Series Of New Quinoline Derivatives Research Articles

Design, synthesis and antimicrobial activity of novel quinoline derivatives: an in silico and in vitro study

A series of new quinoline derivatives has been designed, synthesized and evaluated as antibacterial and antifungal agents functioning as peptide deformylase enzyme (PDF) inhibitors and fungal cell wall disruptors on the basis of computational and experimental methods. The molecular docking and ADMET assessment aided in the synthesis of quinoline derivatives starting from 6-amino-4-methyl-1H-quinoline-2-one substituted with different types of sulfonyl/benzoyl/propargyl moieties. These newly synthesized compounds were evaluated for their in vitro antibacterial and antifungal activity. Antibacterial screening of all compounds showed excellent MIC value (MIC, 50 − 3.12 µg/mL) against bacterial strains, viz. Bacillus cerus, Staphylococcus, Pseudomonas and Escherichia coli. Compounds 2 and 6 showed better activity. Fractional inhibitory concentration (FIC) values of compounds were lowered by 1/2 to 1/128 of the original MIC values when a combinatorial screening with reference drugs was performed. Further, antifungal screening against fungal strains, viz. A. flavus, A. niger, F. oxysporum and C. albicans also showed that all compounds were potentially active and compound 6 being the most potent. Further, the cytotoxicity experiments revealed that compound 6 was the least toxic molecule. The molecular dynamics (MD) simulation investigations elucidated the conformational stability of compound 6-PDF complex with flexible binding pocket residues. The highest number of stable hydrogen bonds with the PDF residues during the entire simulation time illustrated strong binding affinity of compound 6 with PDF. Communicated by Ramaswamy H. Sarma

BIOLOGICAL ACTIVITY AND DRUG LIKE SCORE OF NEW SYNTHESIZED QUINOLINE DERIVATIVES INCORPORATED WITH PYRIDINE AND 1,3,4 - THIADIAZOLE MOIETY

A new series of quinoline derivatives has been synthesized by two different methods. In the first methods, 6-subtituted 2-(pyridin-3/4-yloxy) quinoline-3-carbaldehyde 2 was reduced with NaBH4 in methanol and then reacted with thionylchloride in DMC to give 3 which on chloramines coupling with 1,3,4 thiadiazole derivatives to give final compounds 5a-l. In the second methods, 6-substituted 2-(pyridin-3/4-yloxy) quinoline-3-carbaldehyde formed Schiff base 4 with 1,3,4 thiadiazole derivatives which on reduction with NaBH4 in DMC give 5a-l as final compounds. The synthesized compounds were confirmed for their structure by IR, 13C NMR, 1 H NMR and mass spectroscopic methods. All the synthesized compounds were evaluated for antimicrobial activity and their bioactivity score determined by Molinspiration cheminformatics software. From all the compounds, 5b, 5h and 5l have shown significant activity as compared to standard drugs.

Synthesis of new series of quinoline derivatives with insecticidal effects on larval vectors of malaria and dengue diseases

Mosquito borne diseases are on the rise because of their fast spread worldwide and the lack of effective treatments. Here we are focusing on the development of a novel anti-malarial and virucidal agent with biocidal effects also on its vectors. We have synthesized a new quinoline (4,7-dichloroquinoline) derivative which showed significant larvicidal and pupicidal properties against a malarial and a dengue vector and a lethal toxicity ranging from 4.408 µM/mL (first instar larvae) to 7.958 µM/mL (pupal populations) for Anopheles stephensi and 5.016 µM/mL (larva 1) to 10.669 µM/mL (pupae) for Aedes aegypti. In-vitro antiplasmodial efficacy of 4,7-dichloroquinoline revealed a significant growth inhibition of both sensitive strains of Plasmodium falciparum with IC50 values of 6.7 nM (CQ-s) and 8.5 nM (CQ-r). Chloroquine IC50 values, as control, were 23 nM (CQ-s), and 27.5 nM (CQ-r). In vivo antiplasmodial studies with P. falciparum infected mice showed an effect of 4,7-dichloroquinoline compared to chloroquine. The quinoline compound showed significant activity against the viral pathogen serotype 2 (DENV-2). In vitro conditions and the purified quinoline exhibited insignificant toxicity on the host system up to 100 µM/mL. Overall, 4,7-dichloroquinoline could provide a good anti-vectorial and anti-malarial agent.

