinoline nuclei. METHODS: We have comprehensively and critically discussed all the information available in the literature regarding 1,2,3-triazole- and quinoline-based hybrids with potent antiplasmodial activity. RESULTS: The quinoline nucleus has already been proven to lead to new chemical entities in the pharmaceutical market, such as drugs for the treatment of malaria and other diseases. The same can be said about the 1,2,3-triazole heterocycle, which has been shown to be a beneficial scaffold for the construction of new drugs with several activities. However, only a few triazoles have entered the pharmaceutical market as drugs. CONCLUSION: Many studies have been conducted to develop new substances that may circumvent the resistance developed by the parasite that causes malaria, thereby improving the therapy currently used.

Total Synthesis of Decahydroquinoline Poison Frog Alkaloids ent-cis-195A and cis-211A.

The total synthesis of two decahydroquinoline poison frog alkaloids ent-cis-195A and cis-211A were achieved in 16 steps (38% overall yield) and 19 steps (31% overall yield), respectively, starting from known compound 1. Both alkaloids were synthesized from the common key intermediate 11 in a divergent fashion, and the absolute stereochemistry of natural cis-211A was determined to be 2R, 4aR, 5R, 6S, and 8aS. Interestingly, the absolute configuration of the parent decahydroquinoline nuclei of cis-211A was the mirror image of that of cis-195A, although both alkaloids were isolated from the same poison frog species, Oophaga (Dendrobates) pumilio, from Panama.

One-Pot Multicomponent Synthesis of Methoxybenzo[h]quinoline-3-carbonitrile Derivatives; Anti-Chagas, X-ray, and In Silico ADME/Tox Profiling Studies.

Several methoxybenzo[h]quinoline-3-carbonitrile analogs were designed and synthesized in a repositioning approach to developing compounds with anti-prostate cancer and anti-Chagas disease properties. The compounds were synthesized through a sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-tetralone in the presence of ammonium acetate and acetic acid (catalytic). The effect of the one-pot method on the generation of the target product has been studied. The compounds were in vitro screened against bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and were most effective at showing a better activity profile than nifurtimox and benznidazole (reference drugs). A study in silico on absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) profiling to help describe the molecular properties related to the pharmacokinetic aspects in the human body of these compounds was reported. In addition, X-ray data for the compound 2-Amino-5,6-dihydro-4-(3-hydroxy-4-methoxy-phenyl)-8-methoxybenzo[h]quinoline-3-carbonitrile 6 was being reported. Spectral (IR, NMR, and elemental analyses) data on all final compounds were consistent with the proposed structures.

Synthetic enamine naphthoquinone derived from lawsone as cytotoxic agents assessed by in vitro and in silico evaluations.

We synthesized ten enamine naphthoquinones with yields ranging from 43 to 76%. These compounds were screened for their in vitro antiproliferative activities by MTT assay against four types of human cancer cell lines: HCT116, PC3, HL60 and SNB19. The naphthoquinones bearing the picolylamine (7) and quinoline (12) moieties were the most actives (IC50 < 24 µM for all the cell lines), which were comparable or better to the values obtained for the control drugs. In silico evaluations allowed us to develop a qualitative Structure-Activity Relationship which suggest that electrostatic features, particularly the C2-C3 internuclear repulsion and the molecular dipole moment, relate to the biological response. Furthermore, Molecular Docking simulations indicate that the synthetic compounds have the potential to act as anticancer molecules by inhibiting topoisomerase-II and thymidylate synthase.

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.

A DNA intercalating dye-based RT-qPCR alternative to diagnose SARS-CoV-2.

Early detection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been proven crucial during the efforts to mitigate the effects of the COVID-19 pandemic. Several diagnostic methods have emerged in the past few months, each with different shortcomings and limitations. The current gold standard, RT-qPCR using fluorescent probes, relies on demanding equipment requirements plus the high costs of the probes and specific reaction mixes. To broaden the possibilities of reagents and thermocyclers that could be allocated towards this task, we have optimized an alternative strategy for RT-qPCR diagnosis. This is based on a widely used DNA-intercalating dye and can be implemented with several different qPCR reagents and instruments. Remarkably, the proposed qPCR method performs similarly to the broadly used TaqMan-based detection, in terms of specificity and sensitivity, thus representing a reliable tool. We think that, through enabling the use of vast range of thermocycler models and laboratory facilities for SARS-CoV-2 diagnosis, the alternative proposed here can increase dramatically the testing capability, especially in countries with limited access to costly technology and reagents.

Synthesis and antimalarial and anticancer evaluation of 7-chlorquinoline-4-thiazoleacetic derivatives containing aryl hydrazide moieties.