Design, synthesis, and molecular dynamics simulation studies of quinoline derivatives as protease inhibitors against SARS-CoV-2

A new series of quinoline derivatives has been designed and synthesized as probable protease inhibitors (PIs) against severe acute respiratory syndrome coronavirus 2. In silico studies using DS v20.1.0.19295 software have shown that these compounds behaved as PIs while interacting at the allosteric site of target Mpro enzyme (6LU7). The designed compounds have shown promising docking results, which revealed that all compounds formed hydrogen bonds with His41, His164, Glu166, Tyr54, Asp187, and showed π-interaction with His41, the highly conserved amino acids in the target protein. Toxicity Prediction by Komputer Assisted Technology results confirmed that the compounds were found to be less toxic than the reference drug. Further, molecular dynamics simulations were performed on compound 5 and remdesivir with protease enzyme. Analysis of conformational stability, residue flexibility, compactness, hydrogen bonding, solvent accessible surface area (SASA), and binding free energy revealed comparable stability of protease:5 complex to the protease: remdesivir complex. The result of hydrogen bonding showed a large number of intermolecular hydrogen bonds formed between protein residues (Glu166 and Gln189) and ligand 5, indicating strong interaction, which validated the docking result. Further, compactness analysis, SASA and interactions like hydrogen-bonding demonstrated inhibitory properties of compound 5 similar to the existing reference drug. Thus, the designed compound 5 might act as a potential inhibitor against the protease enzyme. Communicated by Ramaswamy H. Sarma Highlights Quinoline derivatives have been designed as protease inhibitors against SARS-CoV-2. The compounds were docked at the allosteric site of SARS-CoV-2-Mpro enzyme (PDB ID: 6LU7) to study the stability of protein-ligand complex. Docking studies indicated the stable ligand-protein complexes for all designed compounds. The Toxicity Prediction by Komputer Assisted Technology protocol in DS v20.1.0.19295 software was used to evaluate the toxicity of the designed quinoline derivatives. Molecular dynamics studies indicated the formation of stable ligand-Mpro complexes.

Eco-Friendly Synthesis, Biological Evaluation, and In Silico Molecular Docking Approach of Some New Quinoline Derivatives as Potential Antioxidant and Antibacterial Agents.

A new series of quinoline derivatives 5–12 were efficiently synthesized via one-pot multicomponent reaction (MCR) of resorcinol, aromatic aldehydes, β-ketoesters, and aliphatic/aromatic amines under solvent-free conditions. All products were obtained in excellent yields, pure at low-cost processing, and short time. The structures of all compounds were characterized by means of spectral and elemental analyses. In addition, all the synthesized compounds 5–12 were in vitro screened for their antioxidant and antibacterial activity. Moreover, in silico molecular docking studies of the new quinoline derivatives with the target enzymes, human NAD (P)H dehydrogenase (quinone 1) and DNA gyrase, were achieved to endorse their binding affinities and to understand ligand–enzyme possible intermolecular interactions. Compound 9 displayed promising antioxidant and antibacterial activity, as well as it was found to have the highest negative binding energy of -9.1 and -9.3 kcal/mol for human NAD (P)H dehydrogenase (quinone 1) and DNA gyrase, respectively. Further, it complied with the Lipinski’s rule of five, Veber, and Ghose. Therefore, the quinoline analogue 9 could be promising chemical scaffold for the development of future drug candidates as antioxidant and antibacterial agents.

Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect

A new series of quinoline derivatives of combretastatin A-4 have been designed, synthesised and demonstrated as tubulin polymerisation inhibitors. These novel compounds showed significant antiproliferative activities, among them, 12c exhibited the most potent inhibitory activity against different cancer cell lines (MCF-7, HL-60, HCT-116 and HeLa) with IC50 ranging from 0.010 to 0.042 µM, and with selectivity profile against MCF-10A non-cancer cells. Further mechanistic studies suggest that 12c can inhibit tubulin polymerisation and cell migration, leading to G2/M phase arrest. Besides, 12c induces apoptosis via a mitochondrial-dependant apoptosis pathway and caused reactive oxygen stress generation in MCF-7 cells. These results provide guidance for further rational development of potent tubulin polymerisation inhibitors for the treatment of cancer. Highlights A novel series of quinoline derivatives of combretastatin A-4 have been designed and synthesised. Compound 12c showed significant antiproliferative activities against different cancer cell lines. Compound 12c effectively inhibited tubulin polymerisation and competed with [3H] colchicine in binding to tubulin. Compound 12c arrested the cell cycle at G2/M phase, effectively inducing apoptosis and inhibition of cell migration.

Design, Synthesis, and Cytotoxic Screening of New Quinoline Derivatives over MCF-7 Breast Cancer Cell Line

VEGFR-2 inhibition represents an attractive strategy for anticancer drug design. A new series of quinoline derivatives were synthesized and structurally confirmed with different spectroscopic techniques. VEGFR-2 inhibition assay showed that 2-(4-bromoquinolin-3-yloxy)-1-(4-chlorophenyl)ethanone (V) demonstrated potent VEGFR-2 inhibitory activities. In addition, the brominated quinoline (V) exhibit antitumor activity over MCF-7 cell line via cell cycle arrest at G1 phase and apoptosis inducing activity as revealed by cell cycle analysis and Annexin V/FITC staining assays. Moreover, brominated quinoline (V) was proved to upregulate expression of proteins that trigger apoptosis such as increased Bax, decreased Bcl-2 as well as increased Bax/Bcl-2 ratio.

A Novel and Different Approach for the Synthesis of Quinoline Derivatives Starting Directly from Nitroarenes and Their Evaluation as Anti-Cancer Agents

A series of new quinoline derivatives (6-phenyl-6H-chromeno, [4,3-b] quinoline) have been prepared by using 4-chloro-2-phenyl-2H-chromene-3-carbaldehyde and various substituted nitroarenes as starting materials in the presence of Tin (II) chloride dihydrate and ethanol. The conversion in this synthesis involves the following steps (i) reduction of nitroarenes to anilines, (ii) Coupling of the anilines, chromene aldehydes (iii) Cyclization of resulting species and (iv) dehydration of cyclic intermediates. Several new quinolones have been prepared. We screened eight compounds of this novel series (6a-r) in three different cancer cell lines (B16F10, MCF7 and A549). The screened compounds showed moderate anticancer activity on two of the studied cell lines with best IC50 values of compound 6i (6.10±1.23 µM) and 6m (8.21±2.31 µM) on MCF7 cells. The selected compounds 6i and 6m led to morphological changes after treatment on MCF7 cell line. Interestingly, detailed studies suggested that the compounds 6i and 6m induced apoptosis in MCF7 cells in an oxidative stress independent manner without causing necrosis. In addition, we found destabilization of mitochondrial membrane potential behind the observed anticancer activity. Our results clearly indicate the promising anticancer potential of this novel series. This method is operationally simple and works with a diverse range of substrates.

Design, synthesis and biological evaluation of new quinoline derivatives as potential antitumor agents

A series of new quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 11p, 11s, 11v, 11x and 11y exhibited potent antiproliferative activity with IC50 value of lower than 10 μM against seven human tumor cell lines, and N-(3-methoxyphenyl)-7- (3-phenylpropoxy)quinolin-4-amine 11x was found to be the most potent antiproliferative agent against HCT-116, RKO, A2780 and Hela cell lines with an IC50 value of 2.56, 3.67, 3.46 and 2.71 μM, respectively. The antitumor efficacy of the representative compound 11x in mice was also evaluated, and the results showed that compound 11x effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 11x could inhibit colorectal cancer growth through ATG5-depenent autophagy pathway. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.

Synthesis and Insecticidal Activity of New Quinoline Derivatives Containing Perfluoropropanyl Moiety

A series of new quinoline derivatives containing perfluoropropanyl moiety were designed and synthesized. Their structures were confirmed by 1H‐NMR, MS, and elemental analysis. The bioassay results showed that compound 4e exhibited good insecticidal activity against Plutella xylostella and Mythimna separata at 100 mg/L.

Synthesis of novel amodiaquine analogs and evaluation of their in vitro and in vivo antimalarial activities.