Twelve 7-chloroquinoline derivatives were designed and synthesized using the principle of molecular hybridization through the coupling of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]acetic acid 1 with various benzoyl hydrazines 2a-l. The synthetic compounds were tested as antimalarials. Some of them showed an efficient in vitro activity as inhibitors of ß-hematin formation and an in vivo activity in a murine model, resulting in compounds 8 and 9 as the most active ones with IC50 values of 0.65 ± 0.09 and 0.64 ± 0.16 µM, respectively. The effects of the compounds on the cell viability, cell cycle, and apoptosis induction of A549 and MCF-7 cancer cell lines were also examined. Our data showed that compounds 6 and 12 were the most active agents, decreasing the cell viability of MCF-7 cells with IC50 values of 15.41 and 12.99 µM, respectively. None of the compounds analyzed significantly affected the viability of peripheral blood mononuclear cells. Also, significant induction of apoptosis was observed when both cancer cell lines were incubated with compounds 6 and 12. In MCF-7 cells, treatment with these compounds led to cell cycle arrest in the G0/G1 phase. The results obtained suggest that these structures may be useful in developing new therapies for malaria and cancer treatment.

Computational evidence for nitro derivatives of quinoline and quinoline N-oxide as low-cost alternative for the treatment of SARS-CoV-2 infection.

A new and more aggressive strain of coronavirus, known as SARS-CoV-2, which is highly contagious, has rapidly spread across the planet within a short period of time. Due to its high transmission rate and the significant time-space between infection and manifestation of symptoms, the WHO recently declared this a pandemic. Because of the exponentially growing number of new cases of both infections and deaths, development of new therapeutic options to help fight this pandemic is urgently needed. The target molecules of this study were the nitro derivatives of quinoline and quinoline N-oxide. Computational design at the DFT level, docking studies, and molecular dynamics methods as a well-reasoned strategy will aid in elucidating the fundamental physicochemical properties and molecular functions of a diversity of compounds, directly accelerating the process of discovering new drugs. In this study, we discovered isomers based on the nitro derivatives of quinoline and quinoline N-oxide, which are biologically active compounds and may be low-cost alternatives for the treatment of infections induced by SARS-CoV-2.

Quinoline: An Attractive Scaffold in Drug Design.

Quinoline and its derivatives comprise an important group of heterocyclic compounds that exhibits a wide range of pharmacological properties such as antibacterial, antiviral, anticancer, antiparasitic, anti-Alzheimer and anticholesterol. The quinoline nucleus is found in the structure of many drugs and rational design in medicinal chemistry for the discovery of novel bioactive molecules. Persistent efforts have been made over the years to develop novel congeners with superior biological activities and minimal potential for undesirable side effects. This review highlights some discoveries on the development of quinoline-based compounds in recent years (2013-2019), focusing on their biological activities, including anticancer, antitubercular, antimalarial, anti-ZIKV, anti-DENV, anti- Leishmania and anti-Alzheimer's disease.

7-Amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes]: Synthesis and cholinesterase inhibitory activity of structurally modified tacrines.

Five new examples of 9,10-chloro(bromo)-7-amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes] - in which cycloalkanes = cyclopentane, cyclohexane, and cycloheptane - were synthesized at yields of 42-56%, using a sequential one-pot two-step cyclocondensation reaction of three different scaffolds of 2-aminobenzonitriles and the respective spiro[chroman-2,1'-cycloalkan]-4-ones, and using AlCl3 as the catalyst in a solvent-free method. Subsequently, the five new spirochromeno-quinolines and nine quinolines previously published by us (14 modified tacrine scaffolds) were subjected to AChE and BChE inhibitory activity evaluation. The molecule containing a spirocyclopentane derivative had the highest AChE and BChE inhibitory activity (IC50 = 3.60 and 4.40 µM, respectively), and in general, the non-halogenated compounds were better inhibitors of AChE and BChE than the halogenated molecules. However, the inhibitory potency of compounds 3a-n was weaker than that of tacrine. By molecular docking simulations, it was found that the size of the spirocarbocyclic moieties is inversely proportional to the inhibitory activity of the cholinesterases, probably because an increase in the size of the spirocyclic component sterically hindered the interaction of tacrine derivatives with the active site of tested cholinesterases. The findings obtained here may help in the design and development of new anticholinesterase drugs.

Dihydroquinoline derivative as a potential anticancer agent: synthesis, crystal structure, and molecular modeling studies.

Cancer is one of the leading causes of death worldwide and requires intense and growing research investments from the public and private sectors. This is expected to lead to the development of new medicines. A determining factor in this process is the structural understanding of molecules with potential anticancer properties. Since the major compounds used in cancer therapies fail to encompass every spectrum of this disease, there is a clear need to research new molecules for this purpose. As it follows, we have studied the class of quinolinones that seem effective for such therapy. This paper describes the structural elucidation of a novel dihydroquinoline by single-crystal X-ray diffraction and spectroscopy characterization. Topology studies were carried through Hirshfeld surfaces analysis and molecular electrostatic potential map; electronic stability was evaluated from the calculated energy of frontier molecular orbitals. Additionally, in silico studies by molecular docking indicated that this dihydroquinoline could act as an anticancer agent due to their higher binding affinity with human aldehyde dehydrogenase 1A1 (ALDH 1A1). Tests in vitro were performed for VERO (normal human skin keratinocytes), B16F10 (mouse melanoma), and MDA-MB-231 (metastatic breast adenocarcinoma), and the results certified that compound as a potential anticancer agent. A Dihydroquinoline derivative was tested against three cancer cell lines and the results attest that compound as potential anticancer agent.