Due to the rapid increase of drug resistance in Plasmodium parasites, there is a pressing need of developing new antiplasmodial drugs. In this study, new amodiaquine (AQ) analogs were synthesized, followed by an evaluation of their antiplasmodial activity. A new series of quinoline derivatives containing N-alkyl (piperazin-1-yl)methyl benzamidine moiety was synthesized by reacting 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzonitrile with appropriate primary amines. The synthesized compounds were investigated for inhibitory activity by inhibition test of heme detoxification (ITHD). Their antiplasmodial activity was then evaluated using the classical 4-day suppressive test (Peter's test) against Plasmodium berghei-infected mice (ANKA strain). The results showed that the percentage of heme detoxification inhibition in the active compounds was 90%. The most promising analogs, N-butyl-4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzamidine (compound 1e), and 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl)]-N-(4-methylpentan-2-yl)benzamidine (compound 1f) displayed 97.65 and 99.18% suppressions at the doses of 75 and 50 mg/kg/day, respectively. Further, the mean survival time of the mice treated with these compounds was higher than that of the negative control group. The newly synthesized amodiaquine analogs presented sufficient antiplasmodial activity with excellent suppressions and high in vitro heme detoxification inhibition. Higher mean survival time of the mice treated with synthetic compounds further confirmed the in vivo antimalarial activity of these new AQ analogs. Therefore, these compounds have the potential to replace common drugs from 4-aminoquinoline class. However, further investigations such as pharmacokinetic evaluations, cytotoxicity, toxicity, and formulation seem to be necessary.

Design, synthesis, structure-activity relationships and mechanism of action of new quinoline derivatives as potential antitumor agents

A series of new quinoline derivatives was designed, synthesized and evaluated as potential antitumor agents. The results indicated that most compounds exhibited potent antiproliferative activity, and 7-(4-fluorobenzyloxy)N-(2-(dimethylamino)- ethyl)quinolin-4-amine 10g was found to be the most potent antiproliferative agent against human tumor cell lines with an IC50 value of less than 1.0 μM. Preliminary structure-activity relationships analysis suggested that (1) the large and bulky alkoxy substituent in position-7 might be a beneficial pharmacophoric group for antiproliferative activity; (2) the amino side chain substituents in position-4 facilitated the antiproliferative activity of this class of compounds; and (3) the length of the alkylamino side chain moiety affected the antiproliferative potency, with two CH2 units being the most favorable. Further investigation of the mechanism of action of this class of compounds demonstrated that the representative compound 10g triggered p53/Bax-dependent colorectal cancer cell apoptosis by activating p53 transcriptional activity. Moreover, the results showed that compound 10g effectively inhibited tumor growth in a colorectal cancer xenograft model in nude mice. Thus, these quinoline derivatives might serve as candidates for the development of new antitumor drugs.

Synthesis and Biological Activity of Some New 6‐perfluoropropanyl Quinoline Derivatives

A series of new quinoline derivatives containing perfluoropropanyl moiety were designed and synthesized. Their structures were confirmed by 1H NMR, MS, and elemental analysis. The bioassay results showed that some of them exhibited good control efficacy against Pyricularia oryae. Also, some of the title compounds exhibited good insecticidal activity against Aphis craccivora Koch, Plutella xylostella, Mythimna Separate, and Tetranychus cinnabarinus.

Design, synthesis and in vitro anticancer activity of novel quinoline and oxadiazole derivatives of ursolic acid

A series of new quinoline derivatives of ursolic acid were designed and synthesized in an attempt to develop potential anticancer agents. The structures of these compounds were identified by 1H NMR, 13C NMR, IR and ESI-MS spectra analysis. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (MDA-MB-231, Hela and SMMC-7721). From the results, compounds 3a–d displayed significant antitumor activity against three cancer cell lines. Especially, compound 3b was found to be the most potent derivative with IC50 values of 0.61±0.07, 0.36±0.05, 12.49±0.08μM against MDA-MB-231, HeLa and SMMC-7721 cells, respectively, stronger than positive control etoposide. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound 3b could significantly induce the apoptosis of MDA-MB-231 cells in a dose-dependent manner. The cell cycle analysis also indicated that compound 3b could cause cell cycle arrest of MDA-MB-231 cells at G0/G1 phase.

Design, synthesis of quinolinyl Schiff bases and azetidinones as enoyl ACP-reductase inhibitors

New series of quinoline derivatives were synthesized from 2-chloroquinoline-3-carbaldehydes. In the reaction sequence, substituted acetanilides were cyclized to give 2-chloroquinoline-3-carbaldehydes 2a–d, which were transformed to 6a–d, which were then cyclized to give azetidinones 9a–d. The key scaffolds viz., 2-methoxy derivatives 3a–d, obtained from 2a–d were converted to target Schiff bases 4a–d, 5a–d and azetidinones 7a–d, 8a–d in good yields. Structures of these compounds were established by FTIR, 1H NMR, 13C NMR and mass spectrometry. The compounds 4a–d to 9a–d were evaluated for in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Vibrio cholera and antitubercular activity against Mycobacterium tuberculosis H37Rv. The Schiff bases and azetidinone derivatives exhibited good antibacterial and antitubercular activities. Bacterial enoyl ACP-reductase catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antimicrobial agents. Molecular docking into active site of enoyl ACP-reductase was performed on 2H7M.PDB and 4JX8.PDB files to understand ligand–protein interactions. The compounds obtained from the present research can be used as scaffolds in fragment-based design of new potent drugs. Molecular modeling, synthesis, spectral, antimicrobial studies of quinolinyl Schiff bases and azetidinones using crystal structure of E. coli and M. tuberculosis enoyl ACP-reductase (4JX8/2H7M PDB) and compared with in vitro antimicrobial activity.

ChemInform Abstract: New Quinoline Derivatives: Synthesis and Investigation of Antibacterial and Antituberculosis Properties.

AbstractThe new quinoline derivatives, wherein active pharmacophores, viz.

New quinoline derivatives: Synthesis and investigation of antibacterial and antituberculosis properties

Four new series of quinoline derivatives were synthesized starting from 2-trifluoromethyl aniline through multi-step reactions. In the reaction sequence, substituted aniline was cyclized to 4-hydroxy quinoline 1, which was then transformed to 4-chloro-2,8-bis(trifluoromethyl)quinoline 2. The key scaffold 4-hydrazinyl-2,8-bis(trifluoromethyl)quinoline 3, obtained from the compound 2, was successfully converted to target quinoline derivatives, viz. hydrazones 4a– t, ureas 5a– e, thioureas 6a– c and pyrazoles 7a– d, in good yields. The newly synthesized title compounds were evaluated for their in vitro antibacterial activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae (recultured) and antituberculosis activity against Mycobacterium tuberculosis H 37Rv and MDR-TB. Preliminary results indicated that most of the hydrazone derivatives demonstrated very good antibacterial and antituberculosis activities while other derivatives showed moderate activity.

Antifungal properties of new series of quinoline derivatives

The series of quinoline derivatives were prepared. The synthetic approach, analytical, and spectroscopic data of all synthesized compounds are presented. All the prepared derivatives were analyzed using the reversed-phase high performance liquid chromatography (RP-HPLC) method for the lipophilicity measurement. In the present study, the correlation between RP-HPLC retention parameter log K (the logarithm of capacity factor K) and various calculated log P data is shown. The relationships between the lipophilicity and the chemical structure of the studied compounds are discussed as well. The prepared compounds were tested for their in vitro antifungal activity. 2-[(3-Hydroxyphenylimino)methyl]quinolin-8-ol ( 8), 2-[(4-hydroxyphenylimino)methyl]quinolin-8-ol ( 9) and 2-[(2,5-dichloro-4-nitrophenylamino)methoxymethyl]quinolin-8-ol ( 10) showed in vitro antifungal activity comparable to or higher than that of the standard fluconazole. Structure–activity relationships among the chemical structure, the physical properties, and the biological activities of the evaluated compounds are discussed in the article.

Synthesis, Structure−Activity Relationship, and Receptor Pharmacology of a New Series of Quinoline Derivatives Acting as Selective, Noncompetitive mGlu1 Antagonists

We describe the discovery and the structure-activity relationship of a new series of quinoline derivatives acting as selective and highly potent noncompetitive mGlu1 antagonists. We first identified cis-10 as a fairly potent mGlu1 antagonist (IC(50) = 20 nM) in a cell-based signal transduction assay on the rat mGlu1 receptor expressed in CHO-K1 cells, and then we were able to design and synthesize highly potent compounds on both rat and human mGlu1 receptors as exemplified by compound cis-64a, which has an antagonist potency of 0.5 nM for the human mGlu1 receptor. We briefly present and discuss the in vitro metabolic stability of the compounds in human liver microsomes. We finally report the pharmacokinetic properties of our lead compound cis-64a.