Role of 7-chloro-4-(phenylselanyl) quinoline in the treatment of oxaliplatin-induced hepatic toxicity in mice.

There is an increasing incidence of hepatotoxicity induced by oxaliplatin (OXA); therefore, researchers' attention has been drawn to therapeutic alternatives that may decrease OXA-induced hepatotoxicity. Studies indicate that oxidative stress plays a major role in OXA-induced liver injury. As several pharmacological effects of 7-chloro-4-(phenylselanyl) quinole (4-PSQ) involve its antioxidant action, the hypothesis that this organoselenium compound could be promising for the treatment or prevention of hepatotoxicity induced by treatment with OXA was investigated. To test this hypothesis, male Swiss mice received OXA (10 mg·kg-1) on days 0 and 2, followed by oral administration of 4-PSQ (1 mg·kg-1) on days 2 to 14. 4-PSQ reduced the plasma aspartate, and alanine aminotransferase activity increased by exposure to OXA. The histopathological examination of the liver showed that 4-PSQ markedly improved OXA-induced hepatic injury. In addition, treatment with 4-PSQ reduced the oxidation of lipids and proteins (thiobarbituric acid reactive species levels and protein carbonyl content) and attenuated the increase of hepatic catalase and glutathione peroxidase activity caused by OXA. The inhibition of hepatic δ-aminolevulinic dehydratase activity induced by OXA was reverted by 4-PSQ. In conclusion, results indicate that 4-PSQ may be a good therapeutic strategy for attenuating OXA-induced liver damage.

Antileishmanial activity of synthetic analogs of the naturally occurring quinolone alkaloid N-methyl-8-methoxyflindersin.

Leishmaniasis is a neglected, parasitic tropical disease caused by an intracellular protozoan from the genus Leishmania. Quinoline alkaloids, secondary metabolites found in plants from the Rutaceae family, have antiparasitic activity against Leishmania sp. N-methyl-8-methoxyflindersin (1), isolated from the leaves of Raputia heptaphylla and also known as 7-methoxy-2,2-dimethyl-2H,5H,6H-pyran[3,2-c]quinolin-5-one, shows antiparasitic activity against Leishmania promastigotes and amastigotes. This study used in silico tools to identify synthetic quinoline alkaloids having structure similar to that of compound 1 and then tested these quinoline alkaloids for their in vitro antiparasitic activity against Leishmania (Viannia) panamensis, in vivo therapeutic response in hamsters suffering from experimental cutaneous leishmaniasis (CL), and ex vivo immunomodulatory potential in healthy donors' human peripheral blood (monocyte)-derived macrophages (hMDMs). Compounds 1 (natural), 2 (synthetic), and 8 (synthetic) were effective against intracellular promastigotes (9.9, 3.4, and 1.6 µg/mL medial effective concentration [EC50], respectively) and amastigotes (5.07, 7.94, and 1.91 µg/mL EC50, respectively). Compound 1 increased nitric oxide production in infected hMDMs and triggered necrosis-related ultrastructural alterations in intracellular amastigotes, while compound 2 stimulated oxidative breakdown in hMDMs and caused ultrastructural alterations in the parasite 4 h posttreatment, and compound 8 failed to induce macrophage modulation but selectively induced apoptosis of infected hMDMs and alterations in the intracellular parasite ultrastructure. In addition, synthetic compounds 2 and 8 improved the health of hamsters suffering from experimental CL, without evidence of treatment-associated adverse toxic effects. Therefore, synthetic compounds 2 and 8 are potential therapeutic candidates for topical treatment of CL.

Protein quantification by bicinchoninic acid (BCA) assay follows complex kinetics and can be performed at short incubation times.

Amongst the available methodologies for protein determination, the bicinchoninic acid (BCA) assay highlights for its simplicity, sensitivity, repeatability and reproducibility. Nevertheless, in spite that the general principle behind this methodology is known, there are still unanswered questions regarding the chemistry behind the assay and the experimental conditions commonly employed. The present work explored the kinetics, and the analytical response of the assay to free amino acids, peptides (containing tryptophan and tyrosine), and proteins. Results revealed kinetic profiles characterized by the absence of plateaus, with behaviors depending on the type of the sample. The latter, along with contribution to the BCA index elicited by oxidation products generated at the side chain of tryptophan and tyrosine, as well as pre-oxidized ß-casein, evidenced the presence of complex reaction mechanisms. In spite of such complexity, our results showed that the BCA index is not modulated by the incubation time. This applies for responses producing absorbance intensities (at 562 nm) higher than 0.1. Therefore, we propose that the assay can be applied at shorter incubation times (15 min) than those indicated in manufactures specifications, and usually used by researches and industry (30 min at 37 °C).